Author: "Patrick, Dallemagne" - Searchworks@Jio Institute Digital Library Search Results

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195 results on '"Patrick, Dallemagne"'

1. Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy

Author: Maxime Mistretta, Mena Cimino, Pascal Campagne, Stevenn Volant, Etienne Kornobis, Olivier Hebert, Christophe Rochais, Patrick Dallemagne, Cédric Lecoutey, Camille Tisnerat, Alban Lepailleur, Yann Ayotte, Steven R. LaPlante, Nicolas Gangneux, Monika Záhorszká, Jana Korduláková, Sophie Vichier-Guerre, Frédéric Bonhomme, Laura Pokorny, Marvin Albert, Jean-Yves Tinevez, and Giulia Manina
Subjects: Science
Abstract: Abstract Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective antimicrobial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. In this work, we develop a multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells during transitions between separate environmental conditions. With this platform, we implement a dynamic single-cell screening for pheno-tuning compounds, which induce a phenotypic change and decrease cell-to-cell variation, aiming to undermine the entire bacterial population and make it more vulnerable to other drugs. We apply this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our lead compound impairs Mycobacterium tuberculosis via a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that harnessing phenotypic variation represents a successful approach to tackle pathogens that are increasingly difficult to treat.
Published: 2024
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2. A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity

Author: Alaa Al Assi, Solène Posty, Frédéric Lamarche, Amel Chebel, Jérôme Guitton, Cécile Cottet-Rousselle, Renaud Prudent, Laurence Lafanechère, Stéphane Giraud, Patrick Dallemagne, Peggy Suzanne, Aurélie Verney, Laurent Genestier, Marie Castets, Eric Fontaine, Marc Billaud, and Martine Cordier-Bussat
Subjects: Cytology, QH573-671
Abstract: Abstract Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.
Published: 2024
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3. Inducing neuronal regeneration and differentiation via the BDNF/TrkB signaling pathway: a key target against neurodegenerative diseases?

Author: Mirjana Antonijevic, Patrick Dallemagne, and Christophe Rochais
Subjects: Neurology. Diseases of the nervous system, RC346-429
Published: 2024
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4. Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

Author: Mirjana Antonijevic, Despoina Charou, Audrey Davis, Thomas Curel, Maria Valcarcel, Isbaal Ramos, Patricia Villacé, Sylvie Claeysen, Patrick Dallemagne, Achille Gravanis, Ioannis Charalampopoulos, and Christophe Rochais
Subjects: neurodegeneration, TrkB receptor, 5-HT4 receptor, neuronal survival, neurite differentiation, Organic chemistry, QD241-441
Abstract: One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders.
Published: 2024
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5. Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Author: Thomas Guiselin, Cédric Lecoutey, Christophe Rochais, and Patrick Dallemagne
Subjects: drug, pleiotropic, neurodegeneration, Alzheimer’s disease, Pharmacy and materia medica, RS1-441
Abstract: The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.
Published: 2023
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6. C3-Symmetric Ligands in Drug Design: When the Target Controls the Aesthetics of the Drug

Author: Mirjana Antonijevic, Christophe Rochais, and Patrick Dallemagne
Subjects: symmetry, C3, homo-trimeric, drug design, Organic chemistry, QD241-441
Abstract: A number of proteins are able to adopt a homotrimeric spatial conformation. Among these structures, this feature appears as crucial for biologic targets, since it facilitates the design of C3-symmetric ligands that are especially suitable for displaying optimized ligand–target interactions and therapeutic benefits. Additionally, DNA as a therapeutic target, even if its conformation into a superhelix does not correspond to a C3-symmetry, can also take advantage of these C3-symmetric ligands for better interactions and therapeutic effects. For the moment, this opportunity appears to be under-exploited, but should become more frequent with the discovery of new homotrimeric targets such as the SARS-CoV2 spike protein. Besides their potential therapeutic interest, the synthetic access to these C3-symmetric ligands often leads to chemical challenges, although drug candidates with an aesthetic structure are generally obtained.
Published: 2023
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7. Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation

Author: Rim Malek, Alexey Simakov, Audrey Davis, Maciej Maj, Paul J. Bernard, Artur Wnorowski, Helene Martin, José Marco-Contelles, Fakher Chabchoub, Patrick Dallemagne, Christophe Rochais, Krzysztof Jozwiak, and Lhassane Ismaili
Subjects: Biginelli reaction, multitarget-directed ligands, calcium channel antagonism, Nrf2, Organic chemistry, QD241-441
Abstract: Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
Published: 2022
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8. New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease

Author: Nicolas Sergeant, Valérie Vingtdeux, Sabiha Eddarkaoui, Marion Gay, Caroline Evrard, Nicolas Le Fur, Cyril Laurent, Raphaelle Caillierez, Hélène Obriot, Paul-Emmanuel Larchanché, Amaury Farce, Mathilde Coevoet, Pascal Carato, Mostafa Kouach, Amandine Descat, Patrick Dallemagne, Valérie Buée-Scherrer, David Blum, Malika Hamdane, Luc Buée, and Patricia Melnyk
Subjects: Alzheimer's disease, Amyloid, Microtubule-associated protein tau, Multi-effect drugs, Neurofibrillary tangles, Tauopathies, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N′-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Aβ peptides while preserving the processing of other metabolites of the amyloid precursor protein.We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments.
Published: 2019
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9. A chemical screen identifies two novel small compounds that alter Arabidopsis thaliana pollen tube growth

Author: Ferdousse Laggoun, Flavien Dardelle, Jérémy Dehors, Denis Falconet, Azeddine Driouich, Christophe Rochais, Patrick Dallemagne, Arnaud Lehner, and Jean-Claude Mollet
Subjects: Pollen tubes, Chemical screen, Callose, Cell wall deposition, Pectins, ROS, Botany, QK1-989
Abstract: Abstract Background During sexual reproduction, pollen grains land on the stigma, rehydrate and produce pollen tubes that grow through the female transmitting-tract tissue allowing the delivery of the two sperm cells to the ovule and the production of healthy seeds. Because pollen tubes are single cells that expand by tip-polarized growth, they represent a good model to study the growth dynamics, cell wall deposition and intracellular machineries. Aiming to understand this complex machinery, we used a low throughput chemical screen approach in order to isolate new tip-growth disruptors. The effect of a chemical inhibitor of monogalactosyldiacylglycerol synthases, galvestine-1, was also investigated. The present work further characterizes their effects on the tip-growth and intracellular dynamics of pollen tubes. Results Two small compounds among 258 were isolated based on their abilities to perturb pollen tube growth. They were found to disrupt in vitro pollen tube growth of tobacco, tomato and Arabidopsis thaliana. We show that these 3 compounds induced abnormal phenotypes (bulging and/or enlarged pollen tubes) and reduced pollen tube length in a dose dependent manner. Pollen germination was significantly reduced after treatment with the two compounds isolated from the screen. They also affected cell wall material deposition in pollen tubes. The compounds decreased anion superoxide accumulation, disorganized actin filaments and RIC4 dynamics suggesting that they may affect vesicular trafficking at the pollen tube tip. Conclusion These molecules may alter directly or indirectly ROP1 activity, a key regulator of pollen tube growth and vesicular trafficking and therefore represent good tools to further study cellular dynamics during polarized-cell growth.
Published: 2019
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10. Screening of potential antiviral molecules against equid herpesvirus-1 using cellular impedance measurement: Dataset of 2,891 compounds.

Author: Côme Thieulent, Christine Fortier, Hélène Munier-Lehmann, Peggy Suzanne, Patrick Dallemagne, Stephan Zientara, Aymeric Hans, Romain Paillot, Pierre-Olivier Vidalain, Stéphane Pronost, and Erika Hue
Subjects: Real-time cell assay, Chemical library screening, Antiviral, Equid herpesvirus-1, Computer applications to medicine. Medical informatics, R858-859.7, Science (General), Q1-390
Abstract: Data presented in this article are associated with the research article “Identification of antiviral compounds against equid herpesvirus-1 using real-time cell assay screening: efficacy of decitabine and valganciclovir alone and in combination” [1]. These data correspond to the in vitro screening of 2,891 potential antiviral compounds against equid herpesvirus-1 (EHV-1) based on impedance measurements using the xCELLigence® RTCA MP System. This dataset includes compounds from three different libraries: i) 1,199 compounds from the Prestwick® Chemical Library, which contains mostly US Food and Drug Administration approved drugs (Prestwick® Chemical, Illkirch, France); ii) 1,651 compounds from the Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN, Caen, France); iii) 41 compounds (called herein in-house antiviral library) selected for their effects against different human viruses. Compounds effective against EHV-1 were selected using the area under normalised curves (AUCn) and the time required for the Cell Index to decrease by 50% after virus infection (CIT50). The full dataset from the screen is made publicly available for further analyses.
Published: 2020
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11. Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer’s Disease Treatment

Author: Line Séguy, Léna Guyon, Manon Maurel, Pascal Verdié, Audrey Davis, Sophie Corvaisier, Vincent Lisowski, Patrick Dallemagne, Anne-Claire Groo, and Aurélie Malzert-Fréon
Subjects: repurposing, Alzheimer’s disease, brain-targeting, nanoemulsions, peptide-22, Pharmacy and materia medica, RS1-441
Abstract: Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C18/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies.
Published: 2021
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12. A Novel in vivo Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HT4R) Agonist and Serotonergic Subtype 6 Receptor (5-HT6R) Inverse Agonist Activities, With a Potential Interest Against Alzheimer’s Disease

Author: Bérénice Hatat, Samir Yahiaoui, Cédric Lecoutey, Audrey Davis, Thomas Freret, Michel Boulouard, Sylvie Claeysen, Christophe Rochais, and Patrick Dallemagne
Subjects: Alzheimer’s disease, acetylcholinesterase, 5-HT4 receptors, 5-HT6 receptors, MTDL, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer’s disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan-1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.
Published: 2019
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13. Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy

Author: Maxime Mistretta, Mena Cimino, Pascal Campagne, Stevenn Volant, Etienne Kornobis, Olivier Hebert, Christophe Rochais, Patrick Dallemagne, Cédric Lecoutey, Camille Tisnerat, Alban Lepailleur, Yann Ayotte, Steven R. LaPlante, Nicolas Gangneux, Monika Záhorszká, Jana Korduláková, Sophie Vichier-Guerre, Frédéric Bonhomme, Laura Pokorny, Marvin Albert, Jean-Yves Tinevez, and Giulia Manina
Abstract: Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective anti-microbial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. To address this, we developed a flow-controlled multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells, compressed inside separate microchambers by a soft hydro-pneumatic membrane. With this platform, we implemented a dynamic single-cell screening for compounds that induce a phenotypic change while decreasing cell-to-cell variation, aiming to undermine the bacterial population, making it more vulnerable to other drugs. We first applied this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our top hit impairsMycobacterium tuberculosisvia a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that pheno-tuning compounds represent a successful approach to tackle pathogens that are increasingly difficult to treat.
Published: 2023
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14. Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

Author: Cédric Lecoutey, Rémi Legay, Audrey Davis, Jana Sopková-de Oliveira Santos, Patrick Dallemagne, and Christophe Rochais
Subjects: Alzheimer’s disease, acetylcholinesterase, 5-HT6R, donecopride, MTDL, Organic chemistry, QD241-441
Abstract: The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer’s disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.
Published: 2021
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15. Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation

Author: Rim Malek, Alexey Simakov, Audrey Davis, Maciej Maj, Paul J. Bernard, Artur Wnorowski, Helene Martin, José Marco-Contelles, Fakher Chabchoub, Patrick Dallemagne, Christophe Rochais, Krzysztof Jozwiak, Lhassane Ismaili, Conseil régional of Franche-Comté, and Centre d’Etudes et de Recherche sur le Médicament de Normandie (Francia)
Subjects: Chemistry (miscellaneous), Organic Chemistry, Drug Discovery, Biginelli reaction, multitarget-directed ligands, calcium channel antagonism, Nrf2, Molecular Medicine, Pharmaceutical Science, Physical and Theoretical Chemistry, Analytical Chemistry
Abstract: Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software., This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 ACCURATE PROJECT) and CERMN (Centre d’Etudes et de Recherche sur le Médicament de Normandie)
Published: 2023

16. First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer’s Disease

Author: Benjamin Guieu, Cedric Lecoutey, Rémi Legay, Audrey Davis, Jana Sopkova de Oliveira Santos, Cosimo Damiano Altomare, Marco Catto, Christophe Rochais, and Patrick Dallemagne
Subjects: Alzheimer’s disease, acetylcholinesterase, monoamine oxidase, donepezil, rasagiline, MTDL, Organic chemistry, QD241-441
Abstract: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).
Published: 2020
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17. Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer’s Disease Treatment

Author: Thomas Adnet, Anne-Claire Groo, Céline Picard, Audrey Davis, Sophie Corvaisier, Marc Since, Frédéric Bounoure, Christophe Rochais, Loïc Le Pluart, Patrick Dallemagne, and Aurélie Malzert-Fréon
Subjects: nose-to-brain delivery, nanocomposite, thermosensitive hydrogel, Pharmacy and materia medica, RS1-441
Abstract: Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer’s disease. The osmolarity and the gelation temperature (T° sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w) was selected for intranasal administration in terms of T° sol-gel and for the compatibility with the olfactory mucosal (280 ± 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer’s disease treatment.
Published: 2020
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18. Aminothiaindanone as an Accessible Scaffold for a Three-Point Chemical Diversity

Author: Christophe Rochais, Patrick Dallemagne, Jana Sopkova-de Oliveira Santos, Julien Lalut, and Pauline Zipfel
Subjects: Scaffold, 010405 organic chemistry, Chemistry, Organic Chemistry, 010402 general chemistry, 01 natural sciences, Chemical reaction, Combinatorial chemistry, Catalysis, 0104 chemical sciences, chemistry.chemical_compound, Chemical diversity, Thiophene, Surface modification
Abstract: Aminothiaindanone heterocycle appears to be a scaffold of interest in medicinal chemistry. To increase the chemical diversity in this series, the introduction of three-point chemical diversity on the cyclopenta[b]thiophen-4-one scaffold was explored. About thirty newly functionalized thiophene-containing bicycles were obtained using various chemical reactions, paving the way for novel possibilities in medicinal chemistry projects.
Published: 2021
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19. Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Author: François-Xavier Toublet, Cédric Lecoutey, Julien Lalut, Bérénice Hatat, Audrey Davis, Marc Since, Sophie Corvaisier, Thomas Freret, Jana Sopkova de Oliveira Santos, Sylvie Claeysen, Michel Boulouard, Patrick Dallemagne, and Christophe Rochais
Subjects: Alzheimer’s disease, prodrug, acetylcholinesterase, 5-HT4 receptors, MTDL, Organic chemistry, QD241-441
Abstract: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
Published: 2019
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20. 26th Annual GP2A Medicinal Chemistry Conference & 32nd Journées Franco-Belges de Pharmacochimie

Author: Patrick Dallemagne, Christophe Rochais, Pascal Marchand, and Thierry Besson
Subjects: medicinal chemistry, drug design, chemical tools, Medicine, Pharmacy and materia medica, RS1-441
Abstract: As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to engage. Topics included chemical tools for medicinal chemistry, protein-protein interactions, epigenetics, natural product-inspired molecules, computer-aided drug design, and new strategies for the design and development of drugs. Abstracts of invited lectures, proffered young researcher communications, flash communications and posters presented during the meeting are collected in this report.
Published: 2019
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21. Virtual Screening Discovery of New Acetylcholinesterase Inhibitors Issued from CERMN Chemical Library.

Author: Jana Sopkova-de Oliveira Santos, Aurélien Lesnard, Jean-Hugues Agondanou, Nathalie Dupont, Anne-Marie Godard, Silvia Stiebing, Christophe Rochais, Frédéric Fabis, Patrick Dallemagne, Ronan Bureau, and Sylvain Rault
Published: 2010
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22. Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present)

Author: Christophe Rochais, Patrick Dallemagne, Caroline Lanthier, Cédric Lecoutey, Sylvie Claeysen, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), This work was supported by funding from Normandie Valorisation, the French Agence Nationale de la Recherche [project MALAD ANR-12-JS007-0012-01, project ADAMGUARD ANR-12-BSV4-008-01], the Fondation Plan Alzheimer [AAP2015 Project TRIAD 016]. The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER)., ANR-12-JS07-0012,MALAD,Developpement de Ligands pluriactifs d'intérêt potentiel dans le traitement de la maladie d'Alzheimer(2012), ANR-12-BSV4-0008,ADAMGUARD,Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP(2012), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Guerineau, Nathalie C., Jeunes Chercheuses et Jeunes Chercheurs - Developpement de Ligands pluriactifs d'intérêt potentiel dans le traitement de la maladie d'Alzheimer - - MALAD2012 - ANR-12-JS07-0012 - JC - VALID, and BLANC - Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP - - ADAMGUARD2012 - ANR-12-BSV4-0008 - BLANC - VALID
Subjects: Serotonin, [SDV]Life Sciences [q-bio], Central nervous system, 5-HT4 receptor, macromolecular substances, Biology, gastrointestinal disorders, 01 natural sciences, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, medicine, 5-HT 4 receptor, Pharmacology, General Medicine, central nervous system, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, 030220 oncology & carcinogenesis, depression, Alzheimer, Neuroscience
Abstract: International audience; Introduction: Numerous chemotypes have been described over time in order to generate potent and selective 5-HT4R ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years.Areas covered: This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HT4R modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses.Expert opinion: The therapeutic potential of 5-HT4R modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HT4R modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HT4R modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.
Published: 2020
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23. Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

Author: Patrick Dallemagne, Pierre-Olivier Vidalain, Aymeric Hans, Anthony Madeline, D. Gaudaire, José Carlos Valle-Casuso, Lydie Martin-Faivre, Stéphane Pronost, Hélène Munier-Lehmann, Stéphan Zientara, Physiopathologie et épidémiologie des maladies équines (PhEED), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Chimie et Biocatalyse, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Fonds Eperon, AnsesFonds EperonRegion Normandie, IFCE (Institut Francais du Cheval et de l'Equitation), Région Normandie, ANSES, Laboratoire de Santé Animale - site de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris-Est (UPE), Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was supported by Anses, IFCE (Institut Français du Cheval et de l’Equitation), Fonds Eperon and Région Normandie., AnsesIFCE (Institut Francais du Cheval et de l'Equitation)Fonds EperonRegion Normandie, Bodescot, Myriam, École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Dihydroorotate Dehydrogenase, lcsh:Medicine, Virus Replication, chemistry.chemical_compound, Cytopathogenic Effect, Viral, Coronaviridae, lcsh:Science, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, education.field_of_study, Multidisciplinary, Arterivirus Infections, Drug discovery, 3. Good health, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Pyrimidine metabolism, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Oxidoreductases Acting on CH-CH Group Donors, 030106 microbiology, Population, Biology, Antiviral Agents, Microbiology, Article, Cell Line, 03 medical and health sciences, Equartevirus, Ribavirin, Animals, Horses, education, 030304 developmental biology, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, 030306 microbiology, lcsh:R, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, RNA, RNA virus, biology.organism_classification, Virology, 030104 developmental biology, Pyrimidines, chemistry, Viral replication, Purines, Dihydroorotate dehydrogenase, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Horse Diseases, lcsh:Q
Abstract: RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two vaccines are available, the vaccination coverage of the equine population is largely insufficient to prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly inhibited viral replication and production of infectious particles. Since ribavirin is already approved in human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results open new perspectives for the management of EAV outbreaks.
Published: 2020
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24. Advances in prodrug design for Alzheimer's disease: the state of the art

Author: Valentin Travers--Lesage, Serge M. Mignani, Patrick Dallemagne, and Christophe Rochais
Subjects: Alzheimer Disease, Drug Design, Drug Discovery, Brain, Humans, Neurodegenerative Diseases, Prodrugs
Abstract: Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that remains today a challenge for drug discovery. Like many pathologies of the central nervous system, one of the first hurdle is the development of a compound with a sufficient brain exposure to ensure a potential therapeutic benefit. In this direction, the development of prodrugs has been an intense field of research in the last years.Two main strategies of prodrugs development are analyzed in this review. First, the application of the classical modulation of an active compound to incorporate a promoiety has been exemplified in the field of AD. In a second chapter, a series of innovative prodrugs based on a polypharmacological approach is described to take into account the complexity of AD.In the past 10 years, prodrugs have been approved by the FDA for the treatment of CNS pathologies. Most of them have been developed in order to improve membrane permeability of the parent drugs. Facing the limitation of AD drug discovery, the development of prodrugs will likely play a central role in the next years with the rise of innovative pleiotropic prodrugs.
Published: 2022

25. Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor

Author: Mirjana Antonijevic, Despoina Charou, Isbaal Ramos, Maria Valcarcel, Achille Gravanis, Patricia Villace, Noelle Callizot, Marc Since, Patrick Dallemagne, Ioannis Charalampopoulos, and Christophe Rochais
Subjects: Pharmacology, Organic Chemistry, Drug Discovery, General Medicine
Published: 2023
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26. 5-HT4R modulators: a patent landscape

Author: Patrick Dallemagne and Christophe Rochais
Subjects: business.industry, Medicine, General Medicine, business, Depression (differential diagnoses), Clinical psychology
Published: 2021

27. Facing the complexity of Alzheimer's disease

Author: Christophe Rochais and Patrick Dallemagne
Subjects: Pharmacology, Amyloid, medicine.medical_specialty, business.industry, MEDLINE, Disease, Clinical trial, Neuroprotective Agents, Alzheimer Disease, Drug Discovery, medicine, Animals, Humans, Molecular Medicine, Polypharmacology, Intensive care medicine, business
Published: 2020
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28. Screening and evaluation of antiviral compounds against Equid alpha-herpesviruses using an impedance-based cellular assay

Author: Pierre-Hugues Pitel, Aymeric Hans, Côme Thieulent, Christine Fortier, Erika Hue, Guillaume Fortier, Stéphan Zientara, Patrick Dallemagne, Stéphane Pronost, Pierre-Olivier Vidalain, Hélène Munier-Lehmann, LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), ImpedanCELL, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Virologie UMR1161 (VIRO), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire d'Alfort (ENVA), Chimie et Biocatalyse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Unité de virologie et parasitologie équine, Laboratoire de pathologie équine de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Equipe Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), This work was supported by LABÉO, IFCE (Institut Français du Cheval et de l′Equitation, project AMIE), Fonds Eperon (project N87-2014, N07-2015, N07-2016 and N13-2017) and Région Normandie (CPER R25 P3)., Interactions Cellules Organismes Environnement (ICORE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-CHU Caen, Normandie Université (NU), Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-École nationale vétérinaire d'Alfort (ENVA), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Ganciclovir, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Population, Alpha (ethology), Cell analysis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Spironolactone, Biology, Antiviral Agents, Equid herpesviruses, NERVOUS DISORDERS, Cell Line, Real-time cell analysis, 03 medical and health sciences, Cytopathogenic Effect, Viral, xCELLigence, Virology, Electric Impedance, medicine, Lack of efficacy, Animals, Horses, Aciclovir, Antiviral, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Cellular Assay, 030302 biochemistry & molecular biology, Impedance, Herpesviridae Infections, High-Throughput Screening Assays, 3. Good health, Screening, Herpesvirus 3, Equid, Herpesvirus 4, Equid, Herpesvirus 1, Equid, medicine.drug
Abstract: International audience; Equid alpha-herpesviruses (EHV) are responsible for different diseases in equine population. EHV-1 causes respiratory diseases, abortions and nervous disorders, EHV-4 causes respiratory diseases and sporadic abortion, while EHV-3 is responsible of equine coital exanthema. In view of the lack of efficacy of vaccines against EHV-1 and EHV-4 and in the absence of vaccines against EHV-3, the use of antiviral treatment is of great interest. In this study, we documented the interest of the Real-Time Cell Analysis (RTCA) technology to monitor the cytopathic effects induced by these viruses on equine dermal cells, and established the efficacy of this method to evaluate the antiviral effect of aciclovir (ACV) and ganciclovir (GCV). In addition, the RTCA technology has also been found appropriate for the high-throughput screening of small molecules against EHV, allowing the identification of spironolactone as a novel antiviral against EHV.
Published: 2019
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29. Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy

Author: Rémi Legay, Jana Sopkova-de Oliveira Santos, Christophe Rochais, Patrick Dallemagne, Audrey Davis, and Cédric Lecoutey
Subjects: Agonist, medicine.drug_class, Molecular Conformation, Pharmaceutical Science, Context (language use), Computational biology, Chemistry Techniques, Synthetic, Molecular Dynamics Simulation, Ligands, Article, MTDL, Analytical Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, QD241-441, 0302 clinical medicine, Docking (dog), Drug Development, Drug Discovery, medicine, Humans, Physical and Theoretical Chemistry, Receptor, 030304 developmental biology, 5-HT6R, 0303 health sciences, Binding Sites, Chemistry, donecopride, Organic Chemistry, Hydrogen Bonding, acetylcholinesterase, Ligand (biochemistry), Acetylcholinesterase, In vitro, Molecular Docking Simulation, Acetylcholinesterase inhibitor, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Molecular Medicine, Cholinesterase Inhibitors, Alzheimer’s disease, Protein Binding
Abstract: The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer’s disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.
Published: 2021
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30. Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease

Author: Thomas Freret, Michel Boulouard, Audrey Davis, Marc Since, Bérénice Hatat, Sylvie Claeysen, François-Xavier Toublet, Patrick Dallemagne, Julien Lalut, Jana Sopkova-de Oliveira Santos, Sophie Corvaisier, Christophe Rochais, Cédric Lecoutey, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by funding from the Fondation Vaincre Alzheimer (#FR-15072) and the Fondation Plan Alzheimer (AAP2015 Project TRIAD 016). The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER) for theircontribution to the CERMN’s analytical platform. European COST action CA15135 (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) supports this article. Part of this work was performed using computing resources of CRIANN (Normandy, France) as well as the European Community (FEDER) for the molecular modeling software. We thank Oksana Lockridge at Eppley Institute University of Nebraska Medical Center Omaha, for providing us human BuChE., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Guerineau, Nathalie C., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Context (language use), Idalopirdine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 01 natural sciences, MTDL, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Prodrugs, Receptor, Butyrylcholinesterase, 030304 developmental biology, Cholinesterase, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Antagonist, General Medicine, 5-HT(6) receptors, Acetylcholinesterase, 3. Good health, 0104 chemical sciences, 5-HT6 receptor, biology.protein, Alzheimer’s disease
Abstract: International audience; Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 μM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.
Published: 2021
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31. Screening of potential antiviral molecules against equid herpesvirus-1 using cellular impedance measurement: dataset of 2,891 compounds

Author: Christine Fortier, Erika Hue, Aymeric Hans, Pierre-Olivier Vidalain, Patrick Dallemagne, Romain Paillot, Peggy Suzanne, Stéphane Pronost, Côme Thieulent, Hélène Munier-Lehmann, Stéphan Zientara, LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), ImpedanCELL, Interactions Cellules Organismes Environnement (ICORE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-CHU Caen, Normandie Université (NU), Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de pathologie équine de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Biologie cellulaire des infections virales – Cell biology of viral infection, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HUE, Erika, École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Equid herpesvirus-1, Chemical library screening, Decitabine, lcsh:Computer applications to medicine. Medical informatics, Virus, Chemical library, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Molecule, Research article, Antiviral, lcsh:Science (General), Data Article, 030304 developmental biology, Real-time cell assay, 0303 health sciences, Multidisciplinary, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Focused Impedance Measurement, Chemistry, screening, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Valganciclovir, Virology, In vitro, 3. Good health, lcsh:R858-859.7, 030217 neurology & neurosurgery, lcsh:Q1-390, medicine.drug
Abstract: International audience; Data presented in this article are associated with the research article “Identification of antiviral compounds against equid herpesvirus-1 using real-time cell assay screening: efficacy of decitabine and valganciclovir alone and in combination” [1]. These data correspond to the in vitro screening of 2,891 potential antiviral compounds against equid herpesvirus-1 (EHV-1) based on impedance measurements using the xCELLigence® RTCA MP System. This dataset includes compounds from three different libraries: i) 1,199 compounds from the Prestwick® Chemical Library, which contains mostly US Food and Drug Administration approved drugs (Prestwick® Chemical, Illkirch, France); ii) 1,651 compounds from the Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN, Caen, France); iii) 41 compounds (called herein in-house antiviral library) selected for their effects against different human viruses. Compounds effective against EHV-1 were selected using the area under normalised curves (AUCn) and the time required for the Cell Index to decrease by 50% after virus infection (CIT50). The full dataset from the screen is made publicly available for further analyses.
Published: 2020
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32. Un nouvel arsenal thérapeutique contre la rhinopneumonie équine

Author: Côme Thieulent, Erika HUE, Christine Fortier, Patrick Dallemagne, Stephan Zientara, Aymeric Hans, Hélène Munier-Lehmann, Pierre-Olivier Vidalain, Stéphane Pronost, LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), ImpedanCELL, Interactions Cellules Organismes Environnement (ICORE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-CHU Caen, Normandie Université (NU), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de pathologie équine de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HUE, Erika, École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Épidémiologie, Herpèsvirus Équin Hve-1 Et Hve-4, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Pharmacologie, Rhinopneumonie
Abstract: National audience; L’herpèsvirus équin1 (HVE-1)est l’un des deux agents responsables de la rhinopneumonie équine. Ce virus peut provoquer des troubles respiratoires, des avortements, une mort néonatale du jeune poulain et des troubles nerveux appelés myéloencéphalopathie équine. Les vaccins existant à l’heure actuelle permettent de réduire les problèmes respiratoires et donc la dissémination du virus. Cependant, ils ne préviennent pas suffisamment les formes graves de la maladie. Par ailleurs, aucune molécule antivirale ne possède d’autorisation de mise sur le marché en santé équine en France. Nous avons développé un système permettant de tester à haut débit un grand nombre de molécules contre l’HVE-1 en conditions de laboratoire. Parmi les 3000 molécules testées, 23 ont été identifiées comme potentiellement efficaces contre ce virus. Le ganciclovir et sa pro-drogue le valganciclovir se sont montrés parmi les molécules les plus efficaces contre l’HVE-1. Ces résultats encourageants, couplés aux données de pharmacocinétique déjà existantes de ces molécules sur le modèle équin nous ont conduits à envisager une étude expérimentale sur des poneys.
Published: 2020

33. Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease

Author: Patrick Dallemagne, Véronique Lelong-Boulouard, Ronan Bureau, Charles Dolladille, Basile Chrétien, Christophe Rochais, Sophie Fedrizzi, Audrey Davis, Marion Sassier, Jean-Pierre Jourdan, and Joachim Alexandre
Subjects: Drug, Databases, Factual, media_common.quotation_subject, Disease, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Alzheimer Disease, Medicine, Adverse Drug Reaction Reporting Systems, Humans, Pharmacology (medical), 030212 general & internal medicine, Adverse effect, Clozapine, media_common, Sertraline, business.industry, Drug Repositioning, Drug repositioning, Pharmaceutical Preparations, Aripiprazole, business, medicine.drug
Abstract: Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). Methods Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. Results We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 μM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. Conclusion We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.
Published: 2020

34. Identification of antiviral compounds against equid herpesvirus-1 using real-time cell assay screening: Efficacy of decitabine and valganciclovir alone or in combination

Author: Pierre-Olivier Vidalain, Patrick Dallemagne, Aymeric Hans, Côme Thieulent, Christine Fortier, Erika Hue, Stéphan Zientara, Stéphane Pronost, Romain Paillot, Hélène Munier-Lehmann, Gabrielle Sutton, LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), ImpedanCELL, Interactions Cellules Organismes Environnement (ICORE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-CHU Caen, Normandie Université (NU), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Chimie et Biocatalyse, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Laboratoire de pathologie équine de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), ANSES, Laboratoire de Santé Animale - site de Dozulé, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was supported by LABÉO, IFCE (Institut Français du Cheval et de l'Equitation, project AMIE), Fonds Eperon (project N87–2014, N07–2015, N07–2016, N13–2017 and N62-2017), Région Normandie (CPER R25 P3) and CENTAURE European project co-funded by Normandy County Council, European Union in the framework of the ERDF-ESF operationnal programme 2014–2020., Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et épidémiologie des maladies équines (PhEED), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), HUE, Erika, École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Aphidicolin, Ganciclovir, Equid herpesvirus-1, 030106 microbiology, Chemical library screening, Decitabine, Antiviral Agents, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Virology, Drug Discovery, Medicine, Animals, Valganciclovir, Synergism, Horses, Antiviral, Pharmacology, Real-time cell assay, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, business.industry, Idoxuridine, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Drug Synergism, Deoxycytidine kinase, Herpesviridae Infections, 3. Good health, High-Throughput Screening Assays, Drug Combinations, 030104 developmental biology, chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Deoxycytidine, Rabbits, business, Nucleoside, medicine.drug, Herpesvirus 1, Equid
Abstract: International audience; Equid herpesvirus-1 infections cause respiratory, neurological and reproductive syndromes. Despite preventive treatments with vaccines, resurgence of EHV-1 infection still constitutes a major threat to equine industry. However, no antiviral compound is available to treat infected horses. In this study, 2891 compounds were screened against EHV-1 using impedance measurement. 22 compounds have been found to be effective in vitro against EHV-1. Valganciclovir, ganciclovir, decitabine, aphidicolin, idoxuridine and pritelivir (BAY 57-1293) are the most effective compounds identified, and their antiviral potency was further assessed on E. Derm, RK13 and EEK cells and against 3 different field strains of EHV-1 (ORF30 2254 A/G/C). We also provide evidences of synergistic interactions between valganciclovir and decitabine in our in vitro antiviral assay as determined by MacSynergy II, isobologramm and Chou-Talalay methods. Finally, we showed that deoxycytidine reverts the antiviral effect of decitabine, thus supporting some competition at the level of nucleoside phosphorylation by deoxycytidine kinase and/or DNA synthesis. Deoxycitidine analogues, like decitabine, is a family of compounds identified for the first time with promising antiviral efficacy against herpesviruses.
Published: 2020
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35. Phenanthrolinic analogs of quinolones show antibacterial activity against M. tuberculosis

Author: Patrick Dallemagne, Mahama Ouattara, Cédric Lecoutey, Songuigama Coulibaly, Julien Briffotaux, Maria Virginia Buchieri, Christophe Rochais, Noelia Alonso-Rodriguez, Mena Cimino, Brigitte Gicquel, Damien Mornico, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Félix Houphouët-Boigny (UFHB), Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris], Shenzhen Nanshan Center for Chronic Disease Control [Shenzhen, China] (ShenZhenCDC), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work has received the financial support of the Service de Coopération et d’Action Culturelle of the French Embassy in Ivory Coast. This work was also supported by the European Seventh Framework Program Nanotherapeutics against Resistant Emerging Bacterial Patho-gens (NAREB Project 604237), as well as the Sanming Project of Medicine in Shenzhen (No. SZSM201603029). The analytical platform of CERMN is financially supported by Région Normandie and FEDER., European Project: 604237,EC:FP7:NMP,FP7-NMP-2013-LARGE-7,NAREB(2014), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Tuberculosis, MESH: Mycobacterium tuberculosis, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Mutant, Antitubercular Agents, Microbial Sensitivity Tests, Quinolones, MESH: Drug Design, medicine.disease_cause, 01 natural sciences, Microbiology, Mycobacterium tuberculosis, 03 medical and health sciences, Drug Resistance, Bacterial, Drug Discovery, MESH: Drug Resistance, Bacterial, medicine, MESH: Phenanthrolines, 030304 developmental biology, Pharmacology, 0303 health sciences, MESH: Microbial Sensitivity Tests, MESH: Quinolones, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, General Medicine, medicine.disease, biology.organism_classification, MESH: Antitubercular Agents, 3. Good health, 0104 chemical sciences, Dihydrophenanthrolinones, Staphylococcus aureus, Drug Design, Antibacterial activity, Rifampicin, Bacteria, Phenanthrolines, medicine.drug, Fluoroquinolones
Abstract: International audience; Several phenanthrolinic analogs of quinolones have been synthesized and their antibacterial activity tested against Mycobacterium tuberculosis, other mycobacterial species and bacteria from other genera. Some of them show high activity (of the range observed for rifampicin) against M. tuberculosis replicating in vitro and in vivo (infected macrophages) conditions. These derivatives show the same activity with all or several M. tuberculosis complex bacterial mutants resistant to fluoroquinolones (FQ). This opens the way to the construction of new drugs for the treatment of FQ resistant bacterial infections, including tuberculosis. Several compounds showed also activity against Staphylococcus aureus and probably other species. These compounds do not show major toxicity. We conclude that the novel phenanthrolinic derivatives described here are potent hits for further developments of new antibiotics against bacterial infectious diseases including tuberculosis in particular those resistant to FQ.
Published: 2020
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36. Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT

Author: François-Xavier, Toublet, Julien, Lalut, Bérénice, Hatat, Cédric, Lecoutey, Audrey, Davis, Marc, Since, Sophie, Corvaisier, Thomas, Freret, Jana, Sopková-de Oliveira Santos, Sylvie, Claeysen, Michel, Boulouard, Patrick, Dallemagne, and Christophe, Rochais
Subjects: Male, Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Mice, Structure-Activity Relationship, Alzheimer Disease, Butyrylcholinesterase, Drug Design, Receptors, Serotonin, Electrophorus, Animals, Humans, Prodrugs, Cholinesterase Inhibitors, Locomotion
Abstract: Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT
Published: 2020

37. Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Author: Anne-Sophie Ribba, Sacnicte Ramirez-Rios, Patrick Dallemagne, Anna Akhmanova, María A. Oliva, Daniel Lucena-Agell, Audrey Vernet, Eric Denarier, Peggy Suzanne, Jean-Luc Coll, J. Fernando Díaz, Annie Andrieux, Julien Vollaire, Lauralie Peronne, Renaud Prudent, Laurence Lafanechère, Sophie Michallet, Ankit Rai, Véronique Josserand, Mélanie Guidetti, Karin Sadoul, Université Grenoble Alpes, Institut National de la Santé et de la Recherche Médicale (France), Centre National de la Recherche Scientifique (France), Institut National du Cancer (France), Fondation ARC pour la Recherche sur le Cancer, European Commission, Ministerio de Economía y Competitividad (España), Netherlands Organization for Scientific Research, 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), Sub Cell Biology, and Celbiologie
Subjects: drug synergy, Cancer therapy, Carbazole, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:RC254-282, Article, microtubules, 03 medical and health sciences, chemistry.chemical_compound, paclitaxel, 0302 clinical medicine, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Microtubule, In vivo, carbazole, Cytotoxic T cell, Colchicine, 030304 developmental biology, 0303 health sciences, biology, Chemistry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Effective dose (pharmacology), 3. Good health, Tubulin, Paclitaxel, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, biology.protein, cancer therapy
Abstract: Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action., This work was supported by INSERM, Université Grenoble Alpes, CNRS, and by l’Institut National du Cancer (INCa, PLBIO16186), Fondation ARC (PJA 20151203348) and Association “Le Cancer du Sein, Parlons-en!”, to L.L., by Grant Ministerio de Economia y Competitividad grant BFU2016-75319-R, (AEI/FEDER, UE), European Union H2020-MSCA-ITN-ETN/0582 ITN TubInTrain to FDP, and The Netherlands Organization for Scientific Research (NWO) CW ECHO grant (711.015.005) to Anna Akhmanova The Optimal imaging platform is supported by France Life Imaging (French program “Investissement d’Avenir” grant; “Infrastructure d’avenir en Biologie Santé”, ANR-11-INBS-0006) and the IBISA French consortium “Infrastructures en Biologie Santé et Agronomie”.
Published: 2020
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38. Desirable drug-drug interactions or when a matter of concern becomes a renewed therapeutic strategy

Author: Patrick Dallemagne, Benjamin Guieu, Aurore Dreneau, Nicolas Willand, Christophe Rochais, and Jean-Pierre Jourdan
Subjects: 0301 basic medicine, Drug, medicine.medical_specialty, medicine.drug_class, media_common.quotation_subject, Antibiotics, Antineoplastic Agents, 03 medical and health sciences, 0302 clinical medicine, Anti-Infective Agents, Drug Discovery, medicine, Animals, Humans, Drug Interactions, Intensive care medicine, Adverse effect, Therapeutic strategy, media_common, Pharmacology, business.industry, Drug Synergism, 030104 developmental biology, 030220 oncology & carcinogenesis, Drug Design, Drug Therapy, Combination, business
Abstract: Drug-drug interactions are sometimes considered to be detrimental and responsible for adverse effects. In some cases, however, some are stakeholders of the efficiency of the treatment and this combinatorial strategy is exploited by some drug associations, including levodopa (L-Dopa) and dopadecarboxylase inhibitors, β-lactam antibiotics and clavulanic acid, 5-fluorouracil (5-FU) and folinic acid, and penicillin and probenecid. More recently, some drug-drug combinations have been integrated in modern drug design strategies, aiming to enhance the efficiency of already marketed drugs with new compounds acting not only as synergistic associations, but also as real boosters of activity. In this review, we provide an update of examples of such strategies, with a special focus on microbiology and oncology.
Published: 2020

39. hERG toxicity assessment: Useful guidelines for drug design

Author: Serge Mignani, Patrick Dallemagne, Christophe Rochais, Amanda Garrido, Alban Lepailleur, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Universidade da Madeira (UMA)
Subjects: Drug, media_common.quotation_subject, hERG, Bioinformatics, 01 natural sciences, Food and drug administration, 03 medical and health sciences, Drug Discovery, Humans, [CHIM]Chemical Sciences, Adverse effect, 030304 developmental biology, media_common, Pharmacology, 0303 health sciences, Cardiotoxicity, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, General Medicine, Ether-A-Go-Go Potassium Channels, 0104 chemical sciences, 3. Good health, Drug development, Drug Design, Toxicity, Practice Guidelines as Topic, biology.protein
Abstract: All along the drug development process, one of the most frequent adverse side effects, leading to the failure of drugs, is the cardiac arrhythmias. Such failure is mostly related to the capacity of the drug to inhibit the human ether-a-go-go-related gene (hERG) cardiac potassium channel. The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years. In order to prevent the cardiac side effects, a great number of in silico, in vitro and in vivo assays have been performed. The main goal of these studies is to understand the reasons of these effects, and then to give information or instructions to scientists involved in drug development to avoid the cardiac side effects. To evaluate anticipated cardiovascular effects, early evaluation of hERG toxicity has been strongly recommended for instance by the regulatory agencies such as U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Thus, following an initial screening of a collection of compounds to find hits, a great number of pharmacomodulation studies on the novel identified chemical series need to be performed including activity evaluation towards hERG. We provide in this concise review clear guidelines, based on described examples, illustrating successful optimization process to avoid hERG interactions as cases studies and to spur scientists to develop safe drugs.
Published: 2020
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40. Matrix Metalloproteinases as New Targets in Alzheimer's Disease: Opportunities and Challenges

Author: Pauline Zipfel, Patrick Dallemagne, Kévin Baranger, Christophe Rochais, and Santiago Rivera
Subjects: Central Nervous System, 0303 health sciences, Chemistry, Disease, Matrix metalloproteinase, Matrix Metalloproteinase Inhibitors, 01 natural sciences, Matrix Metalloproteinases, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Drug Delivery Systems, Alzheimer Disease, Drug Discovery, Molecular Medicine, Humans, Peptidomimetics, Neuroscience, 030304 developmental biology
Abstract: Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidence of their pathological roles have also been obtained in the last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries of their involvement in central nervous system (CNS) disorders, and in particular in Alzheimer's disease (AD), have paved the way to consider MMP modulators as promising therapeutic strategies. Over the past few decades, diverse approaches have been undertaken in the design of therapeutic agents targeting MMPs for various purposes, leading, more recently, to encouraging developments. In this article, we will present recent examples of inhibitors ranging from small molecules and peptidomimetics to biologics. We will also discuss the scientific knowledge that has led to the development of emerging tools and techniques to overcome the challenges of selective MMP inhibition.
Published: 2020

41. Therapeutic modulators of the serotonin 5-HT

Author: Caroline, Lanthier, Patrick, Dallemagne, Cédric, Lecoutey, Sylvie, Claeysen, and Christophe, Rochais
Subjects: Patents as Topic, Serotonin 5-HT4 Receptor Agonists, Serotonin 5-HT4 Receptor Antagonists, Drug Development, Central Nervous System Diseases, Gastrointestinal Diseases, Animals, Humans, Receptors, Serotonin, 5-HT4, Ligands
Abstract: Numerous chemotypes have been described over time in order to generate potent and selective 5-HTThis review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HTThe therapeutic potential of 5-HT
Published: 2020

42. Drug repositioning: a brief overview

Author: Patrick Dallemagne, Ronan Bureau, Christophe Rochais, and Jean-Pierre Jourdan
Subjects: Drug, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), media_common.quotation_subject, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), indication, Pharmaceutical Science, Reviews, Review, History, 21st Century, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, medicine, Data Mining, Humans, Intensive care medicine, 030304 developmental biology, media_common, Pharmacology, 0303 health sciences, repositioning, Drug discovery, Serendipity, business.industry, generic, Drug Repositioning, drug, History, 19th Century, History, 20th Century, Drug repositioning, 030220 oncology & carcinogenesis, business
Abstract: Objectives Drug repositioning, that is, the use of a drug in an indication other than the one for which it was initially marketed, is a growing trend. Its origins lie mainly in the attrition experienced in recent years in the field of new drug discovery. Key findings Despite some regulatory and economic challenges, drug repositioning offers many advantages, and a number of recent successes have confirmed both its public health benefits and its commercial value. The first examples of successful drug repositioning mainly came about through serendipity like acetylsalicylic acid, thalidomide, sildenafil or dimethylfumarate. Conclusion The history of great-repositioned drugs has given some solutions to various pathologies. Serendipity is not yet useful to find repositioning drugs. Drug repositioning is of growing interest. Nowadays, a more rational approach to the identification of drug candidates for repositioning is possible, especially using data mining.
Published: 2020

43. Donecopride, a Swiss army knife with potential against Alzheimer's disease

Author: Kévin Baranger, Patrick Dallemagne, Thomas Freret, Joël Bockaert, Eleazere Cem, Serge Mignani, Michel Boulouard, Katia Hamidouche, Sylvie Claeysen, Patrizia Giannoni, Christophe Rochais, Cédric Lecoutey, Santiago Rivera, and Florence Gaven
Subjects: 0301 basic medicine, Genetically modified mouse, Neurite, Transgene, Morris water navigation task, Mice, Transgenic, Neuroprotection, 03 medical and health sciences, chemistry.chemical_compound, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Piperidines, In vivo, Alzheimer Disease, Medicine, Animals, Maze Learning, Pharmacology, Amyloid beta-Peptides, Aniline Compounds, biology, business.industry, Brain, Acetylcholinesterase, Research Papers, 3. Good health, Rats, Disease Models, Animal, 030104 developmental biology, chemistry, biology.protein, business, Neuroscience, 030217 neurology & neurosurgery, Neurotrophin
Abstract: BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit acetylcholinesterase and to activate serotonin subtype 4 receptor. The purpose of the present article is to establish its potential therapeutic interest against Alzheimer's disease (AD). EXPERIMENTAL APPROACH: The present work used both in cellulo and in vivo models of AD. KEY RESULTS: In the present study, we show that, in vivo under chronic administration, donecopride displays potent anti-amnesic properties in two different animal models of Alzheimer's disease (AD) (transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides). Donecopride preserved learning capacities, including working and long-term spatial memories, which were evaluated with various behavioral tests (novel object recognition, Y-maze, Morris water maze). These behavioral observations found molecular correlation with the interactions of donecopride related to the two main types of molecular damage in AD. Indeed, a decrease in amyloid aggregation was observed in the brain of the treated transgenic mice, as well as a reduction in tau hyperphosphorylation in rat primary cultures of hippocampal neurons. At the cellular level, donecopride exerted neuroprotective effects toward neurons and the neurite network, as well as neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS & IMPLICATIONS: Pleiotropic donecopride acts like a Swiss army knife, displaying sustainable symptomatic therapeutic effects and potential disease-modifying roles against AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.
Published: 2020

44. Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT

Author: Julien, Lalut, Hugo, Payan, Audrey, Davis, Cédric, Lecoutey, Rémi, Legay, Jana, Sopkova-de Oliveira Santos, Sylvie, Claeysen, Patrick, Dallemagne, and Christophe, Rochais
Subjects: Models, Molecular, Binding Sites, Medicinal chemistry, Isoxazoles, Alzheimer's disease, Article, Molecular Docking Simulation, Alzheimer Disease, Drug Design, Acetylcholinesterase, Humans, Donepezil, Drug discovery and development, Cholinesterase Inhibitors, Receptors, Serotonin, 5-HT4, Structure-based drug design
Abstract: A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.
Published: 2019

45. Novel multi target-directed ligands targeting 5-HT

Author: Caroline, Lanthier, Hugo, Payan, Irene, Liparulo, Bérénice, Hatat, Cédric, Lecoutey, Marc, Since, Audrey, Davis, Christian, Bergamini, Sylvie, Claeysen, Patrick, Dallemagne, Maria-Laura, Bolognesi, and Christophe, Rochais
Subjects: Dose-Response Relationship, Drug, Molecular Structure, Cell Survival, Biphenyl Compounds, Ligands, Antioxidants, Serotonin 5-HT4 Receptor Agonists, Structure-Activity Relationship, Picrates, Alzheimer Disease, Cell Line, Tumor, COS Cells, Chlorocebus aethiops, Animals, Humans, Receptors, Serotonin, 5-HT4, Drug Screening Assays, Antitumor, Reactive Oxygen Species, Cell Proliferation
Abstract: Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aβ protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT
Published: 2019

46. 26th Annual GP2A Medicinal Chemistry Conference & 32nd Journées Franco-Belges de Pharmacochimie

Author: Pascal Marchand, Christophe Rochais, Thomas CAILLY, Thierry BESSON, Patrick Dallemagne, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, drug design, lcsh:R, lcsh:Medicine, lcsh:RS1-441, Pharmaceutical Science, Meeting Report, Medicinal chemistry, 3. Good health, lcsh:Pharmacy and materia medica, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Political science, medicinal chemistry, chemical tools, Drug Discovery, Molecular Medicine, [CHIM]Chemical Sciences, 030304 developmental biology
Abstract: International audience; As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to engage. Topics included chemical tools for medicinal chemistry, protein-protein interactions, epigenetics, natural product-inspired molecules, computer-aided drug design, and new strategies for the design and development of drugs. Abstracts of invited lectures, proffered young researcher communications, flash communications and posters presented during the meeting are collected in this report.
Published: 2019
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47. A chemical screen identifies two novel small compounds that alter Arabidopsis thaliana pollen tube growth

Author: Denis Falconet, Patrick Dallemagne, Azeddine Driouich, Ferdousse Laggoun, Flavien Dardelle, Jean-Claude Mollet, Arnaud Lehner, Jérémy Dehors, Christophe Rochais, Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale (Glyco-MEV), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), LIPID, Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Universite de Rouen Normandie Ministry of Research, FranceRegion Normandie, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: 0106 biological sciences, 0301 basic medicine, Arabidopsis, Molecular Conformation, Germination, Pollen Tube, Plant Science, Biology, medicine.disease_cause, 01 natural sciences, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, Cell wall deposition, Cell Wall, Superoxides, lcsh:Botany, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pollen, otorhinolaryngologic diseases, medicine, Pollen tube tip, Ovule, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis, Tip-polarized growth, Callose, food and beverages, RIC4, ROS, Chemical screen, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Sperm, Actins, lcsh:QK1-989, Cell biology, Sexual reproduction, Actin Cytoskeleton, Pollen tubes, 030104 developmental biology, chemistry, Pectins, Pollen tube, Actin dynamics, Research Article, 010606 plant biology & botany
Abstract: International audience; Background: During sexual reproduction, pollen grains land on the stigma, rehydrate and produce pollen tubes that grow through the female transmitting-tract tissue allowing the delivery of the two sperm cells to the ovule and the production of healthy seeds. Because pollen tubes are single cells that expand by tip-polarized growth, they represent a good model to study the growth dynamics, cell wall deposition and intracellular machineries. Aiming to understand this complex machinery, we used a low throughput chemical screen approach in order to isolate new tip-growth disruptors. The effect of a chemical inhibitor of monogalactosyldiacylglycerol synthases, galvestine-1, was also investigated. The present work further characterizes their effects on the tip-growth and intracellular dynamics of pollen tubes. Results: Two small compounds among 258 were isolated based on their abilities to perturb pollen tube growth. They were found to disrupt in vitro pollen tube growth of tobacco, tomato and Arabidopsis thaliana. We show that these 3 compounds induced abnormal phenotypes (bulging and/or enlarged pollen tubes) and reduced pollen tube length in a dose dependent manner. Pollen germination was significantly reduced after treatment with the two compounds isolated from the screen. They also affected cell wall material deposition in pollen tubes. The compounds decreased anion superoxide accumulation, disorganized actin filaments and RIC4 dynamics suggesting that they may affect vesicular trafficking at the pollen tube tip.Results: Two small compounds among 258 were isolated based on their abilities to perturb pollen tube growth. They were found to disrupt in vitro pollen tube growth of tobacco, tomato and Arabidopsis thaliana. We show that these 3 compounds induced abnormal phenotypes (bulging and/or enlarged pollen tubes) and reduced pollen tube length in a dose dependent manner. Pollen germination was significantly reduced after treatment with the two compounds isolated from the screen. They also affected cell wall material deposition in pollen tubes. The compounds decreased anion superoxide accumulation, disorganized actin filaments and RIC4 dynamics suggesting that they may affect vesicular trafficking at the pollen tube tip.Conclusion: These molecules may alter directly or indirectly ROP1 activity, a key regulator of pollen tube growth and vesicular trafficking and therefore represent good tools to further study cellular dynamics during polarized-cell growth.
Published: 2019
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48. A Novel

Author: Bérénice, Hatat, Samir, Yahiaoui, Cédric, Lecoutey, Audrey, Davis, Thomas, Freret, Michel, Boulouard, Sylvie, Claeysen, Christophe, Rochais, and Patrick, Dallemagne
Subjects: acetylcholinesterase, 5-HT6 receptors, Alzheimer’s disease, 5-HT4 receptors, MTDL, Neuroscience, Original Research
Abstract: This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer’s disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan-1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.
Published: 2019

49. Novel multi target-directed ligands targeting 5-HT4 receptors with in cellulo antioxidant properties as promising leads in Alzheimer's disease

Author: Irene Liparulo, Maria-Laura Bolognesi, Christophe Rochais, Christian Bergamini, Audrey Davis, Patrick Dallemagne, Hugo Payan, Bérénice Hatat, Caroline Lanthier, Cédric Lecoutey, Sylvie Claeysen, Marc Since, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), University of Bologna, This work was supported by funding from the Fondation Plan Alzheimer (AAP2015 Project TRIAD 016). The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER) for their contribution to the CERMN's analytical platform. European COST action CA15135 (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) supports this article with the funding of a Short-Term Scientific Mission attributed to CL, Lanthier, Caroline, Payan, Hugo, Liparulo, Irene, Hatat, Bérénice, Lecoutey, Cédric, Since, Marc, Davis, Audrey, Bergamini, Christian, Claeysen, Sylvie, Dallemagne, Patrick, Bolognesi, Maria-Laura, and Rochais, Christophe
Subjects: Antioxidant, antioxidant, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, medicine.disease_cause, Alzheimer's Disease, MTDL, 03 medical and health sciences, 0302 clinical medicine, Multi target, Aβ protein, Drug Discovery, medicine, phenol, 5-HT4 receptor, Receptor, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, Chemistry, Alzheimer's disease, 5-HT4 receptor, Antioxidant, Phenol, MTDL, Organic Chemistry, General Medicine, 3. Good health, Active compound, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aβ protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT4R agonists, and diverse antioxidant chemotypes. Interestingly, the most active compound 9g possesses a Ki of 12.7 nM towards 5-HT4R and an antioxidant activity in vitro and in cellulo.
Published: 2019
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50. Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Author: Patrick Dallemagne, François-Xavier Toublet, Julien Lalut, Marc Since, Bérénice Hatat, Cédric Lecoutey, Thomas Freret, Jana Sopkova-de Oliveira Santos, Christophe Rochais, Audrey Davis, Sophie Corvaisier, Sylvie Claeysen, Michel Boulouard, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by funding from the Fondation Vaincre Alzheimer (#FR-15072) and the Fondation Plan Alzheimer (AAP2015 Project TRIAD 016). The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER) for their contribution to the CERMN’s analytical platform. European COST action CA15135 (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) supports this article., and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 5-HT4 receptors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Ligands, Neuroprotection, Article, MTDL, Analytical Chemistry, lcsh:QD241-441, Pathogenesis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, lcsh:Organic chemistry, Alzheimer Disease, In vivo, Drug Discovery, Humans, Medicine, Prodrugs, Physical and Theoretical Chemistry, Receptor, Active metabolite, 030304 developmental biology, 0303 health sciences, biology, business.industry, Organic Chemistry, Brain, acetylcholinesterase, Prodrug, Acetylcholinesterase, 3. Good health, chemistry, Chemistry (miscellaneous), Chaperone (protein), biology.protein, Molecular Medicine, Carbamates, Cholinesterase Inhibitors, Receptors, Serotonin, 5-HT4, prodrug, business, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract: Alzheimer&rsquo, s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
Published: 2019
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