Search

Your search keyword '"Nicolas Primas"' showing total 70 results
Start Over Author "Nicolas Primas"
70 results on '"Nicolas Primas"'

1. 31st Annual GP2A Medicinal Chemistry Conference

Author

Nicolas Primas, Caroline Castera-Ducros, Romain Paoli-Lombardo, Christophe Curti, Fanny Mathias, Pascal Rathelot, Pascal Marchand, and Patrice Vanelle

Subjects
medicinal chemistry, drug design, chemical biology, chemical tools, pharmaceutical chemistry, conference report, Pharmacy and materia medica, RS1-441, Chemistry, QD1-999
Abstract

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP2A) held its 31st annual conference in August 2023 at the Faculty of Pharmacy of Aix-Marseille University, Marseille, France. There were 8 keynote presentations, 10 early career researcher oral presentations and 23 poster presentations. Among them, four awards were delivered, two for best oral communications and two for the best poster presentations.

Published
2024
Full Text
View/download PDF

2. Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential

Author

Omar Khoumeri, Sébastien Hutter, Nicolas Primas, Caroline Castera-Ducros, Sandra Carvalho, Susan Wyllie, Mohamed Lotfi Efrit, Dimitri Fayolle, Marc Since, Patrice Vanelle, Pierre Verhaeghe, Nadine Azas, and Hussein El-Kashef

Subjects
visceral leishmaniasis, L. infantum, thiazolidinedione ring, nitrostyryl moiety, Medicine, Pharmacy and materia medica, RS1-441
Abstract

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2–5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure–activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.

Published
2024
Full Text
View/download PDF

3. N-[1-(2-Chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1H-imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide

Author

Romain Paoli-Lombardo, Nicolas Primas, Caroline Castera-Ducros, Inès Jacquet, Pascal Rathelot, and Patrice Vanelle

Subjects
5-nitroimidazole, N-tosylbenzylimine, tetrakis(dimethylamino)ethylene (TDAE), vicarious nucleophilic substitution (VNS), Inorganic chemistry, QD146-197
Abstract

In continuation of our research program to develop original synthetic methods using TDAE methodology on nitroheterocyclic substrates, we were able to generate for the first time a stable carbanion in position 2 of the 5-nitroimidazole scaffold. Starting from a 2-chloromethyl-4-phenylsulfonylmethyl-5-nitroimidazole intermediate, prepared by the vicarious nucleophilic substitution of hydrogen (VNS) reaction, we selectively introduced a N-tosylbenzylimine moiety at position 2 without reducing the sulfone at position 4, leading to the formation of N-[1-(2-chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1H-imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide in 47% yield. This new synthetic method using TDAE should allow access to new 2-substituted 5-nitroimidazole derivatives with various electrophiles such as carbonyls and other N-tosylbenzylimines.

Published
2023
Full Text
View/download PDF

4. 6-Chloro-3-nitro-8-(phenylthio)-2-[(phenylthio)methyl] imidazo[1,2-a]pyridine

Author

Romain Paoli-Lombardo, Nicolas Primas, Sébastien Hutter, Sandra Bourgeade-Delmas, Clotilde Boudot, Caroline Castera-Ducros, Inès Jacquet, Bertrand Courtioux, Nadine Azas, Pascal Rathelot, and Patrice Vanelle

Subjects
imidazo [1,2-a] pyridine, nitroaromatic, structure–activity relationship, Leishmania spp., Trypanosoma brucei, Inorganic chemistry, QD146-197
Abstract

As part of our ongoing antikinetoplastid structure–activity relationship study focused on positions 2 and 8 of the 3-nitroimidazo[1,2-a]pyridine scaffold, we were able to introduce a phenylthioether moiety at both position 2 and position 8 in one step. Using a previously reported synthetic route developed in our laboratory, we obtained 6-chloro-3-nitro-8-(phenylthio)-2-[(phenylthio)methyl]imidazo[1,2-a]pyridine in 74% yield. The in vitro cell viability of this compound was assessed on the HepG2 cell line, and its in vitro activity was evaluated against the promastigote form of L. donovani, the axenic amastigote form of L. infantum and the trypomastigote blood stream form of T. b. brucei. It showed low solubility in HepG2 culture medium (CC50 > 7.8 µM), associated with weak activity against both the promastigote form of L. donovani (EC50 = 8.8 µM), the axenic amastigote form of L. infantum (EC50 = 9.7 µM) and the trypomastigote blood stream form of T. b. brucei (EC50 = 12.8 µM).

Published
2023
Full Text
View/download PDF

5. 6-Chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-b]pyridazine

Author

Romain Paoli-Lombardo, Nicolas Primas, Sébastien Hutter, Sandra Bourgeade-Delmas, Clotilde Boudot, Caroline Castera-Ducros, Inès Jacquet, Bertrand Courtioux, Nadine Azas, Pascal Rathelot, and Patrice Vanelle

Subjects
imidazo[1,2-b]pyridazine, nitroaromatic, scaffold-hopping, structure-activity relationships, Leishmania spp., Trypanosoma brucei, Inorganic chemistry, QD146-197
Abstract

As part of our ongoing scaffold-hopping work on an antikinetoplastid 3-nitroimidazo[1,2-a]pyridine scaffold, we explored 3-nitroimidazo[1,2-b]pyridazine as a potential new antikinetoplastid series. Using conditions previously described by our lab, we obtained 6-chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-b]pyridazine with 54% yield. In vitro activity of this compound was evaluated against both the promastigote form of Leishmania donovani, the axenic amastigote form of Leishmania infantum and the trypomastigote blood stream form of Trypanosomabrucei brucei, and its influence on cell viability was assessed on the HepG2 cell line. However, despite good activity against the trypomastigote blood stream form of T. b. brucei (EC50 = 0.38 µM), it showed poor solubility in both HepG2 (CC50 > 7.8 µM) and L. infantum axenic amastigotes (EC50 > 1.6 µM) culture media, associated with a loss of activity against the promastigote form of L. infantum (EC50 > 15.6 µM).

Published
2023
Full Text
View/download PDF

6. Low-dose erythromycin in pediatrics: Formulation and stability of 20 mg hard gelatin capsules.

Author

Patrick Thevin, Christophe Curti, Alexandre Benech, Christophe Jean, Edouard Lamy, Caroline Castera Ducros, Nicolas Primas, Pierre Bertault-Peres, and Patrice Vanelle

Subjects
Medicine, Science
Abstract

ObjectiveErythromycin is a macrolide antibiotic that is also prescribed off-label in premature neonates as a prokinetic agent. There is no oral formulation with dosage and/or excipients adapted for these high-risk patients.MethodsClinical studies of erythromycin as a prokinetic agent were reviewed. Capsules of 20 milligrams of erythromycin were compounded with microcrystalline cellulose. Erythromycin capsules were analyzed using the chromatographic method described in the United States Pharmacopoeia which was found to be stability-indicating. The stability of 20 mg erythromycin capsules stored protected from light at room temperature was studied for one year.Results20 mg erythromycin capsules have a beyond use date not lower than one year.Conclusion20 milligrams erythromycin capsules can be compounded in batches of 300 unities in hospital pharmacy with a beyond-use-date of one year at ambient temperature protected from light.

Published
2023
Full Text
View/download PDF

7. Dichloro{4-(4-chlorophenoxy)phthalazin-1-yl} methylphosphonic dichloride

Author

Dyhia Amrane, Omar Khoumeri, Patrice Vanelle, and Nicolas Primas

Subjects
phthalazine, chlorination, side product, phosphonic dichloride, P. falciparum, HepG2, Inorganic chemistry, QD146-197
Abstract

As part of our ongoing scaffold-hopping work on an antiplasmodial 2-trichloromethylquinazoline scaffold, we aimed to explore the 1-trichloromethylphthalazine scaffold as a potential new antimalarial series. Using previously chlorination conditions described by our lab to obtain a trichloromethyl group from a methyl group, we did not obtain the target compound; instead, we obtained a dichloro methylphosphonic dichloride side product 3. The nature of this compound was then characterized by NMR, HRMS and X-ray crystallography. The same issue was previously reported by Kato et al., starting from the 2-methyl-3-nitropyridine. Finally, compound 3, although not cytotoxic, was not active against P. falciparum, the parasite responsible for human malaria.

Published
2022
Full Text
View/download PDF

8. Stability Study of Parenteral N-Acetylcysteine, and Chemical Inhibition of Its Dimerization

Author

Nicolas Primas, Guillaume Lano, Damien Brun, Christophe Curti, Marion Sallée, Emmanuelle Sampol-Manos, Edouard Lamy, Charleric Bornet, Stéphane Burtey, and Patrice Vanelle

Subjects
N-acetylcysteine, stability study, parenteral administration, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Parenteral N-acetylcysteine has a wide variety of clinical applications, but its use can be limited by a poor chemical stability. We managed to control parenteral N-acetylcysteine stability, and to study the influence of additives on the decrease of N-acetylcysteine degradation. First, an HPLC-UV dosing method of N-acetylcysteine and its main degradation product, a dimer, was validated and the stability without additive was studied. Then, the influence of several additives (ascorbic acid, sodium edetate, tocopherol and zinc) and of temperature on N-acetylcysteine dimerization was evaluated. Finally, the influence of zinc gluconate at different concentrations (administrable to patients) was investigated. Zinc gluconate at 62.5 µg·mL−1 allows the stabilization of 25 mg·mL−1 N-acetylcysteine solution for at least 8 days when stored at 5 ± 3 °C.

Published
2023
Full Text
View/download PDF

9. 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
Full Text
View/download PDF

10. Nitro-Containing Self-Immolative Systems for Biological Applications

Author

Cédric Spitz, Nicolas Primas, Thierry Terme, and Patrice Vanelle

Subjects
self-immolation, nitro, prodrug, probe, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Since its introduction in 1981, the chemistry of self-immolative systems has received increasing attention in different application areas, such as analytical chemistry, medicinal chemistry, and materials science. This strategy is based on a stimulation that triggers a cascade of disassembling reactions leading to the release of smaller molecules. The particular reactivity of the nitro group, due to its powerful electron-withdrawing nature, has been exploited in the field of self-immolative chemistry. In this context, the present review describes the major role of the nitro group in self-immolative processes depending on its position.

Published
2022
Full Text
View/download PDF

11. 2-Cyclopropyl-6-phenyl-2,3-dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one

Author

Romain Mustière, Patrice Vanelle, and Nicolas Primas

Subjects
boron, diazaborininone, thiophene, aqueous stability, Inorganic chemistry, QD146-197
Abstract

As part of our ongoing scaffold hopping work on antimalarial 2-aminothieno[3,2-d]pyrimidin-4-one scaffold, we explored the dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one as a potential new antimalarial series. Using conditions found in the literature, we obtained 2-cyclopropyl-6-phenyl-2,3-dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one with 93% yield through a simple treatment. It was then characterized by NMR (1H and 13C) and HRMS. Given the structure of this molecule, its aqueous stability was assessed to determine its suitability for biological tests. To our knowledge, this is the first dihydrothieno[3,2-d][1,3,2]diazaborinin-4(1H)-one described.

Published
2021
Full Text
View/download PDF

12. Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore

Author

Romain Paoli-Lombardo, Nicolas Primas, Sandra Bourgeade-Delmas, Sébastien Hutter, Alix Sournia-Saquet, Clotilde Boudot, Emilie Brenot, Caroline Castera-Ducros, Sophie Corvaisier, Marc Since, Aurélie Malzert-Fréon, Bertrand Courtioux, Alexis Valentin, Pierre Verhaeghe, Nadine Azas, Pascal Rathelot, and Patrice Vanelle

Subjects
Imidazo[1,2-a]pyridine, nitroaromatic, nitroreductases, Leishmania spp., structure-activity relationships, thermodynamic solubility, Medicine, Pharmacy and materia medica, RS1-441
Abstract

An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.

Published
2022
Full Text
View/download PDF

13. 4-Substituted Thieno[3,2-d]pyrimidines as Dual-Stage Antiplasmodial Derivatives

Author

Prisca Lagardère, Romain Mustière, Nadia Amanzougaghene, Sébastien Hutter, Jean-François Franetich, Nadine Azas, Patrice Vanelle, Pierre Verhaeghe, Nicolas Primas, Dominique Mazier, Nicolas Masurier, and Vincent Lisowski

Subjects
Malaria, thienopyrimidine, erythocytic, hepatic, Plasmodium, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Malaria remains one of the major health problems worldwide. The increasing resistance of Plasmodium to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-d]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of P. falciparum and the hepatic stage of P. berghei. Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of P. falciparum, moderate toxicity on HepG2, and better activity against hepatic P. berghei parasites, compared to Gamhepathiopine.

Published
2022
Full Text
View/download PDF

14. Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives

Author

Fanny Mathias, Youssef Kabri, Damien Brun, Nicolas Primas, Carole Di Giorgio, and Patrice Vanelle

Subjects
chagas disease, T. cruzi, pyrrole, nitro-heterocycle, Organic chemistry, QD241-441
Abstract

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski’s rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC50 = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC50 = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.

Published
2022
Full Text
View/download PDF

15. 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
Full Text
View/download PDF

16. Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Author

Romain Mustière, Patrice Vanelle, and Nicolas Primas

Subjects
kinase inhibitor, Plasmodium, malaria, SAR, medicinal chemistry, Organic chemistry, QD241-441
Abstract

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.

Published
2020
Full Text
View/download PDF

17. Cross-Coupling Synthesis of Methylallyl Alkenes: Scope Extension and Mechanistic Study

Author

Clémence Tabélé, Christophe Curti, Youssef Kabri, Nicolas Primas, and Patrice Vanelle

Subjects
palladium, cross-coupling reactions, boronic acids, allyl alcohol, Organic chemistry, QD241-441
Abstract

Cross-coupling reactions between 2-methyl-2-propen-1-ol and various boronic acids are used to obtain aromatic-(2-methylallyl) derivatives. However, deboronation or isomerization side reactions may occur for several boronic acids. We describe herein the synthesis of original alkenes with good yields under mild reaction conditions that decrease these side reactions. The scope of this environmentally benign reaction is thereby extended to a wide variety of boronic acids. A mechanistic study was conducted and suggested a plausible catalytic cycle mechanism, pointing to the importance of the Lewis acidity of the boronic acid used.

Published
2015
Full Text
View/download PDF

18. Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

Author

Dyhia Amrane, Armand Gellis, Sébastien Hutter, Marion Prieri, Pierre Verhaeghe, Nadine Azas, Patrice Vanelle, and Nicolas Primas

Subjects
2-trichloromethylquinazoline, Plasmodium falciparum, in vitro HepG2 cytotoxicity, structure-activity relationships, Organic chemistry, QD241-441
Abstract

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

Published
2020
Full Text
View/download PDF

19. A New Synthetic Route to Original Sulfonamide Derivatives in 2-Trichloromethylquinazoline Series: A Structure-Activity Relationship Study of Antiplasmodial Activity

Author

Nadine Azas, Sylvain Rault, Pascal Rathelot, Sébastien Hutter, Aurélien Dumètre, Charline Kieffer, Anita Cohen, Pierre Verhaeghe, Nicolas Primas, and Patrice Vanelle

Subjects
quinazoline, trichloromethyl group, sulfonamide, microwaves, antiplasmodial activity, Organic chemistry, QD241-441
Abstract

We report herein a simple and efficient two-step synthetic approach to new 2-trichloromethylquinazolines possessing a variously substituted sulfonamide group at position 4 used to prepare new quinazolines with antiparasitic properties. Thus, an original series of 20 derivatives was synthesized, which proved to be less-toxic than previously synthesized hits on the human HepG2 cell line, but did not display significant antiplasmodial activity. A brief Structure-Activity Relationship (SAR) evaluation shows that a more restricted conformational freedom is probably necessary for providing antiplasmodial activity.

Published
2012
Full Text
View/download PDF

21. An intermolecular dative B←N bond in 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole

Author

Jana Sopková-de Oliveira Santos, Nicolas Primas, Jean-François Lohier, Alexandre Bouillon, and Sylvain Rault

Subjects
Crystallography, QD901-999
Abstract

The title compound, C9H14BNO2S, is in an unusual bend conformation and the B atom of one molecule within the crystal forms an intermolecular dative bond with the N atom of a neighbouring molecule, an infrequent phenomenon in boronic derivative crystals.

Published
2010
Full Text
View/download PDF

22. Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy

Author

Romain Mustière, Prisca Lagardère, Sébastien Hutter, Viviana Dell’Orco, Nadia Amanzougaghene, Shahin Tajeri, Jean-François Franetich, Sophie Corvaisier, Marc Since, Aurélie Malzert-Fréon, Nicolas Masurier, Vincent Lisowski, Pierre Verhaeghe, Dominique Mazier, Nadine Azas, Patrice Vanelle, Nicolas Primas, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), 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), 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), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), 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), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Fondation pour la Recherche Médicale (FRM Palukill DMC20181039565), and ANR-18-CE18-0009,plasmodrug,Développement d'un nouvel antipaludique ciblant plusieurs étapes du cycle de Plasmodium(2018)

Subjects
Pharmacology, Antimalarials, Structure-Activity Relationship, Plasmodium falciparum, Organic Chemistry, Drug Discovery, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Hep G2 Cells, General Medicine
Abstract

International audience; Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were tested on the K1 multi-resistant strain of Plasmodium falciparum and the human HepG2 cell-line, to evaluate their antiplasmodial activity and their cytotoxicity. Analogues’ biological results also highlighted the mandatory presence of a heteroatom at position 5 of the thieno[3,2-d]pyrimidin-4(3H)-one moeity for the antiplasmodial activity. However, modifications at position 7 were detrimental for the antiplasmodial activity. We identified furane bioisostere 3j as a promising candidate, showing good blood stage antiplasmodial activity, better water solubility and highly improved intestinal permeability in the PAMPA assay.

Published
2022

23. 4-Substituted Thieno[3,2

Author

Prisca, Lagardère, Romain, Mustière, Nadia, Amanzougaghene, Sébastien, Hutter, Jean-François, Franetich, Nadine, Azas, Patrice, Vanelle, Pierre, Verhaeghe, Nicolas, Primas, Dominique, Mazier, Nicolas, Masurier, and Vincent, Lisowski

Abstract

Malaria remains one of the major health problems worldwide. The increasing resistance of

Published
2022

24. Stability Studies of Fludrocortisone Acetate Capsules and Fludrocortisone Acetate Titrated Powders (Powder Triturates)

Author

Thibaut, Brandin, Maya, Wasilewski, Camille, Panuccio, Cyrielle, Bouguergour, Nicolas, Primas, Edouard, Lamy, Christophe, Jean, Pierre, Bertault-Peres, Pascal, Rathelot, Christophe, Curti, and Patrice, Vanelle

Subjects
Drug Stability, Emollients, Drug Compounding, Fludrocortisone, Humans, Capsules, Powders, Child
Abstract

Fludrocortisone acetate is a drug used to treat adrenal insufficiencies which can be prescribed to hospitalized or ambulatory pediatric patients at dosages not commercially available. For these patients, 10-µg fludrocortisone capsules are currently compounded from a pre-compounded titrated powder (powder triturate). Fludrocortisone stability studies were carried out to ensure a valid beyond-use date. First, a stability-indicating fludrocortisone acetate dosing method was validated. Then fludrocortisone acetate 10-µg capsules and 1% fludrocortisone acetate titrated powders (powder triturates) were realized. Finally, stability studies were performed. The fludrocortisone acetate titrated powders (powder triturates) were stable for one year at controlled ambient temperature and protected from light, whereas 10-µg fludrocortisone acetate capsules were stable for six months. One year after, even if the fludrocortisone content remained conformed, an increase in product degradation was noted. Our work allowed us to determine a six-month beyond-use date for fludrocortisone acetate titrated powder (powder triturate) with the three most commonly used excipients for capsule compounding. We also confirmed the sixmonth theoretical stability for capsules.

Published
2022

25. Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives

Author

Vanelle, Fanny Mathias, Youssef Kabri, Damien Brun, Nicolas Primas, Carole Di Giorgio, and Patrice

Subjects
parasitic diseases, chagas disease, T. cruzi, pyrrole, nitro-heterocycle
Abstract

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski’s rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC50 = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC50 = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.

Published
2022
Full Text
View/download PDF

26. Synthesis and Anti

Author

Fanny, Mathias, Youssef, Kabri, Damien, Brun, Nicolas, Primas, Carole, Di Giorgio, and Patrice, Vanelle

Subjects
Structure-Activity Relationship, Cricetulus, Cricetinae, Trypanosoma cruzi, Animals, Humans, Chagas Disease, Pyrroles, Trypanocidal Agents
Abstract

Human American trypanosomiasis, called Chagas disease, caused by

Published
2022

27. Paediatric capsule compounding in hospital practices: by weight or by volume?

Author

Maya Wasilewski, Christophe Curti, Cyrielle Bouguergour, Camille Panuccio, Patrick Thevin, Nicolas Primas, Edouard Lamy, and Patrice Vanelle

Subjects
General Pharmacology, Toxicology and Pharmaceutics
Abstract

Capsule compounding is common for paediatric patients. In Europe, pharmacists often use a volume-based method whereas, in the USA, the weight-based method prevails. These two methods should be compared in order to help hospital pharmacists to make their choice.We evaluated the difference between the volume-based method and the weight-based method with 10 mg spironolactone capsules. Six independent batches were made with each technique and their conformity was evaluated with a high-performance liquid chromatography assay.The weight-based method showed superiority over the volume-based method for the following parameters: spironolactone content homogeneity, total weight content homogeneity, batch reproducibility and batch conformity. No differences were seen in spironolactone content between the two methods, but an overall trend towards underweighing the excipient was found with the volume-based method.Capsule compounding with the weight-based method increases the quality of the resulting formulation. The weight-based method requires knowledge of the galenic parameters of the active pharmaceutical ingredient and excipients, but should be preferred to the volume-based method.

Published
2021

28. Antiplasmodial 2-thiophenoxy-3-trichloromethyl quinoxalines target the apicoplast of Plasmodium falciparum

Author

Nadia Amanzougaghene, Beatrice Louis, Pierre Verhaeghe, Dyhia Amrane, Amaya Azqueta, Sébastien Hutter, Christophe-Sébastien Arnold, Julen Sanz-Serrano, Patrice Vanelle, Nadine Azas, Cyrille Y. Botté, Nicolas Primas, Shahin Tajeri, Dominique Mazier, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Hôpital de la Conception - APHM] (CIC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), CHU Toulouse [Toulouse], Fondation pour la Recherche Médicale [grant number DCM20181039565], ANR-17-CE11-0017,NINTARMAL,Nouveaux inhibiteurs de Pfrab6 et PfpyrK1 ciblant le paludisme(2017), Pharmaceutical and Pharmacological Sciences, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre d'Immunologie et des Maladies Infectieuses (CIMI), 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 Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Quinoxaline, Plasmodium falciparum, Structure-activity relationships, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Apicoplasts, Plasmodium, 03 medical and health sciences, Structure-Activity Relationship, Quinoxalines, Apicoplast, Drug Discovery, medicine, Humans, Cytotoxicity, Trichloromethyl goup, 030304 developmental biology, Pharmacology, 0303 health sciences, In vitro antiplasmodial activity, biology, 030306 microbiology, Chemistry, Chinese hamster ovary cell, Organic Chemistry, General Medicine, biology.organism_classification, 3. Good health, Biochemistry, Mechanism of action, Biological target, medicine.symptom, Biogenesis
Abstract

International audience; The identification of a plant-like Achille's Heel relict, i.e. the apicoplast, that is essential for Plasmodium spp., the causative agent of malaria lead to an attractive drug target for new antimalarials with original mechanism of action. Although it is not photosynthetic, the apicoplast retains several anabolic pathways that are indispensable for the parasite. Based on previously identified antiplasmodial hit-molecules belonging to the 2-trichloromethylquinazoline and 3-trichloromethylquinoxaline series, we report herein an antiplasmodial Structure-Activity Relationships (SAR) study at position two of the quinoxaline ring of 16 newly synthesized compounds. Evaluation of their activity toward the multi-resistant K1 Plasmodium falciparum strain and cytotoxicity on the human hepatocyte HepG2 cell line revealed a hit compound (3k) with a PfK1 EC50 value of 0.3 μM and a HepG2 CC50 value of 56.0 μM (selectivity index = 175). Moreover, hit-compound 3k was not cytotoxic on VERO or CHO cell lines and was not genotoxic in the in vitro comet assay. Activity cliffs were observed when the trichloromethyl group was replaced by CH3, CF3 or H, showing that this group played a key role in the antiplasmodial activity. Biological investigations performed to determine the target and mechanism of action of the compound 3k strongly suggest that the apicoplast is the putative target as showed by severe alteration of apicoplaste biogenesis and delayed death response. Considering that there are very few molecules that affect the Plasmodium apicoplast, our work provides, for the first time, evidence of the biological target of trichloromethylated derivatives.

Published
2021

29. 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

30. Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

Author

Alexis Valentin, Pierre Verhaeghe, Patrice Vanelle, Sophie Corvaisier, Damián Muruzabal, Caroline Castera-Ducros, Nadine Azas, Sébastien Hutter, Emilie Pinault, Alexandre Destere, Alan H. Fairlamb, Clotilde Boudot, Cyril Fersing, Pascal Rathelot, Susan Wyllie, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Aurélie Malzert-Fréon, Julien Pedron, Bertrand Courtioux, Amaya Azqueta, Marc Since, Jean Luc Stigliani, Nicolas Primas, Carole Di Giorgio, Youssef Kabri, Romain Paoli-Lombardo, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Biologie Intégrative Santé Chimie Environnement (BISCEm), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), 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), 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), 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), Universidad de Navarra [Pamplona] (UNAV), CHU Limoges, University of Dundee, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), and Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS)

Subjects
SARs, Imidazopyridine, Pyridines, Trypanosoma brucei brucei, Redox potentials, Trypanosoma brucei, Pharmacology, 01 natural sciences, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, 03 medical and health sciences, Nitroreductase, chemistry.chemical_compound, Nitroaromatic, Parasitic Sensitivity Tests, Pharmacokinetics, Drug Discovery, Animals, Humans, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Serum Albumin, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Drug discovery, Organic Chemistry, Imidazoles, Kinetoplastids, Hep G2 Cells, General Medicine, Hit to lead, Nitroreductases, biology.organism_classification, Trypanocidal Agents, 0104 chemical sciences, 3. Good health, Imidazo[1 2-a]pyridine, Imidazo[1,2-a]pyridine, Pharmacophore, DNA Damage, Fexinidazole
Abstract

International audience; To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.

Published
2020

31. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Author

Line Seguy, Cyril Fersing, Sébastien Hutter, Marc Since, Alexandre Destere, Bertrand Courtioux, Julien Pedron, Sophie Corvaisier, Elisa Boutet-Robinet, Pascal Rathelot, Alexis Valentin, Alix Sournia-Saquet, Jean Yves Brossas, Caroline Castera-Ducros, Dominique Mazier, Sandra Bourgeade-Delmas, Aurélie Malzert-Fréon, Susan Wyllie, Romain Paoli-Lombardo, Clotilde Boudot, Patrice Vanelle, Jean Luc Stigliani, Nicolas Primas, Luc Paris, Nadine Azas, Emilie Pinault, Pierre Verhaeghe, Alan H. Fairlamb, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Biologie Intégrative Santé Chimie Environnement (BISCEm), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), 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), 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), 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), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Dundee, Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), CHU Limoges, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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 de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées, Service de Parasitologie - Mycologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Aix-Marseille Université, Université de Toulouse, CNRS, CCSD, Accord Elsevier, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), 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), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN)

Subjects
SARs, Pyridines, Stereochemistry, Trypanosoma cruzi, [SDV]Life Sciences [q-bio], Trypanosoma brucei brucei, Sonogashira coupling, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Nitroaromatic, Parasitic Sensitivity Tests, Drug Discovery, medicine, Moiety, Cytotoxicity, Comet assay, Imidazo[1, 030304 developmental biology, Pharmacology, 0303 health sciences, 2-a]pyridine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Kinetoplastids, General Medicine, Nitroreductases, Trypanocidal Agents, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], Nitroimidazoles, Benznidazole, Pharmacophore, Lead compound, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Imidazo[1,2-alpha]pyridine, Fexinidazole, medicine.drug
Abstract

International audience; An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.

Published
2020

32. The Renewal of Interest in Nitroaromatic Drugs

Author

Pierre Verhaeghe, Caroline Ducros, Patrice Vanelle, and Nicolas Primas

Subjects
Flavin adenine dinucleotide, chemistry.chemical_classification, Nitrofurazone, biology, Flavin mononucleotide, Biological activity, Nicotinamide adenine dinucleotide, Cofactor, chemistry.chemical_compound, Enzyme, Biochemistry, chemistry, biology.protein, Nicotinamide adenine dinucleotide phosphate
Abstract

In the 1940s, nitroaromatic compounds showed their potential as chemotherapeutic agents. Many furans were synthesized as part of the search for new antibacterials. Though nitrofurazone did not find applications in the treatment of neglected tropical diseases, its structure encouraged the industry to synthesize and test numerous nitro-containing heterocycles. Nitroreductases cover a family of proteins whose first members were discovered in eubacteria and were classified by sequence similarities. These enzymes can catalyze the reduction of nitroaromatics by using flavin mononucleotide or flavin adenine dinucleotide as prosthetic groups, and nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate as reducing agents. The chapter presents a survey of the recent literature concerning anti-kinetoplastid nitroaromatics. In the survey, the molecules are presented according to their biological activity: antichagasic derivatives, anti-Trypanosoma brucei derivatives and antileishmanial derivatives.

Published
2019

33. Nongenotoxic 3-Nitroimidazo[1,2

Author

Cyril, Fersing, Louise, Basmaciyan, Clotilde, Boudot, Julien, Pedron, Sébastien, Hutter, Anita, Cohen, Caroline, Castera-Ducros, Nicolas, Primas, Michèle, Laget, Magali, Casanova, Sandra, Bourgeade-Delmas, Mélanie, Piednoel, Alix, Sournia-Saquet, Valère, Belle Mbou, Bertrand, Courtioux, Élisa, Boutet-Robinet, Marc, Since, Rachel, Milne, Susan, Wyllie, Alan H, Fairlamb, Alexis, Valentin, Pascal, Rathelot, Pierre, Verhaeghe, Patrice, Vanelle, and Nadine, Azas

Subjects
parasitic diseases
Abstract

[Image: see text] Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC(50) > 100 μM) alongside good antileishmanial activities (IC(50) = 1–2.1 μM) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC(50) = 1.3–2.2 μM) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC(50) = 0.6 to 13.3 μM). Molecule 5, presenting a low reduction potential (E° = −0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.

Published
2018

34. 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a] pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Author

Maxime D. Crozet, Alan H. Fairlamb, Geneviève Pratviel, Alexis Valentin, Pascal Rathelot, Alix Sournia-Saquet, Clotilde Boudot, Anita Cohen, Patrice Vanelle, Julien Pedron, Jean-Luc Stigliani, Sandra Bourgeade-Delmas, Susan Wyllie, Pierre Verhaeghe, Nadine Azas, Caroline Castera-Ducros, Cyril Fersing, Alain Moreau, Sébastien Hutter, Nicolas Primas, Bertrand Courtioux, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), 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), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), 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), 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), Department of Biochemistry, Medical Sciences Institute, Dundee University, Dundee, 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 Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), and Université de Toulouse (UT)

Subjects
Models, Molecular, 0301 basic medicine, SARs, Redox potentials, HepG2 cytotoxicity, Crystallography, X-Ray, MESH: Parasitic Sensitivity Tests, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Parasitic Sensitivity Tests, In vitro activity, Drug Discovery, Nitroheterocycles, Moiety, MESH: Trypanocidal Agents, Imidazo[1, Leishmania, 2-a]pyridine, Molecular Structure, MESH: Drug Screening Assays, Antitumor, Hep G2 Cells, General Medicine, Trypanocidal Agents, 3. Good health, MESH: Nitroreductases, MESH: Cell Survival, Imidazo[1,2-a]pyridine, Pharmacophore, MESH: Models, Molecular, Trypanosoma, MESH: Cell Line, Tumor, Cell Survival, Stereochemistry, Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, 030106 microbiology, MESH: Molecular Structure, Substituent, Antineoplastic Agents, MESH: Hep G2 Cells, Article, Structure-Activity Relationship, 03 medical and health sciences, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Humans, Amastigote, Cell Proliferation, Pharmacology, MESH: Humans, MESH: Leishmania donovani, Dose-Response Relationship, Drug, Aryl, Organic Chemistry, MESH: Trypanosoma brucei brucei, Nitroreductases, MESH: Crystallography, X-Ray, 030104 developmental biology, chemistry, Nitro, Suzuki-Miyaura cross-coupling reaction, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Screening Assays, Antitumor, Leishmania donovani, Fexinidazole
Abstract

International audience; Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

Published
2018

35. Discovery of new hit-molecules targeting Plasmodium falciparum through a global SAR study of the 4-substituted-2-trichloromethylquinazoline antiplasmodial scaffold

Author

Sébastien Hutter, Nadine Azas, Nicolas Primas, Pascal Rathelot, Patrice Vanelle, Justine Desroches, Charline Kieffer, Armand Gellis, Hussein El-Kashef, Pierre Verhaeghe, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Department of Chemistry, Assiut University, 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), AMU, CNRS, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), 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 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), and 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)

Subjects
Quinoxaline, Stereochemistry, Cell Survival, Plasmodium falciparum, Quinoline, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Sensitivity and Specificity, Structure-Activity Relationships, chemistry.chemical_compound, Antimalarials, Structure-Activity Relationship, Drug Discovery, Quinazoline, Structure–activity relationship, Moiety, Humans, In vitro HepG2 cytotoxicity, Trichloromethyl goup, Pharmacology, In vitro antiplasmodial activity, biology, 010405 organic chemistry, Drug discovery, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, General Medicine, Hep G2 Cells, biology.organism_classification, Combinatorial chemistry, 0104 chemical sciences, 3. Good health, Thienopyrimidine, chemistry, Quinazolines, Pharmacophore
Abstract

International audience; From 4 antiplasmodial hit-molecules identified in 2-trichloromethylquinazoline series, we conducted a global Structure-Activity relationship (SAR) study involving 26 compounds and covering 5 molecular regions (I – V), aiming at defining the corresponding pharmacophore and identifying new bioactive derivatives. Thus, after studying the aniline moiety in detail, thienopyrimidine, quinoline and quinoxaline bio-isosters were synthesized and tested on the K1 multi-resistant P. falciparum strain, along with a cytotoxicity evaluation on the human HepG2 cell line, to define selectivity indecies. SARs first showed that thienopyrimidines and quinolines were globally more cytotoxic, while quinoxaline analogs appeared as active asandless cytotoxic than their quinazoline counterparts. Such pharmacomodulation in quinoxaline series not only provided a new antiplasmodial reference hit-molecule (IC50 = 0.4 μM, selectivity index = 100), but also highlighted an active (IC50 = 0.4 μM) and quite selective (SI = 265) synthesis intermediate.

Published
2017

36. A new DMAP-catalyzed and microwave-assisted approach for introducing heteroarylamino substituents at position-4 of the quinazoline ring

Author

Michel Giorgi, Pierre Verhaeghe, Patrice Vanelle, Charline Kieffer, Nicolas Primas, Armand Gellis, Gilles Lanzada, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Spectropôle - Aix Marseille Université (AMU SPEC), Aix Marseille Université (AMU)-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), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), 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), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Organic Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Reaction intermediate, Ring (chemistry), Biochemistry, Combinatorial chemistry, Toluene, Catalysis, chemistry.chemical_compound, DMAP, Nucleophile, Nucleophilic aromatic substitution, Drug Discovery, Quinazoline, Moiety, Heteroaryl moiety, Pharmaceutical chemistry, Microwave, Quinazoline ring
Abstract

International audience; We report herein a new methodology for synthesizing quinazoline derivatives bearing an heteroarylamino moiety at position 4 of the quinazoline ring. As an alternative to the Buchwald-Hartwig cross-coupling reaction which appears, until now, as the only efficient way to react 4-chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol% of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2-substitued-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest.

Published
2014

37. Exploring the Synthesis and the Reactivity of 4-[4-(Chloromethyl)styryl]-1,2-dimethyl-5-nitro-1H-imidazole in TDAE Strategy

Author

Thierry Terme, Maxime D. Crozet, Kevin Neilde, Nicolas Primas, Youssef Kabri, and Patrice Vanelle

Subjects
chemistry.chemical_compound, Nitroimidazole, Ethylene, chemistry, Organic Chemistry, Electrophile, Nitro, Imidazole, Reactivity (chemistry), Medicinal chemistry, Catalysis, Carbanion, Stille reaction
Abstract

We describe herein the preparation of 4-[4-(chloromethyl)styryl]-1,2-dimethyl-5-nitro-1 H -imidazole via a Stille cross-­coupling reaction. After determining the best reaction conditions, we investigated the reactivity of this activated chloromethyl compound in a TDAE [tetrakis(dimethylamino)ethylene] strategy toward 10 various electrophiles, obtaining 4-(4-substituted)styryl-1,2-dimethyl-5-nitro-1 H -imidazoles in moderate to good yields.

Published
2013

38. Looking for new antiplasmodial quinazolines: DMAP-catalyzed synthesis of 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines and their in vitro evaluation toward Plasmodium falciparum

Author

Pierre Verhaeghe, Nadine Azas, Vincent Remusat, Armand Gellis, Sébastien Hutter, Gilles Lanzada, Nicolas Primas, Patrice Vanelle, Institut de Chimie Radicalaire (ICR), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), 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), AMU, CNRS, Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, 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), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
SARs, Time Factors, Stereochemistry, Pyridines, Plasmodium falciparum, Substituent, 4-benzyloxyquinazoline, HepG2 cytotoxicity, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Chemistry Techniques, Synthetic, antiplasmodial activity, 010402 general chemistry, SNAr reaction, 01 natural sciences, Catalysis, microwave-assisted chemistry, chemistry.chemical_compound, Antimalarials, Structure-Activity Relationship, Nucleophile, DMAP-catalysis, Drug Discovery, Quinazoline, Moiety, Molecule, 2-trichloromethylquinazoline, Humans, Phenols, Pharmacology, 4-phenoxyquinazoline, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, General Medicine, Hep G2 Cells, In vitro, 0104 chemical sciences, chemistry, Drug Design, Quinazolines, Selectivity
Abstract

International audience; A DMAP catalyzedsynthesis of new 4-benzyloxy-and 4-aryloxy-2-trichloromethylquinazolines was studied, in a view to react 4-chloroquinazolines with poorly nucleophilic alcohols such as benzylic alcohols, via a simple and cheapS N Ar reaction approach. A fast (1 h) general operating procedure, affording good reaction yields,was achieved under microwave irradiation. Thus, a series of 35 molecules was obtained and evaluated in vitro on the K1 multi-resistant P. falciparum strain, in parallel with a cytotoxicity assessment on the human HepG2 cell line. 5 hit-molecules were identified, presenting both promising antiplasmodial activity (1.5 µM < IC 50 < 2 µM) and low cytotoxicities (25 µM < CC 50 < 45 µM). Apart for 2 molecules, the global series displayed a satisfying solubility in the aqueous biological media. Structure-activity relationships showed that the molecules presenting a benzyloxy moiety were less cytotoxic than the ones bearing a phenoxy moiety at position 4 of the quinazoline ring. It also appeared that the introduction of a heteroaryl moiety afforded inactive compounds. Finally, the most active and selective molecules (Selectivity index = 22-27) were the ones presenting either an unsubstituted benzyloxy group or a phenoxy group, this last bearing a p-bromo or an o-acetyl substituent. Highlights:► The DMAP-catalyzed S N Ar reactionbetween 4-chloro-2-trichloromethylquinazoline and various alcohols or phenols was studied. ► A series of 35 new quinazolineswas synthesized in good yields. ►In vitroevaluationwas made on Plasmodium falciparum.► 5 selective antiplasmodial hit molecules were identified.

Published
2016

39. ChemInform Abstract: An Efficient Method for the Synthesis of 2-Methylallyl Alkenes by Cross-Coupling Reactions

Author

Vincent Remusat, Patrice Vanelle, Nicolas Primas, Youssef Kabri, Christophe Curti, and Clémence Tabélé

Subjects
Solvent, chemistry.chemical_compound, Allylic rearrangement, chemistry, Yield (chemistry), Functional group, chemistry.chemical_element, Substrate (chemistry), Reactivity (chemistry), General Medicine, Combinatorial chemistry, Coupling reaction, Palladium
Abstract

To obtain aromatic 2-methylallyl derivatives, cross-coupling reactions between 2-methyl-2-propen-1-ol and various boronic acids were studied. Among allylic alcohols described for such cross-coupling reactions, 2-methyl-2-propen-1-ol has a low reactivity. Indeed, this substrate did not react with several boronic acids under the previously described conditions and new reaction conditions were investigated. We describe herein a new protocol with small amounts of palladium and ligand, without any additive solvent and under microwave heating. A subsequent simple distillation process not only leads to the product, but also allows the ‘reagent–solvent’ to be recycled for further cross-coupling reactions, without loss of yield. Scope and limitations were studied. Furthermore, when this easy cross-coupling reaction was extended to a wide range of organoboronic acids, high functional group tolerance was observed and a new series of alkenes was synthesized in good yields.

Published
2016

40. Cross-Coupling Synthesis of Methylallyl Alkenes: Scope Extension and Mechanistic Study

Author

Vanelle, Clémence Tabélé, Christophe Curti, Youssef Kabri, Nicolas Primas, and Patrice

Subjects
inorganic chemicals, palladium, cross-coupling reactions, boronic acids, allyl alcohol
Abstract

Cross-coupling reactions between 2-methyl-2-propen-1-ol and various boronic acids are used to obtain aromatic-(2-methylallyl) derivatives. However, deboronation or isomerization side reactions may occur for several boronic acids. We describe herein the synthesis of original alkenes with good yields under mild reaction conditions that decrease these side reactions. The scope of this environmentally benign reaction is thereby extended to a wide variety of boronic acids. A mechanistic study was conducted and suggested a plausible catalytic cycle mechanism, pointing to the importance of the Lewis acidity of the boronic acid used.

Published
2015
Full Text
View/download PDF

41. Triazine-fused β-carbolines: a facile three-step, one-pot synthesis of novel 2-alkyl(aryl)amino and 2-dialkylamino-7H-[1,3,5]triazino [1',2':1,6]pyrido[3,4-b]indol-4-ones

Author

Robert H. Dodd, Nicolas Primas, Jean-Charles Lancelot, Hussein El-Kashef, Aurélien Lesnard, and Sylvain Rault

Subjects
chemistry.chemical_classification, Chemistry, Stereochemistry, Aryl, Organic Chemistry, One-pot synthesis, Ring (chemistry), Medicinal chemistry, lcsh:QD241-441, chemistry.chemical_compound, lcsh:Organic chemistry, Isothiocyanate, Amination, Alkyl, Triazine
Abstract

A straightforward approach to novel fused β-carbolines namely (1,3,5)triazino (1',2':1,6)pyrido(3,4-b)indol-4-ones is presented. The construction of these compounds was achieved by one-pot synthesis involving condensation of 3-amino-β-carbolines with ethoxycarbonyl isothiocyanate followed by amination of the resulting thioureas and finally thermal ring closure of the resulting guanidines which allowed access to the unreported title heterocycles.

Published
2010

42. Synthesis of 2-TIPS-oxazol-5-ylboronic acid pinacol ester: efficient route to 5-(het)aryloxazoles via Suzuki cross-coupling reaction

Author

Alexandre Bouillon, Nicolas Primas, Jean-Charles Lancelot, and Sylvain Rault

Subjects
Chemistry, Pinacol, Aryl, Organic Chemistry, Biochemistry, Chemical synthesis, Coupling reaction, chemistry.chemical_compound, Suzuki reaction, Drug Discovery, Moiety, Organic chemistry, Reactivity (chemistry), Oxazole
Abstract

A facile synthetic route to the new 2-TIPS-oxazol-5-ylboronic acid pinacol ester was described herein. Its reactivity toward Suzuki cross-coupling reaction was studied to provide various 5-(het)aryloxazoles. A wide range of functions on the aryl moiety are tolerated.

Published
2009

43. Synthesis of 5-arylthiazoles. Comparative study between Suzuki cross-coupling reaction and direct arylation

Author

Jean-Charles Lancelot, Hussein El-Kashef, Alexandre Bouillon, Sylvain Rault, and Nicolas Primas

Subjects
Chemistry, Pinacol, Organic Chemistry, Ring (chemistry), Biochemistry, Chemical synthesis, Coupling reaction, Catalysis, chemistry.chemical_compound, Suzuki reaction, Drug Discovery, Organic chemistry, Reactivity (chemistry), Thiazole
Abstract

A facile synthetic route to the new thiazol-5-ylboronic acid pinacol ester was described herein. Its reactivity toward Suzuki cross-coupling reaction was studied to provide various 5-arylthiazoles. A comparative study between Suzuki cross-coupling reactions and palladium-catalyzed C5–H direct arylation on thiazole ring was achieved.

Published
2009

44. A new boronic-acid based strategy to synthesize 4(5)-(het)aryl-1H-imidazoles

Author

Sylvain Rault, Jean-François Lohier, Jana Sopkova‐de Oliveira Santos, Nicolas Primas, Clément Mahatsekake, Jean-Charles Lancelot, and Alexandre Bouillon

Subjects
chemistry.chemical_compound, chemistry, Pinacol, Aryl, Organic Chemistry, Drug Discovery, Halide, Imidazole, Biochemistry, Combinatorial chemistry, Boronic acid
Abstract

This paper describes the synthesis of a new N-THP protected 5-(1H)-imidazolyl boronic acid pinacol ester and its use in Suzuki cross-coupling reactions with a wide range of (het)aryl halides to provide 4(5)-(het)aryl-1H-imidazoles.

Published
2008

45. An Efficient Method for the Synthesis of 2-Methylallyl Alkenes by Cross-Coupling Reactions

Author

Nicolas Primas, Vincent Remusat, Youssef Kabri, Clémence Tabélé, Patrice Vanelle, Christophe Curti, Institut de Chimie Radicalaire (ICR), and Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Allylic rearrangement, Allyl alcohol, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, chemistry.chemical_element, Substrate (chemistry), 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, Catalysis, Coupling reaction, 0104 chemical sciences, chemistry.chemical_compound, Boronic acid, chemistry, Suzuki reaction, Yield (chemistry), Functional group, Organic chemistry, Reactivity (chemistry), Cross-coupling reaction, Palladium
Abstract

International audience; To obtain aromatic 2-methylallyl derivatives, cross-coupling reactions between 2-methyl-2-propen-1-ol and various boronic acids were studied. Among allylic alcohols described for such cross-coupling reactions, 2-methyl-2-propen-1-ol has a low reactivity. Indeed, this substrate did not react with several boronic acids under the previously described conditions and new reaction conditions were investigated. We describe herein a new protocol with small amounts of palladium and ligand, without any additive solvent and under microwave heating. A subsequent simple distillation process not only leads to the product, but also allows the ‘reagent–solvent’ to be recycled for further cross-coupling reactions, without loss of yield. Scope and limitations were studied. Furthermore, when this easy cross-coupling reaction was extended to a wide range of organoboronic acids, high functional group tolerance was observed and a new series of alkenes was synthesized in good yields

Published
2015

46. ChemInform Abstract: A New DMAP-Catalyzed and Microwave-Assisted Approach for Introducing Heteroarylamino Substituents at Position-4 of the Quinazoline Ring

Author

Michel Giorgi, Armand Gellis, Nicolas Primas, Patrice Vanelle, Charline Kieffer, Gilles Lanzada, and Pierre Verhaeghe

Subjects
chemistry.chemical_compound, chemistry, Quinazoline, Organic chemistry, General Medicine, Ring (chemistry), Combinatorial chemistry, Microwave assisted, Catalysis
Abstract

A broad variety of hetarylamines and anilines reacted with 2-trichloro-4-chloroquinazoline (II) to give corresponding 4-aminated compounds in varying yields.

Published
2015

47. ChemInform Abstract: Exploring the Synthesis and the Reactivity of 4-[4-(Chloromethyl)styryl]-1,2-dimethyl-5-nitro-1H-imidazole in TDAE Strategy

Author

Youssef Kabri, Maxime D. Crozet, Patrice Vanelle, Kevin Neilde, Nicolas Primas, and Thierry Terme

Subjects
chemistry.chemical_compound, Chemistry, Nitro, Organic chemistry, Imidazole, Reactivity (chemistry), General Medicine, Stannane, Stille reaction
Abstract

The synthesis of the title species (IV) is based on Stille cross-coupling of stannane (I) with 4-bromoimidazole (II) followed by deprotection and chlorination.

Published
2014

48. New series of monoamidoxime derivatives displaying versatile antiparasitic activity

Author

Ahlem Bouhlel, Patrice Vanelle, Nicolas Primas, Vincent Remusat, Sébastien Hutter, Thierry Terme, Anita Cohen, Christophe Curti, Clémence Tabélé, Nadine Azas, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), AMU, CNRS, and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées

Subjects
Spectrometry, Mass, Electrospray Ionization, Stereochemistry, Antiparasitic, medicine.drug_class, Manganese(III) acetate, Leishmania donovani, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Coupling reaction, Inhibitory Concentration 50, chemistry.chemical_compound, Oximes, Drug Discovery, parasitic diseases, Dihydrofuran, medicine, Phenyl group, Antiprotozoan activity in vitro, Carbon-13 Magnetic Resonance Spectroscopy, Cytotoxicity in vitro, Pharmacology, Antiparasitic Agents, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, General Medicine, biology.organism_classification, Amidoximes, chemistry, Wittig reaction, Pharmacomodulation, Palladium-catalyzed coupling reactions, Pharmacophore
Abstract

International audience; Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R1, R2 or R3 substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 μM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 μM). Modulating chemical substituents in R2 and R3 only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.

Published
2014

49. A New Methodology to Prepare 2-Halogenoimidazoles via a N-THP Protection

Author

Jean-Charles Lancelot, Jana Sopkova-de Oliveira Santos, Nicolas Primas, Alexandre Bouillon, Sylvain Rault, and Jean-François Lohier

Subjects
chemistry.chemical_compound, chemistry, Organic Chemistry, Electrophile, Imidazole, lipids (amino acids, peptides, and proteins), hemic and immune systems, Protecting group, Biochemistry, Combinatorial chemistry
Abstract

A straightforward access to 2-halogenoimidazoles via a N-THP protection was described in this paper. The NTHP protecting group is easily introduced by reaction of 2-chloro-THP with imidazole. Lithiation followed by reaction with an appropriate electrophile affords 2-halogeno N-THP derivatives. The THP protecting group is then cleaved to get the title compounds in good to high yields.

Published
2008

50. ChemInform Abstract: One-Pot Chemoselective Bis(Suzuki-Miyaura Cross-Coupling): Efficient Access to 3,9-Bis[(hetero)aryl]-4H-pyrido[1,2-a]pyrimidin-4-one Derivatives under Microwave Irradiation

Author

Youssef Kabri, Patrice Vanelle, Nicolas Primas, and Maxime D. Crozet

Subjects
Coupling (electronics), chemistry.chemical_compound, Chemistry, Aryl, Microwave irradiation, Polymer chemistry, General Medicine, Ring (chemistry)
Abstract

The different reactivities of the ring positions in compound (I) allow for chemoselective one-pot double Suzuki-Miyaura cross-coupling reactions.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results