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1. Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum

Author

Thibaud Reyser, Lucie Paloque, Jean-Michel Augereau, Luisa Di Stefano, and Françoise Benoit-Vical

Subjects
Plasmodium, Epigenetics, Histone modifications, Epidrugs, Antiplasmodial drugs, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Over the past thirty years, epigenetic regulation of gene expression has gained increasing interest as it was shown to be implicated in illnesses ranging from cancers to parasitic diseases. In the malaria parasite, epigenetics was shown to be involved in several key steps of the complex life cycle of Plasmodium, among which asexual development and sexual commitment, but also in major biological processes like immune evasion, response to environmental changes or DNA repair. Because epigenetics plays such paramount roles in the Plasmodium parasite, enzymes involved in these regulating pathways represent a reservoir of potential therapeutic targets. This review focuses on epigenetic regulatory processes and their effectors in the malaria parasite, as well as the inhibitors of epigenetic pathways and their potential as new anti-malarial drugs. Such types of drugs could be formidable tools that may contribute to malaria eradication in a context of widespread resistance to conventional anti-malarials.

Published
2024
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2. Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: 'Digging Their Graves with Their Forks'

Author

Ange W. Embo-Ibouanga, Michel Nguyen, Jean-Patrick Joly, Mathilde Coustets, Jean-Michel Augereau, Lucie Paloque, Nicolas Vanthuyne, Raphaël Bikanga, Anne Robert, Françoise Benoit-Vical, Gérard Audran, Philippe Mellet, Jérôme Boissier, and Sylvain R. A. Marque

Subjects
schistosoma, alkoxyamines, prodrug, new concept, Medicine
Abstract

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm’s digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals—which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.

Published
2024
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3. Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs

Author

Ange W. Embo-Ibouanga, Michel Nguyen, Lucie Paloque, Mathilde Coustets, Jean-Patrick Joly, Jean-Michel Augereau, Nicolas Vanthuyne, Raphaël Bikanga, Naomie Coquin, Anne Robert, Gérard Audran, Jérôme Boissier, Philippe Mellet, Françoise Benoit-Vical, and Sylvain R. A. Marque

Subjects
alkoxyamine, drug resistance, prodrug, malaria, Plasmodium, Organic chemistry, QD241-441
Abstract

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.

Published
2024
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4. Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites

Author

Thibaud Reyser, Lucie Paloque, Michel Nguyen, Jean-Michel Augereau, Matthew John Fuchter, Marie Lopez, Paola B. Arimondo, Storm Hassell-Hart, John Spencer, Luisa Di Stefano, and Françoise Benoit-Vical

Subjects
malaria, epigenetics, artemisinin resistance, quiescent parasites, epidrugs, Pharmacy and materia medica, RS1-441
Abstract

The use of artemisinin and its derivatives has helped reduce the burden of malaria caused by Plasmodium falciparum. However, artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies. Drugs targeting epigenetic mechanisms (namely epidrugs) are emerging as potential antimalarial drugs. Here, we set out to evaluate a selection of various epidrugs for their activity against quiescent parasites, to explore the possibility of using these compounds to counter artemisinin resistance. The 32 chosen epidrugs were first screened for their antiplasmodial activity and selectivity. We then demonstrated, thanks to the specific Quiescent-stage Survival Assay, that four epidrugs targeting both histone methylation or deacetylation as well as DNA methylation decrease the ability of artemisinin-resistant parasites to recover after artemisinin exposure. In the quest for novel antiplasmodial drugs with new modes of action, these results reinforce the therapeutic potential of epidrugs as antiplasmodial drugs especially in the context of artemisinin resistance.

Published
2023
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5. A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

Author

Henriette Bosson-Vanga, Nicolas Primas, Jean-François Franetich, Catherine Lavazec, Lina Gomez, Kutub Ashraf, Maurel Tefit, Valérie Soulard, Nathalie Dereuddre-Bosquet, Roger Le Grand, Mélanie Donnette, Romain Mustière, Nadia Amanzougaghene, Shahin Tajeri, Peggy Suzanne, Aurélie Malzert-Fréon, Sylvain Rault, Patrice Vanelle, Sébastien Hutter, Anita Cohen, Georges Snounou, Pierre Roques, Nadine Azas, Prisca Lagardère, Vincent Lisowski, Nicolas Masurier, Michel Nguyen, Lucie Paloque, Françoise Benoit-Vical, Pierre Verhaeghe, and Dominique Mazier

Subjects
antimalarials, 2-amino-6-phenyl-thienopyrimidin-4(3H)-one, multistage activity, artemisinin resistance, Microbiology, QR1-502
Abstract

ABSTRACT Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease via the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity. One molecule, named gamhepathiopine (denoted as “M1” herein), was active at submicromolar concentrations against both erythrocytic (50% effective concentration [EC50] = 0.045 μM) and liver (EC50 = 0.45 μM) forms of Plasmodium falciparum. Furthermore, gamhepathiopine efficiently blocked the development of the sporogonic cycle in the mosquito vector by inhibiting the exflagellation step. Moreover, M1 was active against artemisinin-resistant forms (EC50 = 0.227 μM), especially at the quiescent stage. Nevertheless, in mice, M1 showed modest activity due to its rapid metabolization by P450 cytochromes into inactive derivatives, calling for the development of new parent compounds with improved metabolic stability and longer half-lives. These results highlight the thienopyrimidinone scaffold as a novel antiplasmodial chemotype of great interest to search for new drug candidates displaying multistage activity and an original mechanism of action with the potential to be used in combination therapies for malaria elimination in the context of artemisinin resistance. IMPORTANCE This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.

Published
2021
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6. In Vitro and In Silico Antimalarial Evaluation of FM-AZ, a New Artemisinin Derivative

Author

Ioannis Tsamesidis, Farnoush Mousavizadeh, Chinedu O. Egwu, Dionysia Amanatidou, Antonella Pantaleo, Françoise Benoit-Vical, Karine Reybier, and Athanassios Giannis

Subjects
novel artemisinin derivatives, in silico study, artemisinin resistance, ROS, LC-MS, Medicine
Abstract

Artemisinin-based Combination Therapies (ACTs) are currently the frontline treatment against Plasmodium falciparum malaria, but parasite resistance to artemisinin (ART) and its derivatives, core components of ACTs, is spreading in the Mekong countries. In this study, we report the synthesis of several novel artemisinin derivatives and evaluate their in vitro and in silico capacity to counteract Plasmodium falciparum artemisinin resistance. Furthermore, recognizing that the malaria parasite devotes considerable resources to minimizing the oxidative stress that it creates during its rapid consumption of hemoglobin and the release of heme, we sought to explore whether further augmentation of this oxidative toxicity might constitute an important addition to artemisinins. The present report demonstrates, in vitro, that FM-AZ, a newly synthesized artemisinin derivative, has a lower IC50 than artemisinin in P. falciparum and a rapid action in killing the parasites. The docking studies for important parasite protein targets, PfATP6 and PfHDP, complemented the in vitro results, explaining the superior IC50 values of FM-AZ in comparison with ART obtained for the ART-resistant strain. However, cross-resistance between FM-AZ and artemisinins was evidenced in vitro.

Published
2022
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7. Reactive Oxygen Species as the Brainbox in Malaria Treatment

Author

Chinedu Ogbonnia Egwu, Jean-Michel Augereau, Karine Reybier, and Françoise Benoit-Vical

Subjects
ROS, antimalarials, Plasmodium falciparum, malaria and oxidative stress, Therapeutics. Pharmacology, RM1-950
Abstract

Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control.

Published
2021
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8. 2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

Author

Dyhia Amrane, Christophe-Sébastien Arnold, Sébastien Hutter, Julen Sanz-Serrano, Miguel Collia, Amaya Azqueta, Lucie Paloque, Anita Cohen, Nadia Amanzougaghene, Shahin Tajeri, Jean-François Franetich, Dominique Mazier, Françoise Benoit-Vical, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle, Cyrille Botté, and Nicolas Primas

Subjects
quinoxaline, trichloromethyl goup, Plasmodium falciparum, structure-activity relationships, apicoplast, Medicine, Pharmacy and materia medica, RS1-441
Abstract

The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.

Published
2021
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9. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Author

Thibaud Reyser, Tung H. To, Chinedu Egwu, Lucie Paloque, Michel Nguyen, Alexandre Hamouy, Jean-Luc Stigliani, Christian Bijani, Jean-Michel Augereau, Jean-Patrick Joly, Julien Portela, Jeffrey Havot, Sylvain R. A. Marque, Jérôme Boissier, Anne Robert, Françoise Benoit-Vical, and Gérard Audran

Subjects
alkoxyamine, alkylation, heme, malaria, radical chemistry, schistosomiasis, Organic chemistry, QD241-441
Abstract

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

Published
2020
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10. Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

Author

Manel Ouji, Guillaume Barnoin, Álvaro Fernández Álvarez, Jean-Michel Augereau, Catherine Hemmert, Françoise Benoit-Vical, and Heinz Gornitzka

Subjects
malaria, Plasmodium falciparum, gold, NHC-ligands, hybrid molecules, drug resistance, Organic chemistry, QD241-441
Abstract

The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.

Published
2020
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11. An LC–MS Assay to Measure Superoxide Radicals and Hydrogen Peroxide in the Blood System

Author

Ioannis Tsamesidis, Chinedu O. Egwu, Pierre Pério, Jean-Michel Augereau, Françoise Benoit-Vical, and Karine Reybier

Subjects
liquid-chromatography, mass spectrometry, superoxide radicals, hydrogen peroxide species, red blood cells, human plasma, Microbiology, QR1-502
Abstract

Red blood cells are constantly exposed to reactive species under physiological or pathological conditions or during administration of xenobiotics. Regardless of the source, its accurate quantification is paramount in the area of theragnostics, which had been elusive up until now. Even if there are a lot of approaches to evaluate the oxidative stress, very sensitive methods are missing for the blood system. We therefore sought to apply a highly sensitive approach, by liquid chromatography coupled to mass spectrometry (UPLC–MS), for the quantification of reactive species such as superoxide radical and hydrogen peroxide using dihydroethidium (DHE) and coumarin boronic acid (CBA) probes respectively through the detection of 2-hydroxyethidium (2OH-E+) and 7-hydroxycoumarin (COH). The use of the high-resolution mass spectrometry associated to UPLC ensured a selective detection of superoxide and hydrogen peroxide in the blood system under diverse conditions such as oxidized red blood cells (RBCs), untreated and treated parasitized RBCs. Moreover, this technique allowed the determination of reactive species in human plasma. This protocol provides a huge opportunity for in-depth study of several pathological conditions vis-a-vis their treatment in modern medicine.

Published
2020
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12. Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure

Author

Sandie Ménard, Tanila Ben Haddou, Arba Pramundita Ramadani, Frédéric Ariey, Xavier Iriart, Johann Beghain, Christiane Bouchier, Benoit Witkowski, Antoine Berry, Odile Mercereau-Puijalon, and Françoise Benoit-Vical

Subjects
artemisinin, Plasmodium falciparum, parasites, multidrug tolerance, drug pressure, atovaquone, Medicine, Infectious and parasitic diseases, RC109-216
Abstract

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.

Published
2015
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13. Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo.

Author

Dieudonné Makaba Mvumbi, Thierry Lengu Bobanga, Jean-Marie Ntumba Kayembe, Georges Lelo Mvumbi, Hippolyte Nani-Tuma Situakibanza, Françoise Benoit-Vical, Pierrette Melin, Patrick De Mol, and Marie-Pierre Hayette

Subjects
Medicine, Science
Abstract

Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance.

Published
2017
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14. Young Sprague Dawley rats infected by Plasmodium berghei: A relevant experimental model to study cerebral malaria.

Author

Sokhna Keita Alassane, Marie-Laure Nicolau-Travers, Sandie Menard, Olivier Andreoletti, Jean-Pierre Cambus, Noémie Gaudre, Myriam Wlodarczyk, Nicolas Blanchard, Antoine Berry, Sarah Abbes, David Colongo, Babacar Faye, Jean-Michel Augereau, Caroline Lacroux, Xavier Iriart, and Françoise Benoit-Vical

Subjects
Medicine, Science
Abstract

Cerebral malaria (CM) is the most severe manifestation of human malaria yet is still poorly understood. Mouse models have been developed to address the subject. However, their relevance to mimic human pathogenesis is largely debated. Here we study an alternative cerebral malaria model with an experimental Plasmodium berghei Keyberg 173 (K173) infection in Sprague Dawley rats. As in Human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting Experimental Cerebral Malaria (ECM) symptoms while the majority (55%) of the remaining rats developed severe anemia and hyperparasitemia (NoECM). These results allow, within the same population, a comparison of the noxious effects of the infection between ECM and severe malaria without ECM. Among the ECM rats, 77.8% died between day 5 and day 12 post-infection, while the remaining rats were spontaneously cured of neurological signs within 24-48 hours. The clinical ECM signs observed were paresis quickly evolving to limb paralysis, global paralysis associated with respiratory distress, and coma. The red blood cell (RBC) count remained normal but a drastic decrease of platelet count and an increase of white blood cell numbers were noted. ECM rats also showed a decrease of glucose and total CO2 levels and an increase of creatinine levels compared to control rats or rats with no ECM. Assessment of the blood-brain barrier revealed loss of integrity, and interestingly histopathological analysis highlighted cyto-adherence and sequestration of infected RBCs in brain vessels from ECM rats only. Overall, this ECM rat model showed numerous clinical and histopathological features similar to Human CM and appears to be a promising model to achieve further understanding the CM pathophysiology in Humans and to evaluate the activity of specific antimalarial drugs in avoiding/limiting cerebral damages from malaria.

Published
2017
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15. Antiprotozoal Activities of Millettia richardiana (Fabaceae) from Madagascar

Author

Manitriniaina Rajemiarimiraho, Jean-Théophile Banzouzi, Marie-Laure Nicolau-Travers, Suzanne Ramos, Zakaria Cheikh-Ali, Christian Bories, Olga L. Rakotonandrasana, Stéphane Rakotonandrasana, Philippe Antoine Andrianary, and Françoise Benoit-Vical

Subjects
Millettia richardiana, traditional medicine, Madagascar, Plasmodium, Trypanosoma, Leishmania, Candida, Organic chemistry, QD241-441
Abstract

With at least 60% of the Millettia species (Fabaceae) being in medicinal use, we found it relevant to assess the potential antiprotozoal and antifungal activities of Millettia richardiana. Water and methanol crude extracts of the stem barks from M. richardiana and the six fractions resulting from the fractionation of the methanol extract were tested. The dichloromethane extracted fraction showed the best in vitro antiprotozoal activities (IC50 = 5.8 μg/mL against Plasmodium falciparum, 11.8 μg/mL against Leishmania donovani and 12.8 μg/mL against Trypanosoma brucei brucei) as well as low cytotoxicity on several cell lines. The phytochemical analysis showed this selected fraction to be rich in terpenoids and alkaloids, which could explain its antiparasitic activity. A phytochemical study revealed the presence of lonchocarpenin, betulinic acid, β-amyrin, lupeol, palmitic acid, linoleic acid and stearic acid, among which betulinic acid and lupeol could be the compounds responsible of these antiprotozoal activities. By contrast, neither the crude extracts nor the fractions showed antifungal activity against Candida. These results confirm the importance of the genus Millettia in Malagasy ethnomedicine, its potential use in antiparasitic therapy, and the interest of developing a sustainable exploitation of this plant. Moreover, both molecules betulinic acid and lupeol appeared as very relevant molecules for their antiprotozoal properties.

Published
2014
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16. Evidence for the contribution of the hemozoin synthesis pathway of the murine Plasmodium yoelii to the resistance to artemisinin-related drugs.

Author

Benoit Witkowski, Joel Lelièvre, Marie-Laure Nicolau-Travers, Xavier Iriart, Patrice Njomnang Soh, Fatima Bousejra-Elgarah, Bernard Meunier, Antoine Berry, and Françoise Benoit-Vical

Subjects
Medicine, Science
Abstract

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia.

Published
2012
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17. Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid.

Author

Patrice Njomnang Soh, Benoit Witkowski, Amandine Gales, Eric Huyghe, Antoine Berry, Bernard Pipy, and Françoise Benoit-Vical

Subjects
Medicine, Science
Abstract

The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to current drugs. Ellagic acid (EA) is a polyphenol, recently found in various plant products, that has effective antimalarial activity in vitro and in vivo without toxicity. To further understand the antimalarial mechanism of action of EA in vitro, we evaluated the effects of EA, ascorbic acid and N-acetyl-L-cysteine (NAC), alone and/or in combination on the production of reactive oxygen species (ROS) during the trophozoite and schizonte stages of the erythrocytic cycle of P. falciparum. The parasitized erythrocytes were pre-labelled with DCFDA (dichlorofluorescein diacetate). We showed that NAC had no effect on ROS production, contrary to ascorbic acid and EA, which considerably reduced ROS production. Surprisingly, EA reduced the production of the ROS with concentrations (6.6×10(-9) - 6.6×10(-6) M) ten-fold lower than ascorbic acid (113×10(-6) M). Additionally, the in vitro drug sensitivity of EA with antioxidants showed that antiplasmodial activity is independent of the ROS production inside parasites, which was confirmed by the additive activity of EA and desferrioxamine. Finally, EA could act by reducing the glutathione content inside the Plasmodium parasite. This was consolidated by the decrease in the antiplasmodial efficacy of EA in the murine model Plasmodium yoelii- high GSH strain, known for its high glutathione content. Given its low toxicity and now known mechanism of action, EA appears as a promising antiplasmodial compound.

Published
2012
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18. Nrf2, a PPARγ alternative pathway to promote CD36 expression on inflammatory macrophages: implication for malaria.

Author

David Olagnier, Rose-Anne Lavergne, Etienne Meunier, Lise Lefèvre, Christophe Dardenne, Agnès Aubouy, Françoise Benoit-Vical, Bernhard Ryffel, Agnès Coste, Antoine Berry, and Bernard Pipy

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

CD36 is the major receptor mediating nonopsonic phagocytosis of Plasmodium falciparum-parasitized erythrocytes by macrophages. Its expression on macrophages is mainly controlled by the nuclear receptor PPARγ. Here, we demonstrate that inflammatory processes negatively regulate CD36 expression on human and murine macrophages, and hence decrease Plasmodium clearance directly favoring the worsening of malaria infection. This CD36 downregulation in inflammatory conditions is associated with a failure in the expression and activation of PPARγ. Interestingly, using siRNA mediating knock down of Nrf2 in macrophages or Nrf2- and PPARγ-deficient macrophages, we establish that in inflammatory conditions, the Nrf2 transcription factor controls CD36 expression independently of PPARγ. In these conditions, Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and CD36-mediated Plasmodium phagocytosis. These results were confirmed in human macrophages and in vivo where only Nrf2 activators improve the outcome of severe malaria. Collectively, this report highlights that the Nrf2 transcription factor could be an alternative target to PPARγ in the control of severe malaria through parasite clearance.

Published
2011
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19. Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

Author

Christina L. Koumpoura, Michel Nguyen, Christian Bijani, Laure Vendier, Elena G. Salina, Silvia Buroni, Giulia Degiacomi, Sandrine Cojean, Philippe M. Loiseau, Françoise Benoit-Vical, Alfonso T. García-Sosa, null Anne Robert, Michel Baltas, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Russian Academy of Sciences [Moscow] (RAS), Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani' = Department of Biology and Biotechnology [Univ di Pavia] (DBB UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), University of Tartu, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour la Recherche Médicale (FRM), Paris Saclay University, Estonian Research Council, Italian Ministry of Education, University and Research (MIUR), University of Pavia, Gulli, Marie-Hélène, Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse]

Subjects
Aldehydes, Inorganic carbon compounds, General Chemical Engineering, Multicomponent reactions, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Reaction products, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Chemistry, Carbon
Abstract

International audience; The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC50 = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC50 = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions.

Published
2022

20. Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

Author

Youzhi Li, Anthony Loureiro, Michel Nguyen, Marion Laurent, Christian Bijani, Françoise Benoit‐Vical, Anne Robert, Yan Liu, Bernard Meunier, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), NSFC (grants 21977019 and 21502023), Guangdong Province (Program for Innovative Research Teams and Leading Talents Introduction, grant 2050205), Open Project of Guangdong Provincial Key Laboratory of New Drug Screening (No. GDKLNDS-2018OF004), University of Technology of the Guangdong (GDUT) (grant 220418037) of the P. R. China, CNRS, Fondation pour la Recherche Médicale, France (grant FRM Equipe EQU202103012596), ANR-17-CE18-0017,RADICAL,Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires(2017), Gulli, Marie-Hélène, Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires - - RADICAL2017 - ANR-17-CE18-0017 - AAPG2017 - VALID, Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Plasmodium, Plasmodium falciparum, Quinoline, General Chemistry, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Artemisinins, Malaria, Antimalarials, Oxidative stress, parasitic diseases, Folic Acid Antagonists, Quinone, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Metal chelator, Atovaquone
Abstract

International audience; The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50=622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.

Published
2022

21. Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance

Author

Nina F. Gnädig, Françoise Benoit-Vical, Romain Coppée, Jérôme Clain, David A. Fidock, Karamoko Niaré, Jean-Michel Augereau, Barbara H. Stokes, Lucie Paloque, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Columbia University Irving Medical Center (CUIMC), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS), NIH (R01 AI109023), WorldWide Antimalarial Resistance Network (WWARN), ANR-17-CE15-0013,PlasmoPrim,Elucider les mécanismes d'action de deux agents redox antipaludiques aux propriétés gametocytocides et bloquant la transmission -- de la levure aux parasites du paludisme(2017), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Gulli, Marie-Hélène, and Elucider les mécanismes d'action de deux agents redox antipaludiques aux propriétés gametocytocides et bloquant la transmission -- de la levure aux parasites du paludisme - - PlasmoPrim2017 - ANR-17-CE15-0013 - AAPG2017 - VALID

Subjects
medicine.medical_treatment, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Dihydroartemisinin, medicine.disease_cause, Epidemiology and Surveillance, Antimalarials, parasitic diseases, medicine, Coding region, CRISPR, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Pharmacology (medical), Artemisinin, BTB/POZ domain, Gene, Pharmacology, Mutation, biology, K13 mutation, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Editor's Pick, biology.organism_classification, Virology, Artemisinins, Malaria, Infectious Diseases, Artemisinin resistance, BTB-POZ Domain, medicine.drug
Abstract

International audience; Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 (pfk13) gene. Here, we carried out in vitro selection over a 1-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA0-3h = 9.2%). Sanger and whole-genome sequence analyses identified the PfK13 P413A mutation, localized in the BTB/POZ domain, upstream of the propeller domain. This mutation was sufficient to confer in vitro artemisinin resistance when introduced into the PfK13 coding sequence of the parasite strain Dd2 by CRISPR/Cas9 gene editing. These results together with structural studies of the protein demonstrate that the propeller domain is not the sole in vitro mediator of PfK13-mediated artemisinin resistance, and highlight the importance of monitoring for mutations throughout PfK13.

Published
2022

22. Reactive Oxygen Species as the Brainbox in Malaria Treatment

Author

Françoise Benoit-Vical, Jean-Michel Augereau, Karine Reybier, Chinedu O. Egwu, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Alex Ekwueme Federal University Ndufu-Alike, Ikwo (AE-FUNAI), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), CNRS (Centre National de la Recherche Scientifique, France), Université Paul Sabatier, Toulouse III (France), IRD (Institut de Recherche pour le Développement, France), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Pagès, Nathalie

Subjects
malaria and oxidative stress, Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Plasmodium falciparum, RM1-950, Review, medicine.disease_cause, Biochemistry, antimalarials, parasitic diseases, medicine, Artemisinin, Molecular Biology, chemistry.chemical_classification, Reactive oxygen species, biology, ROS, Cell Biology, biology.organism_classification, medicine.disease, [SDV] Life Sciences [q-bio], chemistry, Immunology, Therapeutics. Pharmacology, Malaria control, Malaria, Oxidative stress, medicine.drug
Abstract

International audience; Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control.

Published
2021

23. Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon

Author

Chinedu O, Egwu, Pierre, Pério, Jean-Michel, Augereau, Ioannis, Tsamesidis, Françoise, Benoit-Vical, and Karine, Reybier

Subjects
Antimalarials, Plasmodium falciparum, Drug Resistance, Animals, Parasites, Malaria, Falciparum, Oxidation-Reduction, Artemisinins, Malaria
Abstract

Malaria remains a major public health disease due to its high yearly mortality and morbidity. Resistance to the gold standard drug, artemisinin, is worrisome and needs better understanding in order to be overcome. In this work, we sought to study whether redox processes are involved in artemisinin resistance. As artemisinin is known to act among others via production of reactive species, we first compared the production of reactive oxygen species and concomitant protein oxidation in artemisinin-sensitive and artemisinin-resistant parasites when treated with artemisinin. The results undoubtedly demonstrated, using different original methods, that the level of ROS, including superoxide production, and oxidized protein were lower in the resistant strain. Interestingly, the major in-between strain difference was reported at the earlier ring stages, which are the forms able to enter in a quiescence state according to the ART resistance phenomenon. Moreover, we demonstrated a better homeostasis regulation in relation with higher expression of antioxidants in the artemisinin-resistant parasites than their sensitive counterparts after artemisinin exposure, notably, superoxide dismutase and the glutathione (GSH) system. These findings enrich the body of knowledges about the multifaceted mechanism of artemisinin resistance and will help in the design and development of newer antimalarials strategies active against resistant parasites.

Published
2021

24. Superoxide: A major role in the mechanism of action of essential antimalarial drugs

Author

Karine Reybier, Pierre Perio, Chinedu O. Egwu, Ioannis Tsamesidis, Jean-Michel Augereau, Françoise Benoit-Vical, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Alex Ekwueme Federal University Ndufu-Alike, Ikwo (AE-FUNAI), Laboratoire de chimie de coordination (LCC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016)

Subjects
0301 basic medicine, Artemisinins, medicine.medical_treatment, Plasmodium falciparum, Drug Resistance, Dihydroartemisinin, Pharmacology, Mechanism of action, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Antimalarials, 0302 clinical medicine, Superoxides, Chloroquine, Physiology (medical), parasitic diseases, medicine, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, biology, Superoxide radicals, Superoxide, biology.organism_classification, 3. Good health, LC-MS, 030104 developmental biology, chemistry, medicine.symptom, Drugs, Essential, 030217 neurology & neurosurgery, Atovaquone, medicine.drug
Abstract

International audience; Understanding the mode of action of antimalarials is central to optimizing their use and the discovery of new therapeutics. Currently used antimalarials belong to a limited series of chemical structures and their mechanisms of action are coutinuously debated. Whereas the involvement of reactive species that in turn kill the parasites sensitive to oxidative stress, is accepted for artemisinins, little is known about the generation of such species in the case of quinolines or hydroxynaphtoquinone. Moreover, the nature of the reactive species involved has never been characterized in Plasmodium-infected erythrocytes. The aim of this work was to determine and elucidate the production of the primary radical, superoxide in Plasmodium-infected erythrocytes treated with artemisinin, dihydroartemisinin, chloroquine and atovaquone, as representatives of three major classes of antimalarials. The intracellular generation of superoxide was quantified by liquid chromatography coupled to mass spectrometry (LC-MS). We demonstrated that artemisinins, atovaquone and to a lesser extent chloroquine, generate significant levels of superoxide radicals in Plasmodium falciparum sensitive strains. More so, the production of superoxide was lowered in chloroquine-resistant strain of Plasmodium treated with chloroquine. These results consolidate the knowledge about the mechanism of action of these different antimalarials and should be taken into consideration in the design of future drugs to fight drug-resistant parasites.

Published
2021

25. A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

Author

Sylvain Rault, Maurel Tefit, Vincent Lisowski, Patrice Vanelle, Nicolas Primas, Jean-François Franetich, Dominique Mazier, Lucie Paloque, Pierre Roques, Sébastien Hutter, Georges Snounou, Françoise Benoit-Vical, Michel Nguyen, Prisca Lagardère, Valérie Soulard, Nathalie Dereuddre-Bosquet, Pierre Verhaeghe, Anita Cohen, Nicolas Masurier, Roger Le Grand, Nadia Amanzougaghene, Nadine Azas, Mélanie Donnette, Kutub Ashraf, Catherine Lavazec, Aurélie Malzert-Fréon, Lina Gomez, Henriette Bosson-Vanga, Shahin Tajeri, Romain Mustière, Peggy Suzanne, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Félix Houphouët-Boigny (UFHB), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Casselardit - Junod, Fondation pour la Recherche Médicale (FRM Palukill DMC20181039565), Centre National de la Recherche Scientifique (CNRS), ANR-18-CE18-0009,plasmodrug,Développement d'un nouvel antipaludique ciblant plusieurs étapes du cycle de Plasmodium(2018), ANR-17-CE13-0025,IMHyp,Recherches sur l'Hypnozoïte du Paludisme(2017), ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Gulli, Marie-Hélène, APPEL À PROJETS GÉNÉRIQUE 2018 - Développement d'un nouvel antipaludique ciblant plusieurs étapes du cycle de Plasmodium - - plasmodrug2018 - ANR-18-CE18-0009 - AAPG2018 - VALID, Recherches sur l'Hypnozoïte du Paludisme - - IMHyp2017 - ANR-17-CE13-0025 - AAPG2017 - VALID, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Physiology, Drug Resistance, Drug resistance, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Plasmodium, Madin Darby Canine Kidney Cells, Mice, Multistage activity, Artemisinin, Malaria, Falciparum, 0303 health sciences, Mice, Inbred BALB C, Ecology, biology, Hep G2 Cells, 2-amino-6-phenyl-thienopyrimidin-4(3H)-one, Artemisinins, QR1-502, 3. Good health, Infectious Diseases, Liver, Artemisinin resistance, Female, medicine.symptom, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug, Plasmodium cynomolgi, Research Article, Microbiology (medical), [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, Context (language use), Pyrimidinones, Microbiology, 03 medical and health sciences, Antimalarials, Dogs, Cell Line, Tumor, parasitic diseases, Genetics, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030304 developmental biology, General Immunology and Microbiology, 030306 microbiology, Cell Biology, Plasmodium yoelii, medicine.disease, biology.organism_classification, Virology, Disease Models, Animal, Macaca fascicularis, Mechanism of action, Vector (epidemiology), Malaria
Abstract

International audience; Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease via the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity. One molecule, named gamhepathiopine (denoted as “M1” herein), was active at submicromolar concentrations against both erythrocytic (50% effective concentration [EC50] = 0.045 μM) and liver (EC50 = 0.45 μM) forms of Plasmodium falciparum. Furthermore, gamhepathiopine efficiently blocked the development of the sporogonic cycle in the mosquito vector by inhibiting the exflagellation step. Moreover, M1 was active against artemisinin-resistant forms (EC50 = 0.227 μM), especially at the quiescent stage. Nevertheless, in mice, M1 showed modest activity due to its rapid metabolization by P450 cytochromes into inactive derivatives, calling for the development of new parent compounds with improved metabolic stability and longer half-lives. These results highlight the thienopyrimidinone scaffold as a novel antiplasmodial chemotype of great interest to search for new drug candidates displaying multistage activity and an original mechanism of action with the potential to be used in combination therapies for malaria elimination in the context of artemisinin resistance.IMPORTANCE This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.

Published
2021

26. Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

Author

Manel Ouji, Tony Jimenez, Michel Nguyen, Céline Deraeve, Romain Mustière, Jean-Michel Augereau, Françoise Benoit-Vical, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique, Sanofi-Institut Pasteur award, ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016), Gulli, Marie-Hélène, Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium - - INMAR2016 - ANR-16-CE35-0003 - AAPG2016 - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Clinical Biochemistry, Drug Resistance, Pharmaceutical Science, Quiescence, 01 natural sciences, Biochemistry, Antimalarial drug, Parasitic Sensitivity Tests, Drug Discovery, Artemisinin, Malaria, Falciparum, Drug combination, media_common, biology, Molecular Structure, Chemistry, Mefloquine, Artemisinins, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Artemisinin resistance, Molecular Medicine, Pharmacophore, Atovaquone, medicine.drug, Drug, media_common.quotation_subject, Plasmodium falciparum, Context (language use), Antimalarials, Structure-Activity Relationship, parasitic diseases, medicine, Humans, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, Hybrid molecule, medicine.disease, biology.organism_classification, Triclosan, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Malaria
Abstract

International audience; Malaria is still considered as the major parasitic disease and the development of artemisinin resistance does not improve this alarming situation. Based on the recent identification of relevant malaria targets in the artemisinin resistance context, novel drug combinations were evaluated against artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites. Corresponding hybrid molecules were also synthesized and evaluated for comparison with combinations and individual pharmacophores (e.g. atovaquone, mefloquine or triclosan). Combinations and hybrids showed remarkable antimalarial activity (IC50 = 0.6 to 1.1 nM for the best compounds), strong selectivity, and didn’t present any cross-resistance with artemisinin. Moreover, the combination triclosan + atovaquone showed high activity against artemisinin-resistant parasites at the quiescent stage but the corresponding hybrid lost this pharmacological property. This result is essential since only few molecules active against quiescent artemisinin-resistant parasites are reported. Our promising results highlight the potential of these combinations and paves the way for pharmacomodulation work on the best hybrids.

Published
2020

27. Identification of compounds active against quiescent artemisinin-resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA)

Author

Sandie Menard, Manel Ouji, Michel Nguyen, Lucie Paloque, Thibaud Reyser, Françoise Benoit-Vical, Jean-Michel Augereau, Benoit Witkowski, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Malaria Molecular Epidemiology (MMEU), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS, ANR-13-BSV3-0018,MALARTRES,Résistance de Plasmodium aux antipaludiques de la famille des artémisinines(2013), ANR-14-CE35-0003,CAP-G4,Development of photo-reactive probes to capture G-quadruplex DNA in complex with endogenous proteins and exogenous synthetic ligands(2014), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Malaria Molecular Epidemiology, Gulli, Marie-Hélène, Blanc 2013 - Résistance de Plasmodium aux antipaludiques de la famille des artémisinines - - MALARTRES2013 - ANR-13-BSV3-0018 - Blanc 2013 - VALID, Appel à projets générique - Development of photo-reactive probes to capture G-quadruplex DNA in complex with endogenous proteins and exogenous synthetic ligands - - CAP-G42014 - ANR-14-CE35-0003 - Appel à projets générique - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Microbiology (medical), [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Context (language use), Drug resistance, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 03 medical and health sciences, Antimalarials, Chloroquine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, medicine, Animals, Pharmacology (medical), Parasites, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Artemisinin, Malaria, Falciparum, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Drug discovery, biology.organism_classification, Artemisinins, 3. Good health, Infectious Diseases, Drug development, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cambodia, Artemisinine, Atovaquone, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug
Abstract

Background Quiescence is an unconventional mechanism of Plasmodium survival, mediating artemisinin resistance. This phenomenon increases the risk of clinical failures following artemisinin-based combination therapies (ACTs) by slowing parasite clearance and allowing the selection of parasites resistant to partner drugs. Objectives To thwart this multiresistance, the quiescent state of artemisinin-resistant parasites must be taken into consideration from the very early stages of the drug discovery process. Methods We designed a novel phenotypic assay we have named the quiescent-stage survival assay (QSA) to assess the antiplasmodial activity of drugs on quiescent parasites. This assay was first validated on quiescent forms from different artemisinin-resistant parasite lines (laboratory strain and field isolates), using two reference drugs with different mechanisms of action: chloroquine and atovaquone. Furthermore, the efficacies of different partner drugs of artemisinins used in ACTs were investigated against both laboratory strains and field isolates from Cambodia. Results Our results highlight that because of the mechanism of quiescence and the respective pharmacological targets of drugs, drug efficacies on artemisinin-resistant parasites may be different between quiescent parasites and their proliferating forms. Conclusions These data confirm the high relevance of adding the chemosensitivity evaluation of quiescent parasites by the specific in vitro QSA to the antiplasmodial drug development process in the current worrisome context of artemisinin resistance.

Published
2020

28. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Author

Chinedu O. Egwu, Thibaud Reyser, Jean-Luc Stigliani, Gérard Audran, Tung H To, Christian Bijani, Sylvain R. A. Marque, Françoise Benoit-Vical, Alexandre Hamouy, Jeffrey Havot, Michel Nguyen, Jérôme Boissier, Anne Robert, Lucie Paloque, Jean-Michel Augereau, Jean-Patrick Joly, Julien Portela, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), S.A.S ParaDev, Interactions Hôtes-Pathogènes-Environnements (IHPE), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Perpignan Via Domitia (UPVD), Institut National de la Santé et de la Recherche Médicale (INSERM), Gulli, Marie-Hélène, Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires - - RADICAL2017 - ANR-17-CE18-0017 - AAPG2017 - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Perpignan Via Domitia (UPVD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Aix-Marseille Université, Université de Perpignan, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), ANR-17-CE18-0017,RADICAL,Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires(2017), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Alkylation, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, malaria, Pharmaceutical Science, Schistosomiasis, Drug resistance, Heme, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 010402 general chemistry, 01 natural sciences, Plasmodium, Article, Analytical Chemistry, lcsh:QD241-441, Antimalarials, lcsh:Organic chemistry, schistosomiasis, Drug Discovery, parasitic diseases, Ic50 values, medicine, Animals, Humans, radical chemistry, Physical and Theoretical Chemistry, heme, alkylation, Schistosoma, Biological evaluation, Anthelmintics, biology, 010405 organic chemistry, Organic Chemistry, Radical chemistry, Biological activity, Schistosoma mansoni, Alkoxyamine, biology.organism_classification, medicine.disease, 3. Good health, 0104 chemical sciences, Malaria, Chemistry (miscellaneous), Molecular Medicine, alkoxyamine
Abstract

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

Published
2020

29. Antiprotozoal properties of Indonesian medicinal plant extracts

Author

Lucie Paloque, Alexis Valentin, Arba Pramundita Ramadani, Hady Anshory Tamhid, Hugo Belda, Mustofa, Françoise Benoit-Vical, Jumina, Mahardika Agus Wijayanti, Jean-Michel Augereau, Masriani, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Universitas Gadjah Mada, Department of Pharmacy, Faculty of Science & Mathematics, Islamic University of Indonesia, Islamic University of Indonesia, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Department of Chemistry, Faculty of Mathematics and Natural Science, Gadjah Mada University, Department of Parasitology, Faculty of Medicine, Universitas Gadjah Mada, Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, Antiparasitic drugs, medicine.drug_class, Plasmodium falciparum, 030106 microbiology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, parasitic diseases, Botany, medicine, Pycnarrhena cauliflora, Babesia divergens, biology, Traditional medicine, Antiparasitic Drugs, Tithonia, biology.organism_classification, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Complementary and alternative medicine, Indonesia, Antiprotozoal, Leishmania infantum, Tinospora crispa
Abstract

International audience; Tithonia diversifolia, Cyclea barbata, Tinospora crispa, Arcangelisia flava, Pycnarrhena cauliflora are plants used in Indonesia for the traditional treatment of malaria. In the search for new antiparasitic drugs, the parts traditionally used of these 5 plants were extracted with ethanol and then fractionated with various solvents and evaluated in vitro against Plasmodium falciparum and also against Babesia divergens and Leishmania infantum. Seven crude plant extracts out of 25 tested displayed high antimalarial activities with IC50

Published
2018

31. Small Molecules: The Past or the Future in Drug Innovation?

Author

Anne, Robert, Françoise, Benoit-Vical, Yan, Liu, and Bernard, Meunier

Subjects
Antimalarials, Alzheimer Disease, Drug Design, Iron, Humans, Schistosomiasis, Heme, Artemisinins, Copper, Malaria
Abstract

With the impressive development of molecular life sciences, one may have the feeling that biopharmaceuticals will dominate the world of drug design and production. This is partly due to the evolution of pharmaceutical industry, especially since the 1980s. As a matter of fact, small molecules are still dominating the field of drug innovation, in contradiction with claims predicting their downfall and the exponential raise of biopharmaceuticals. The strong association of chemistry with biochemistry and pharmacology has been the scientific base of the establishment and the success of strong powerful pharmaceutical companies throughout the twentieth century. To meet the needs of new therapeutic agents, it is necessary to assess the role and future position of medicinal chemistry. In fact, the reasonable balance between small molecules and biopharmaceuticals will depend on scientific and economic factors, including the goal of having highly efficient drugs to cure the largest possible number of patients, at a cost that is compatible with the limits of national health budgets. In the present chapter, we would like to emphasize the future important role of small molecules based on new chemicals, to build a new portfolio of efficient, safe and affordable drugs to solve major therapeutic challenges. Two examples are then given. In the blood parasitic diseases such as malaria and schistosomiasis, the iron of heme is an "old" and relevant therapeutic target to kill the parasite. Investigations on the mechanism of action of the antimalarial endoperoxide sesquiterpene artemisinin, have paved the way to the design of new efficient synthetic endoperoxide drugs. In the case of Alzheimer's disease, the loss of copper homeostasis in patient brain is one of the key features of neurodegeneration. The development of small copper specific ligands able to retrieve copper from its pathological sinks to reintroduce it into physiological circulation is a challenging but promising approach to effective therapy.

Published
2019

32. 8. DEVELOPING VANADIUM AS AN ANTIDIABETIC OR ANTICANCER DRUG: A CLINICAL AND HISTORICAL PERSPECTIVE

Author

Françoise Benoit-Vical, Yan Liu, Bernard Meunier, and Anne Robert

Subjects
National health, Drug, 010405 organic chemistry, business.industry, media_common.quotation_subject, 010402 general chemistry, Key features, 01 natural sciences, Small molecule, 0104 chemical sciences, Copper homeostasis, Risk analysis (engineering), In patient, Business, Pharmaceutical industry, media_common
Abstract

With the impressive development of molecular life sciences, one may have the feeling that biopharmaceuticals will dominate the world of drug design and production. This is partly due to the evolution of pharmaceutical industry, especially since the 1980s. As a matter of fact, small molecules are still dominating the field of drug innovation, in contradiction with claims predicting their downfall and the exponential raise of biopharmaceuticals. The strong association of chemistry with biochemistry and pharmacology has been the scientific base of the establishment and the success of strong powerful pharmaceutical companies throughout the twentieth century. To meet the needs of new therapeutic agents, it is necessary to assess the role and future position of medicinal chemistry. In fact, the reasonable balance between small molecules and biopharmaceuticals will depend on scientific and economic factors, including the goal of having highly efficient drugs to cure the largest possible number of patients, at a cost that is compatible with the limits of national health budgets. In the present chapter, we would like to emphasize the future important role of small molecules based on new chemicals, to build a new portfolio of efficient, safe and affordable drugs to solve major therapeutic challenges. Two examples are then given. In the blood parasitic diseases such as malaria and schistosomiasis, the iron of heme is an "old" and relevant therapeutic target to kill the parasite. Investigations on the mechanism of action of the antimalarial endoperoxide sesquiterpene artemisinin, have paved the way to the design of new efficient synthetic endoperoxide drugs. In the case of Alzheimer's disease, the loss of copper homeostasis in patient brain is one of the key features of neurodegeneration. The development of small copper specific ligands able to retrieve copper from its pathological sinks to reintroduce it into physiological circulation is a challenging but promising approach to effective therapy.

Published
2019

33. 2. SMALL MOLECULES: THE PAST OR THE FUTURE IN DRUG INNOVATION?

Author

Anne Robert, Françoise Benoit-Vical, Yan Liu, and Bernard Meunier

Subjects
010405 organic chemistry, 02 engineering and technology, 021001 nanoscience & nanotechnology, 0210 nano-technology, 01 natural sciences, 0104 chemical sciences
Published
2019

34. Résistance de l’agent du paludisme, Plasmodium falciparum aux combinaisons thérapeutiques à base d’artémisinine (ACTs) : Craintes d’une chimiorésistance généralisée

Author

Jean-Michel Augereau, Françoise Benoit-Vical, and Lucie Paloque

Subjects
0301 basic medicine, Drug, Artemisinins, biology, business.industry, media_common.quotation_subject, Plasmodium falciparum, General Medicine, Drug resistance, biology.organism_classification, medicine.disease, Virology, Plasmodium, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Pharmacotherapy, parasitic diseases, medicine, 030212 general & internal medicine, Artemisinin, business, Malaria, media_common, medicine.drug
Abstract

Malaria treatment with ACTs (Artemisinin-based Combination Therapies), combining a chemical derivative of artemisinin, and a partner drug has, for more than 15 years, produced a notable decrease in the mortality in tropical and subtropical areas. However, since 2008, a serious threat has emerged in western Cambodia, where the clinical efficacy of artemisinins has significantly declined, with a delayed parasite clearance rate and high recrudescence rates in the following weeks. Resistance of Plasmodium to artemisinins is now reported in several countries in South-East Asia. ACTs remain effective as long as the partner drug retains its activity but more and more clinical failures related to parasite resistance to both resistant parasites in sub-Saharan Africa, the continent most affected by malaria, as was the case in the past with other antimalarial treatments. It is therefore essential to better understand, from phenotypic and genotypic points of view, the mechanisms of resistance developed by the parasite Plasmodium falciparum face artemisinin and its derivatives in order to offer new therapeutic tools.

Published
2016

35. Multiple phenotypic and genotypic artemisinin sensitivity evaluation of Malian Plasmodium falciparum isolates

Author

Sandie Menard, Antoine Berry, Françoise Benoit-Vical, Pety Tor, Arba Pramundita Ramadani, Antoine Dara, Jean-Michel Augereau, Karamoko Niaré, Ogobara K. Doumbo, Lucie Paloque, Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie-Mycologie [Toulouse], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]

Subjects
0301 basic medicine, Genotype, medicine.medical_treatment, Plasmodium falciparum, 030106 microbiology, 030231 tropical medicine, Drug Resistance, Dihydroartemisinin, Drug resistance, Microbiology, Antimalarials, 03 medical and health sciences, 0302 clinical medicine, Gentamicin protection assay, Virology, parasitic diseases, medicine, Humans, Parasite hosting, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, ComputingMilieux_MISCELLANEOUS, biology, Articles, biology.organism_classification, Artemisinins, 3. Good health, Phenotype, Infectious Diseases, Parasitology, Ex vivo, medicine.drug
Abstract

International audience; We assessed the ex vivo/in vitro sensitivity of 54 Malian Plasmodium falciparum isolates to artemisinin for the monitoring of drug resistance in this area. The artemisinin sensitivity of parasites was evaluated using 1) the ex vivo and in vitro parasite recrudescence detection after treatment of the ring stage with 1–200 nM artemisinin for 48 hours and 2) the in vitro parasite recrudescence kinetics assay over 7 days after 6-hour treatment of the ring stage with 700 nM dihydroartemisinin (DHA). In addition, as recommended by the World Health Organization for artemisinin resistance characterization, the ring-stage survival assay (RSA0–3 h) was performed and the parasite isolates were sequenced at the kelch 13 propeller locus. No clinical and molecular evidence of artemisinin resistance was observed. However, these isolates present different phenotypic profiles in response to artemisinin treatments. Despite all RSA0–3 h values less than 1.5%, six out of 46 (13.0%) isolates tested ex vivo and four out of six (66.7%) isolates tested in vitro were able to multiply after 48-hour treatments with 100 nM artemisinin. Moreover, five out of eight isolates tested showed faster parasite recovery after DHA treatment in kinetic assays. The presence of such phenotypes needs to be taken into account in the assessment of the efficacy of artemisinins in Mali. The assays presented here appear as valuable tools for the monitoring of artemisinin sensitivity in the field and thus could help to evaluate the risk of emergence of artemisinin resistance in Africa.

Published
2018

36. Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Author

Lucie Paloque, Françoise Benoit-Vical, Jean-Michel Augereau, Manel Ouji, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016)

Subjects
0301 basic medicine, Artemisinins, Asia, Veterinary (miscellaneous), 030231 tropical medicine, 030106 microbiology, Plasmodium falciparum, malaria, Drug resistance, Review Article, Biology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Antimalarials, 0302 clinical medicine, Pharmacotherapy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Malaria elimination, parasitic diseases, medicine, Humans, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Artemisinin, Disease Eradication, Malaria, Falciparum, Africa South of the Sahara, Asia, Southeastern, Clinical Trials as Topic, drug resistance, Resistance (ecology), biology.organism_classification, medicine.disease, Virology, Drug Resistance, Multiple, 3. Good health, Parasite, Infectious Diseases, artemisinin, Insect Science, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animal Science and Zoology, Parasitology, Drug Therapy, Combination, Cambodia, Malaria, medicine.drug
Abstract

The use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions.Résistance de Plasmodium falciparum aux combinaisons thérapeutiques à base d’artémisinine : une épée de Damoclès sur les stratégies d’éradication du paludisme.L’utilisation, dans le traitement du paludisme simple, de combinaisons thérapeutiques associant un dérivé de l’artémisinine et une molécule partenaire a largement contribué à une réduction significative de la mortalité due à cette pathologie dans les régions tropicales et subtropicales ainsi qu’une diminution de 18% de nombre de cas de 2010 à 2016. Cependant, ces progrès sont sérieusement menacés par la diminution de l’efficacité clinique des artémisinines caractérisées par des clairances parasitaires retardées et un taux de recrudescence élevé, signalés en 2008 à l’ouest du Cambodge. La résistance aux artémisinines s’est déjà étendue à plusieurs pays d’Asie du Sud-Est. De plus, il a été montré que la résistance aux molécules partenaires des artémisinines dans ces combinaisons thérapeutiques (ACT) a été facilitée suite à une diminution de la sensibilité à l’artémisinine. L’une des principales préoccupations est non seulement la propagation de ces parasites multi-résistants dans le reste de l’Asie, mais aussi leur apparition possible en Afrique subsaharienne, continent le plus touché par le paludisme, comme cela a été le cas dans le passé avec la résistance de parasites à d’autres traitements antipaludiques. Il est donc essentiel de comprendre l’acquisition de la résistance de Plasmodium falciparum aux artémisinines afin d’adapter les politiques de santé face au paludisme et de proposer de nouvelles solutions thérapeutiques.

Published
2018

37. Assessment of Cassia siamea stem bark extracts toxicity and stability in time of aqueous extract analgesic activity

Author

R.D.G. Elion Itou, Suzanne Ramos, Jean-Maurille Ouamba, M.C. Makambila, J.T. Banzouzi, Françoise Benoit-Vical, A. A. Abena, G.F. Nsonde Ntandou, A. W. Etou Ossibi, and D. J. Bassoueka

Subjects
Pharmacology, chemistry.chemical_classification, Stigmasterol, biology, Traditional medicine, Pharmaceutical Science, Polysaccharide, biology.organism_classification, Median lethal dose, chemistry.chemical_compound, chemistry, Cassia, Oral administration, Toxicity, Alkaline phosphatase, Petroleum ether
Abstract

Cassia siamea Lam (Fabaceae), widely used in tropical countries for its nutritional and pharmacological properties, has been toxicologically evaluated. Oral administration of aqueous (CSE4) and ethanol (CSE3) Cassia siamea stem bark extracts did not show mortality up to 3000 mg/kg in albinos Wistar rats. LD 50 of petroleum ether (CSE1) and dichloromethane (CSE2) extracts were estimated at 1300 and 1275 mg/kg respectively. None of the extracts has cytotoxicity activity on KB and Vero cell lines. There were no differences in body weight and macroscopic examinations. Haematocrit, creatinine, alkaline phosphatase (ALP), alanine amino transferase (ALT) and Asparatate Amino Transferase (AST) parameters did not show difference of levels. Contrariwise, a significant increase in animal weight and blood glucose were observed in animals treated group. This increase can be explained by the presence of polysaccharides and phytosterols (stigmasterol, beta-sitosterol) in this plant. The lyophilised aqueous extract keeps its analgesic property for over two years. Key words: Cassia siamea, stem bark extracts, cytoxicity, subchronic toxicity, pharmacological stability, analgesic activity.

Published
2015

38. Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism

Author

Françoise Benoit-Vical, Anne Robert, Jean-Michel Augereau, Manel Ouji, Joël Lelièvre, Lucie Paloque, Didier Menard, Tanila Ben Haddou, Frédéric Ariey, Bernard Meunier, Benoit Witkowski, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Service de parasitologie-mycologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], and CHU Cochin [AP-HP]

Subjects
0301 basic medicine, Microbiology (medical), Drug, Artemisinins, Genotype, media_common.quotation_subject, 030106 microbiology, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Drug resistance, 03 medical and health sciences, Antimalarials, Parasitic Sensitivity Tests, parasitic diseases, medicine, Humans, Pharmacology (medical), [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, Malaria, Falciparum, Selection, Genetic, Cross-resistance, media_common, Pharmacology, Genetics, biology, Whole Genome Sequencing, medicine.disease, biology.organism_classification, 3. Good health, Infectious Diseases, Phenotype, Mutant Proteins, Cambodia, Malaria, medicine.drug
Abstract

International audience; Background: Owing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds. Objectives: To address this issue, the antiplasmodial efficacy of trioxaquines, hybrid endoperoxide-based molecules, was explored, along with their ability to select in vitro resistant parasites under discontinuous and dose-escalating drug pressure. Methods: The in vitro susceptibilities of artemisinin- and trioxaquine-resistant laboratory strains and recent Cambodian field isolates were evaluated by different phenotypic and genotypic assays. Results: Trioxaquines tested presented strong cross-resistance with artemisinin both in the artemisinin-resistant laboratory F32-ART5 line and in Cambodian field isolates. Trioxaquine drug pressure over 4 years led to the in vitro selection of the F32-DU line, which is resistant to trioxaquine and artemisinin, similar to the F32-ART lineage. F32-DU whole genome sequencing (WGS) revealed that resistance to trioxaquine was associated with the same non-synonymous mutation in the propeller domain of the K13 protein (M476I) that was found in the F32-ART lineage. Conclusions : These worrisome results indicate the risk of cross-resistance between artemisinins and endoperoxide-based antiplasmodial drugs in the development of the K13 mutant parasites and question the usefulness of these molecules in the future therapeutic arsenal.

Published
2017

39. Gold(I) complexes bearing phosphole ligands: Synthesis and antimalarial activity

Author

Odile Dechy-Cabaret, Kévin Fourmy, Françoise Benoit-Vical, Maryse Gouygou, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB) - Hôpital Purpan, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]

Subjects
Stereochemistry, General Chemical Engineering, Phosphole, Medicinal chemistry, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, Structure–activity relationships, Ligands phosphorés, Ic50 values, Moiety, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Chimie médicinale, biology, 010405 organic chemistry, Ligand, Chemistry, Plasmodium falciparum, Diffraction des rayons X, General Chemistry, biology.organism_classification, 3. Good health, 0104 chemical sciences, P ligands, X-ray diffraction, Relation structure–activité, Gold, Complexes d'or
Abstract

International audience; A series of gold(I)-monophosphole complexes have been synthesized and characterized. The introduction of a nitrogen moiety in the complex structure was envisioned either by choosing the bis(trifluoromethanesulfonyl)imidate ligand as the X-ligand or by preparing a new pyrrolidinophosphole ligand as the L-ligand. All the complexes have been evaluated in vitro for their antimalarial activity. These gold–phosphole complexes showed moderate activities with IC50 values ranging from 9.7 to 24 μM against Plasmodium falciparum chloroquine-resistant strains.

Published
2017

40. Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo

Author

Françoise Benoit-Vical, Marie-Pierre Hayette, Thierry Lengu Bobanga, Patrick De Mol, Georges Lelo Mvumbi, Pierrette Melin, Dieudonné Makaba Mvumbi, Hippolyte Situakibanza, Jean-Marie Ntumba Kayembe, Biochemistry and Molecular Biology Unit, Department of Basic Sciences, School of Medicine, University of Kinshasa (UNIKIN), Département de microbiologie clinique, Centre Hospitalier Universitaire de Liège (CHU Liège), Centre Hospitalier Universitaire de Liège (CHU-Liège), Department of Parasitology and Tropical Medicine, School of Medicine, Department of Internal Medicine - University Hospital of Kinshasa, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Plasmodium, Heredity, Drug Resistance, Gene Dosage, Protozoan Proteins, lcsh:Medicine, Drug resistance, chemistry.chemical_compound, 0302 clinical medicine, Chloroquine, Medicine and Health Sciences, Malaria, Falciparum, Artemisinin, lcsh:Science, media_common, Protozoans, Multidisciplinary, Geography, biology, Malarial Parasites, Drugs, Artemisinins, Democracy, 3. Good health, Genetic Mapping, Democratic Republic of the Congo, Drug Therapy, Combination, Research Article, medicine.drug, Genetic Markers, media_common.quotation_subject, Plasmodium falciparum, 030106 microbiology, 030231 tropical medicine, Amodiaquine, Lumefantrine, Microbiology, Antimalarials, 03 medical and health sciences, Microbial Control, Parasite Groups, parasitic diseases, Parasitic Diseases, Genetics, medicine, Humans, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Pharmacology, Polymorphism, Genetic, lcsh:R, Organisms, Biology and Life Sciences, Tropical Diseases, medicine.disease, biology.organism_classification, Virology, Parasitic Protozoans, Malaria, Haplotypes, chemistry, Mutation, Parasitology, lcsh:Q, Antimicrobial Resistance, Apicomplexa
Abstract

International audience; Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance.

Published
2017

41. Plasmodium falciparum: multifaceted resistance to artemisinins

Author

Arba Pramundita Ramadani, Jean-Michel Augereau, Françoise Benoit-Vical, Odile Mercereau-Puijalon, Lucie Paloque, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunologie moléculaire des parasites, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ANR-13-BSV3-0018,MALARTRES,Résistance de Plasmodium aux antipaludiques de la famille des artémisinines(2013), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), BMC, BMC, Blanc 2013 - Résistance de Plasmodium aux antipaludiques de la famille des artémisinines - - MALARTRES2013 - ANR-13-BSV3-0018 - Blanc 2013 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Artemisinins, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Resistance, Drug Resistance, Review, Drug resistance, Biology, Quiescence, Models, Biological, Antimalarials, 03 medical and health sciences, parasitic diseases, medicine, Humans, Malaria, Falciparum, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Transcription factor, PI3K/AKT/mTOR pathway, Apicoplast, PfK13, biology.organism_classification, medicine.disease, Virology, Artemisinin-based combination therapy, 3. Good health, Cell biology, Malaria, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Unfolded protein response, Parasitology
Abstract

Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2α cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1206-9) contains supplementary material, which is available to authorized users.

Published
2016

42. Reduced Artemisinin Susceptibility of Plasmodium falciparum Ring Stages in Western Cambodia

Author

Rithea Leang, Sophie Chy, Antoine Berry, Pascal Ringwald, Saorin Kim, Odile Mercereau-Puijalon, Rupam Tripura, Pheaktra Chim, Socheat Duong, Françoise Benoit-Vical, Jean-Christophe Barale, Didier Menard, Nimol Kloeung, Nimol Khim, Olivier Gorgette, Sopheakvatey Ke, Benoit Witkowski, Frédéric Ariey, Arjen M. Dondorp, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), World Health Organization [Geneva], Mahidol University [Bangkok], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Immunologie moléculaire des parasites, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_treatment, Plasmodium falciparum, 030231 tropical medicine, Drug Resistance, Dihydroartemisinin, Drug resistance, Antimalarials, 03 medical and health sciences, 0302 clinical medicine, Parasitic Sensitivity Tests, Gentamicin protection assay, Pulse exposure, parasitic diseases, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Pharmacology (medical), Malaria, Falciparum, Artemisinin, Survival rate, ComputingMilieux_MISCELLANEOUS, Pharmacology, 0303 health sciences, biology, 030306 microbiology, Cell Cycle Checkpoints, medicine.disease, biology.organism_classification, Virology, Artemisinins, 3. Good health, Infectious Diseases, Susceptibility, Cambodia, Malaria, medicine.drug
Abstract

The declining efficacy of artemisinin derivatives against Plasmodium falciparum in western Cambodia is a major concern. The knowledge gap in the understanding of the mechanisms involved hampers designing monitoring tools. Here, we culture-adapted 20 isolates from Pailin and Ratanakiri (areas of artemisinin resistance and susceptibility in western and eastern Cambodia, respectively) and studied their in vitro response to dihydroartemisinin. No significant difference between the two sets of isolates was observed in the classical isotopic test. However, a 6-h pulse exposure to 700 nM dihydroartemisinin (ring-stage survival assay -RSA]) revealed a clear-cut geographic dichotomy. The survival rate of exposed ring-stage parasites (ring stages) was 17-fold higher in isolates from Pailin (median, 13.5%) than in those from Ratanakiri (median, 0.8%), while exposed mature stages were equally and highly susceptible (0.6% and 0.7%, respectively). Ring stages survived drug exposure by cell cycle arrest and resumed growth upon drug withdrawal. The reduced susceptibility to artemisinin in Pailin appears to be associated with an altered in vitro phenotype of ring stages from Pailin in the RSA.

Published
2013

43. Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes

Author

Heinz Gornitzka, Luca Boselli, Álvaro Fernández Álvarez, Jean-Michel Augereau, Françoise Benoit-Vical, Arba Pramundita Ramadani, Catherine Hemmert, Lucie Paloque, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universitas Gadjah Mada, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Stereochemistry, Cell Survival, Clinical Biochemistry, Plasmodium falciparum, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, Crystallography, X-Ray, 01 natural sciences, Biochemistry, Medicinal chemistry, Antimalarials, Inhibitory Concentration 50, Structure-Activity Relationship, Drug Discovery, Chlorocebus aethiops, Organometallic Compounds, Molecule, Animals, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Cytotoxicity, Molecular Biology, Vero Cells, biology, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Cationic polymerization, Chloroquine, biology.organism_classification, In vitro, 0104 chemical sciences, Lipophilicity, Molecular Medicine, Gold, Selectivity, Methane
Abstract

International audience; A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro-and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50 = 210 nM) close to the value obtained with chloroquine (IC50 = 514 nM) and a weak cytotoxicity.

Published
2016

44. In vivo efficacy and parasite clearance of artesunate plus sulfadoxine-pyrimethamine versus artemether-lumefantrine in Mali

Author

Issaka Sagara, Ogobara K. Doumbo, Nana H. Cissé, Pascal Ringwald, Antoine Berry, Antoine Dara, Mahamadou S. Sissoko, Françoise Benoit-Vical, Cheick Oumar Coulibaly, Cheick Oumar Guindo, Abdoulaye A Djimdé, Karamoko Niaré, Gulli, Marie-Hélène, Département d'Epidémiologie des Affections parasitaires, Malaria Research and training center Université de Bamako, Mali, Université de Bamako, Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]

Subjects
Male, Artemether/lumefantrine, Artesunate, Pharmacology, Mali, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, 030212 general & internal medicine, Artemether, Artemisinin, Malaria, Falciparum, Child, biology, Articles, Artemisinins, 3. Good health, Drug Combinations, Infectious Diseases, Pyrimethamine, Ethanolamines, Child, Preschool, Female, medicine.drug, medicine.medical_specialty, 030231 tropical medicine, Plasmodium falciparum, 03 medical and health sciences, Antimalarials, Virology, Internal medicine, Sulfadoxine, parasitic diseases, medicine, Humans, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Fluorenes, business.industry, Artemether, Lumefantrine Drug Combination, [CHIM.COOR] Chemical Sciences/Coordination chemistry, medicine.disease, biology.organism_classification, Sulfadoxine/pyrimethamine, chemistry, Parasitology, business, Malaria
Abstract

International audience; Although artemisinin resistance has yet to be reported in Africa, surveillance of the efficacy of artemisinin-based combination therapies (ACTs) is warranted. Here, the efficacy of artesunate + sulfadoxine-pyrimethamine (AS+SP) and artemether-lumefantrine (AL) was evaluated in Mali. Randomized open-label comparative in vivo assay of AS+SP versus AL were carried out using the 28-day follow-up World Health Organization protocol. Patients with uncomplicated falciparum malaria and at least 6 months of age were recruited between October 2010 and January 2014. A subset of these patients was selected to measure Plasmodium falciparum clearance time. Polymerase chain reaction corrected adequate clinical and parasitological responses were 100% for AS+SP and 98.2% for AL with no significant difference (P = 0.06). The reinfection rates were comparable (P = 0.63) with 8.0% for AS+SP and 12.6% for AL. Individuals under 8 years were more susceptible to treatment failure (relative risk = 1.9; 95% confidence interval = 1.2, 3.3). Median parasite clearance half-life was 1.7 hours (interquartile range [IQR] = 1.3-2.2) for AS+SP and 1.9 hours (IQR = 1.5-2.5) for AL with no statistically significant difference (P = 0.24). Efficacy of AS+SP and AL was high. This study provides baseline information on parasite clearance half-lives after ACT treatment, particularly AS+SP, in Mali.

Published
2016

45. Indole and aminoimidazole moieties appear as key structural units in antiplasmodial molecules

Author

Charlotte Passemar, Christiane Poupat, Françoise Benoit-Vical, Marie-Denise Linas, Patrice Njomnang Soh, Alain Ahond, and Mariette Saléry

Subjects
Antifungal Agents, Indoles, Hydrochloride, Stereochemistry, Plasmodium falciparum, Pharmaceutical Science, Antimalarials, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, Humans, Molecule, Oxindole, Candida sp, Candida, Pharmacology, Indole test, Plants, Medicinal, biology, Plant Extracts, Imidazoles, biology.organism_classification, In vitro, Malaria, Usambarensine, Complementary and alternative medicine, chemistry, Molecular Medicine
Abstract

From a library of compounds of natural sources, a big series of molecules was chosen by random sampling to evaluate their in vitro antimalarial activity against Plasmodium falciparum and their antifungal activity against Candida sp. From 184 molecules tested, no molecules were active against Candida sp. (MIC > 10 μg/ml) whereas 13 clearly showed high antiplasmodial activity in vitro , with an IC 50 less than 1 μg/ml against the chloroquine-resistant strain of P. falciparum FcM29-Cameroon. The molecules with the best antiplasmodial efficacy were 10-hydroxy-ellipticin (IC 50 : 0.08 μg/ml), tchibangensin (IC 50 : 0.13 μg/ml), ellipticin hydrochloride (IC 50 : 0.17 μg/ml), usambarensin (IC 50 : 0.23 μg/ml), 7S,3S-ochropposinine oxindole (IC 50 : 0.25 μg/ml), 3,14-dihydro-ellipticin (IC 50 : 0.25 μg/ml), tetrahydro-4′,5′,6′17-usambarensin 17S (IC 50 : 0.26 μg/ml), ellipticine (IC 50 : 0.28 μg/ml), aricin (IC 50 : 0.3 μg/ml), 10-methoxy-ellipticin (IC 50 : 0.32 μg/ml), aplysinopsin (IC 50 : 0.43 μg/ml), descarbomethoxydihydrogambirtannin (IC 50 : 0.46 μg/ml) and ochrolifuanin A (IC 50 : 0.47 μg/ml). Among these 13 promising molecules, all except descarbomethoxydihydrogambirtannin, ochrolifuanine A and usambarensine presented here novel biological activities since they had never been described in the literature for their antiplasmodial activity. In spite of the large diversity of the molecules which have been tested, it is interesting to note that the ones active against Plasmodium are all indole derivatives (and one is both indolic and aminoimidazolic). To find new antiplasmodial compounds, ethnopharmacological approaches studying traditional medicine treatments for malaria is largely used but random research produced here an interesting yield (7%) of new antiplasmodial hits and appears therefore complementary to the traditional medicine way.

Published
2011

46. Increased Tolerance to Artemisinin in Plasmodium falciparum Is Mediated by a Quiescence Mechanism

Author

Antoine Berry, Victor Laurent, Joël Lelièvre, Benoit Witkowski, María J. López Barragán, Françoise Benoit-Vical, and Xin-zhuan Su

Subjects
Erythrocytes, Plasmodium falciparum, Artesunate, Drug resistance, Pharmacology, Plasmodium, Transcriptome, Antimalarials, Inhibitory Concentration 50, chemistry.chemical_compound, Parasitic Sensitivity Tests, Mechanisms of Resistance, Heat shock protein, Drug Resistance, Bacterial, parasitic diseases, medicine, Humans, Pharmacology (medical), Malaria, Falciparum, Artemisinin, Oligonucleotide Array Sequence Analysis, biology, Gene Expression Profiling, Flow Cytometry, Thailand, biology.organism_classification, Artemisinins, Infectious Diseases, chemistry, Mechanism of action, medicine.symptom, Cambodia, medicine.drug
Abstract

Artemisinin (ART)-based combination therapies (ACTs) are the first-line drugs—and often the last treatments—that can effectively cure Plasmodium falciparum infections. Unfortunately, the decreased clinical efficacy of artesunate, one of the major ART derivatives, was recently reported along the Thailand-Cambodia border. Through long-term artemisinin pressure in vitro , we have obtained an ART-tolerant strain that can survive extremely high doses of ART. We showed that drug pressure could induce a subpopulation of ring stages into developmental arrest, which can explain the ART tolerance in P. falciparum . We also observed interesting transcriptomic modifications possibly associated with the acquisition of ART tolerance. These modifications include the overexpression of heat shock and erythrocyte surface proteins and the downexpression of a cell cycle regulator and a DNA biosynthesis protein. This study highlights a new phenomenon in the Plasmodium response to ART that may explain the delayed clearance of parasites after artesunate treatment observed on the Thailand-Cambodia border and that provides important information for achieving a better understanding of the mechanisms of antimalarial resistance.

Published
2010

47. Pfs 16 pivotal role in Plasmodium falciparum gametocytogenesis: A potential antiplasmodial drug target

Author

Benoit Witkowski, Françoise Benoit-Vical, Antoine Berry, Caroline Deymier, and Mathieu Sertorio

Subjects
Plasmodium falciparum, Immunology, Antigens, Protozoan, Biology, Plasmodium, Gametogenesis, Antimalarials, parasitic diseases, Gene expression, Gametocyte, medicine, Animals, Vector (molecular biology), Malaria, Falciparum, Gene, Reverse Transcriptase Polymerase Chain Reaction, Membrane Proteins, General Medicine, medicine.disease, biology.organism_classification, Virology, Infectious Diseases, Real-time polymerase chain reaction, Gene Expression Regulation, Parasitology, RNA, Protozoan, Malaria
Abstract

Mature gametocytes, the sexual stage of Plasmodium falciparum, ensure the continued transmission of malaria from the human host to the mosquito vector. Even if gametocytes are not implicated in the malaria physiopathology it is crucial to the spread of malaria. Gametocytes are to be a key target for drugs used against Plasmodium in public health. The expression levels of 4 sexual-stage specific genes, Pfs 16, Pfs 25, Pfg 27 and S 18S rRNA, during gametocytogenesis of various P. falciparum strains were analyzed by a real time PCR assay. The strains showed different capacities to produce mature gametocytes and in parallel different patterns of sexual gene expression. There was a correlation only between Pfs 16 cDNA overexpression in the first 48h of the culture and the production of mature gametocytes. Pfs 16 is an early marker of the development of mature gametocytes in cultures and is therefore a potential target for new antimalarial drugs.

Published
2009

48. Resistance to antimalarial compounds: Methods and applications

Author

Benoit Witkowski, Françoise Benoit-Vical, and Antoine Berry

Subjects
Plasmodium, Cancer Research, Genotype, Field data, Plasmodium falciparum, Drug Resistance, Drug resistance, Computational biology, Pharmacology, Antimalarials, Structure-Activity Relationship, In vivo, Animals, Humans, Pharmacology (medical), Available drugs, Molecular Structure, biology, biology.organism_classification, Malaria, Disease Models, Animal, Phenotype, Infectious Diseases, Oncology, Drug Design
Abstract

Considerable progress has been made in antimalarial research; however, much more effort is required to develop new antimalarials which overcome plasmodial resistance to clinically available drugs and limit the emergence of resistance. In particular, research must focus on understanding the mechanisms by which Plasmodium falciparum impedes the action of these drugs. In this review, we discuss the different in vitro and in vivo models used to adequately study resistance to antimalarial compounds. For each molecule studied, the best in vitro and/or in vivo model is highlighted with a detailed discussion of its validity in relation to field data on P. falciparum resistance.

Published
2009

49. PCR-based methods to the diagnosis of imported malaria

Author

Richard Fabre, Jean-François Magnaval, Françoise Benoit-Vical, Antoine Berry, and Sophie Cassaing

Subjects
Plasmodium, medicine.medical_specialty, Veterinary (miscellaneous), Imported disease, Polymerase Chain Reaction, Sensitivity and Specificity, lcsh:Infectious and parasitic diseases, Diagnosis, Differential, molecular diagnosis, parasitic diseases, medicine, Animals, Humans, Travel medicine, lcsh:RC109-216, Intensive care medicine, Protozoal disease, Imported malaria, business.industry, Reproducibility of Results, Gold standard (test), DNA, Protozoan, medicine.disease, Malaria, Diagnosis of malaria, PCR, Infectious Diseases, Insect Science, Immunology, Animal Science and Zoology, Parasitology, imported malaria, business
Abstract

Rapid and precise diagnosis of malaria is needed to take care febrile patient returning from endemic areas. Since the first description of the diagnosis of Plasmodium infection by polymerase-chain-reaction (PCR), the role of this kind of molecular method in the laboratory diagnosis of imported malaria is still a topical question. PCR-based assays were found to be more sensitive and more specific than all conventional methods. The highest contribution of the molecular diagnosis is that a PCR negative result would ascertain the lack of any malaria infection, thus quickly orienting the investigations toward other aetiology. This technique should be now considered as the gold standard for the diagnosis of imported malaria.

Published
2008

50. The Antimalarial Trioxaquine DU1301 Alkylates Heme in Malaria-Infected Mice

Author

Françoise Benoit-Vical, Bernard Meunier, Catherine Claparols, Anne Robert, and Fatima Bousejra-El Garah

Subjects
Drug, Ratón, media_common.quotation_subject, Heme, Alkylation, Biology, Plasmodium, Mass Spectrometry, Microbiology, Antimalarials, Mice, chemistry.chemical_compound, In vivo, parasitic diseases, medicine, Animals, Pharmacology (medical), Artemisinin, Mechanisms of Action: Physiological Effects, media_common, Pharmacology, Molecular Structure, medicine.disease, biology.organism_classification, Malaria, Infectious Diseases, chemistry, Biochemistry, Sesquiterpenes, Chromatography, Liquid, medicine.drug
Abstract

The in vivo alkylation of heme by the antimalarial trioxaquine DU1301 afforded covalent heme-drug adducts that were detected in the spleens of Plasmodium sp.-infected mice. This result indicates that the alkylation capacities of trioxaquines in mammals infected with Plasmodium strains are similar to that of artemisinin, a natural antimalarial trioxane-containing drug.

Published
2008

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