Author: "Jean-Luc Stigliani" - Searchworks@Jio Institute Digital Library Search Results

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1. Investigation of Direct and Retro Chromone-2-Carboxamides Based Analogs of Pseudomonas aeruginosa Quorum Sensing Signal as New Anti-Biofilm Agents

Author: Jeanne Trognon, Gonzalo Vera, Maya Rima, Jean-Luc Stigliani, Laurent Amielet, Salomé El Hage, Barbora Lajoie, Christine Roques, and Fatima El Garah
Subjects: Pseudomonas aeruginosa, Quorum Sensing inhibition, chromone carboxamides, PqsR, Pseudomonas Quinolone Signal (PQS), biofilms, Medicine, Pharmacy and materia medica, RS1-441
Abstract: Biofilm formation is considered a major cause of therapeutic failure because bacteria in biofilms have higher protection against antimicrobials. Thus, biofilm-related infections are extremely challenging to treat and pose major concerns for public health, along with huge economic impacts. Pseudomonas aeruginosa, in particular, is a “critical priority” pathogen, responsible for severe infections, especially in cystic fibrosis patients because of its capacity to form resistant biofilms. Therefore, new therapeutic approaches are needed to complete the pipeline of molecules offering new targets and modes of action. Biofilm formation is mainly controlled by Quorum Sensing (QS), a communication system based on signaling molecules. In the present study, we employed a molecular docking approach (Autodock Vina) to assess two series of chromones-based compounds as possible ligands for PqsR, a LuxR-type receptor. Most compounds showed good predicted affinities for PqsR, higher than the PQS native ligand. Encouraged by these docking results, we synthesized a library of 34 direct and 25 retro chromone carboxamides using two optimized routes from 2-chromone carboxylic acid as starting material for both series. We evaluated the synthesized carboxamides for their ability to inhibit the biofilm formation of P. aeruginosa in vitro. Overall, results showed several chromone 2-carboxamides of the retro series are potent inhibitors of the formation of P. aeruginosa biofilms (16/25 compound with % inhibition ≥ 50% at 50 μM), without cytotoxicity on Vero cells (IC50 > 1.0 mM). The 2,4-dinitro-N-(4-oxo-4H-chromen-2-yl) benzamide (6n) was the most promising antibiofilm compound, with potential for hit to lead optimization.
Published: 2022
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2. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Author: Thibaud Reyser, Tung H. To, Chinedu Egwu, Lucie Paloque, Michel Nguyen, Alexandre Hamouy, Jean-Luc Stigliani, Christian Bijani, Jean-Michel Augereau, Jean-Patrick Joly, Julien Portela, Jeffrey Havot, Sylvain R. A. Marque, Jérôme Boissier, Anne Robert, Françoise Benoit-Vical, and Gérard Audran
Subjects: alkoxyamine, alkylation, heme, malaria, radical chemistry, schistosomiasis, Organic chemistry, QD241-441
Abstract: Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.
Published: 2020
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3. Oxidation of 5-methylaminomethyl uridine (mnm5U) by Oxone Leads to Aldonitrone Derivatives

Author: Qishun Zhou, Bao Tram Vu Ngoc, Grazyna Leszczynska, Jean-Luc Stigliani, and Geneviève Pratviel
Subjects: RNA oxidation, aldonitone, oxaziridine, KHSO5, water solvent, Microbiology, QR1-502
Abstract: Oxidative RNA damage is linked to cell dysfunction and diseases. The present work focuses on the in vitro oxidation of 5-methylaminomethyl uridine (mnm5U), which belongs to the numerous post-transcriptional modifications that are found in tRNA. The reaction of oxone with mnm5U in water at pH 7.5 leads to two aldonitrone derivatives. They form by two oxidation steps and one dehydration step. Therefore, the potential oxidation products of mnm5U in vivo may not be only aldonitrones, but also hydroxylamine and imine derivatives (which may be chemically more reactive). Irradiation of aldonitrone leads to unstable oxaziridine derivatives that are susceptible to isomerization to amide or to hydrolysis to aldehyde derivative.
Published: 2018
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4. Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones

Author: Pierre Verhaeghe, Sébastien Lecommandoux, Antoine Tronnet, Marc Since, Jean-Luc Stigliani, Pedro Salas-Ambrosio, Sandra Bourgeade-Delmas, Bruno Dupuy, Amelie Vax, Colin Bonduelle, Team 3 LCPO : Polymer Self-Assembly & Life Sciences, Laboratoire de Chimie des Polymères Organiques (LCPO), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Ecole Nationale Supérieure de Chimie, de Biologie et de Physique (ENSCBP)-Université de Bordeaux (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Ecole Nationale Supérieure de Chimie, de Biologie et de Physique (ENSCBP)-Université de Bordeaux (UB)-Institut de Chimie du CNRS (INC), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Trimethylsilyl Compounds, Cell Survival, Polymers, Lithium bis(trimethylsilyl)amide, Microbial Sensitivity Tests, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, Ring (chemistry), 01 natural sciences, Biochemistry, Catalysis, Cell Line, Polymerization, Macrocyclic polypeptoids, Peptoids, chemistry.chemical_compound, Colloid and Surface Chemistry, Biological property, Humans, Density Functional Theory, Ring expansion polymerization (REP), chemistry.chemical_classification, Clostridioides difficile, Peptoid, General Chemistry, Polymer, Combinatorial chemistry, 0104 chemical sciences, [CHIM.POLY]Chemical Sciences/Polymers, Monomer, chemistry, Cyclization
Abstract: International audience; Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections.
Published: 2021
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5. Involvement of Pazopanib and Sunitinib Aldehyde Reactive Metabolites in Toxicity and Drug–Drug Interactions in Vitro and in Patient Samples

Author: Vania Bernardes-Génisson, Florent Puisset, Marie-Noëlle Paludetto, Jean-Luc Stigliani, Cécile Arellano, Anne Robert, Etienne Chatelut, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Drug, hepatotoxicity, Arginine, sunitinib, media_common.quotation_subject, 010501 environmental sciences, Pharmacology, Toxicology, 01 natural sciences, Pazopanib, 03 medical and health sciences, lysine adduct, drug-drug interactions, pazopanib, medicine, [CHIM.COOR]Chemical Sciences/Coordination chemistry, 030304 developmental biology, 0105 earth and related environmental sciences, media_common, 0303 health sciences, biology, CYP3A4, Sunitinib, Chemistry, reactive aldehyde metabolites, Cytochrome P450, General Medicine, 3. Good health, Docking (molecular), [SDV.TOX]Life Sciences [q-bio]/Toxicology, Toxicity, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, biology.protein, medicine.drug
Abstract: International audience; Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug–drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug–drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.
Published: 2019
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6. Gold(III) porphyrins: Synthesis and interaction with G-quadruplex DNA

Author: Pierre Verhaeghe, Geneviève Pratviel, Jean-Luc Stigliani, Samir Amrane, Emmanuelle Mothes, Tiffany Rundstadler, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANRS Maladies Infectieuses Emergentes – Agence autonome de l’Inserm (ECTZ103899), Gulli, Marie-Hélène, Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Stereochemistry, Anti-HIV Agents, Metalloporphyrins, 010402 general chemistry, G-quadruplex, 01 natural sciences, Biochemistry, Inorganic Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, G4, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Au3+-complexes, 030304 developmental biology, 0303 health sciences, Molecular Structure, Chemistry, Cationic polymerization, Modeling, RNA, Promoter, DNA, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Small molecule, Porphyrin, 3. Good health, 0104 chemical sciences, Cationic porphyrins, G-Quadruplexes, Molecular Docking Simulation, FRET melting, Nucleic acid, HIV-1, Gold
Abstract: International audience; G-quadruplex nucleic acids (G4s) are RNA and DNA secondary structures involved in the regulation of multiple key biological processes. They can be found in telomeres, oncogene promoters, RNAs, but also in viral genomes. Due to their unique structural features, very distinct from the canonical duplexes or single-strands, G4s represent promising pharmacological targets for small molecules, namely G4-ligands. Gold(III) penta-cationic porphyrins, as specific G4 ligands, are able to inhibit HIV-1 infectivity and their antiviral activity correlates with their affinity for G4s. Up to now, one of the best antiviral compounds is meso-5,10,15,20-tetrakis[4-(N-methyl-pyridinium-2-yl)phenyl]porphyrinato gold(III) (1). Starting from this compound, we report a structure/affinity relationship study of gold(III) cationic porphyrins to find out the best porphyrin candidate for functionalization, in order to study the antiviral mechanism of action of these gold(III) porphyrins.
Published: 2021
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7. Chlorinated bianthrones from the cyanolichen Nephroma laevigatum

Author: Jean-Luc Stigliani, Yves Champavier, Marion Millot, Phuong-Y. Mai, Mehdi A. Beniddir, Aurélie Lagarde, Lengo Mambu, Faculté de Pharmacie, Université de Limoges, Université de Limoges (UNILIM), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and ANR-17-CE35-0005,LICSYFILM,Les infections impliquant les biofilms à Candida : la solution serait-elle dans les lichens ?(2017)
Subjects: Magnetic Resonance Spectroscopy, Lichens, NMR calculations, Anthraquinones, 01 natural sciences, Nephroma laevigatum, Bianthrones, chemistry.chemical_compound, Cyanolichen, Ascomycota, Tandem Mass Spectrometry, Drug Discovery, Organic chemistry, Nephroma, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Lichen, Dichloromethane, Pharmacology, Anthracenes, biology, Molecular Structure, 010405 organic chemistry, Chemistry, General Medicine, biology.organism_classification, Dereplication, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Molecular networking, France, Emodin
Abstract: International audience; While depsidones, depsides or dibenzofuran-like compounds dominate the chemical composition of lichens, the cyanolichen Nephroma laevigatum affords a diversity of quinoid pigments represented by chlorinated anthraquinones derived from emodin and new bianthrones resulting from the homo- or heterodimerization of monomers. Bianthrones were pointed out from the dichloromethane extract by MS/MS-based molecular networking, then isolated and characterized on the basis of extensive spectroscopic analyzes and GIAO NMR shift calculation followed by CP3 analyzes.
Published: 2021
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8. Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

Author: Alexis Valentin, Pierre Verhaeghe, Patrice Vanelle, Sophie Corvaisier, Damián Muruzabal, Caroline Castera-Ducros, Nadine Azas, Sébastien Hutter, Emilie Pinault, Alexandre Destere, Alan H. Fairlamb, Clotilde Boudot, Cyril Fersing, Pascal Rathelot, Susan Wyllie, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Aurélie Malzert-Fréon, Julien Pedron, Bertrand Courtioux, Amaya Azqueta, Marc Since, Jean Luc Stigliani, Nicolas Primas, Carole Di Giorgio, Youssef Kabri, Romain Paoli-Lombardo, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Biologie Intégrative Santé Chimie Environnement (BISCEm), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Universidad de Navarra [Pamplona] (UNAV), CHU Limoges, University of Dundee, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), and Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS)
Subjects: SARs, Imidazopyridine, Pyridines, Trypanosoma brucei brucei, Redox potentials, Trypanosoma brucei, Pharmacology, 01 natural sciences, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, 03 medical and health sciences, Nitroreductase, chemistry.chemical_compound, Nitroaromatic, Parasitic Sensitivity Tests, Pharmacokinetics, Drug Discovery, Animals, Humans, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Serum Albumin, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Drug discovery, Organic Chemistry, Imidazoles, Kinetoplastids, Hep G2 Cells, General Medicine, Hit to lead, Nitroreductases, biology.organism_classification, Trypanocidal Agents, 0104 chemical sciences, 3. Good health, Imidazo[1 2-a]pyridine, Imidazo[1,2-a]pyridine, Pharmacophore, DNA Damage, Fexinidazole
Abstract: International audience; To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
Published: 2020
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9. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Author: Line Seguy, Cyril Fersing, Sébastien Hutter, Marc Since, Alexandre Destere, Bertrand Courtioux, Julien Pedron, Sophie Corvaisier, Elisa Boutet-Robinet, Pascal Rathelot, Alexis Valentin, Alix Sournia-Saquet, Jean Yves Brossas, Caroline Castera-Ducros, Dominique Mazier, Sandra Bourgeade-Delmas, Aurélie Malzert-Fréon, Susan Wyllie, Romain Paoli-Lombardo, Clotilde Boudot, Patrice Vanelle, Jean Luc Stigliani, Nicolas Primas, Luc Paris, Nadine Azas, Emilie Pinault, Pierre Verhaeghe, Alan H. Fairlamb, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Biologie Intégrative Santé Chimie Environnement (BISCEm), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Dundee, Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), CHU Limoges, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées, Service de Parasitologie - Mycologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Aix-Marseille Université, Université de Toulouse, CNRS, CCSD, Accord Elsevier, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN)
Subjects: SARs, Pyridines, Stereochemistry, Trypanosoma cruzi, [SDV]Life Sciences [q-bio], Trypanosoma brucei brucei, Sonogashira coupling, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Nitroaromatic, Parasitic Sensitivity Tests, Drug Discovery, medicine, Moiety, Cytotoxicity, Comet assay, Imidazo[1, 030304 developmental biology, Pharmacology, 0303 health sciences, 2-a]pyridine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Kinetoplastids, General Medicine, Nitroreductases, Trypanocidal Agents, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], Nitroimidazoles, Benznidazole, Pharmacophore, Lead compound, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Imidazo[1,2-alpha]pyridine, Fexinidazole, medicine.drug
Abstract: International audience; An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.
Published: 2020
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10. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Author: Chinedu O. Egwu, Thibaud Reyser, Jean-Luc Stigliani, Gérard Audran, Tung H To, Christian Bijani, Sylvain R. A. Marque, Françoise Benoit-Vical, Alexandre Hamouy, Jeffrey Havot, Michel Nguyen, Jérôme Boissier, Anne Robert, Lucie Paloque, Jean-Michel Augereau, Jean-Patrick Joly, Julien Portela, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), S.A.S ParaDev, Interactions Hôtes-Pathogènes-Environnements (IHPE), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Perpignan Via Domitia (UPVD), Institut National de la Santé et de la Recherche Médicale (INSERM), Gulli, Marie-Hélène, Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires - - RADICAL2017 - ANR-17-CE18-0017 - AAPG2017 - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Perpignan Via Domitia (UPVD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Aix-Marseille Université, Université de Perpignan, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), ANR-17-CE18-0017,RADICAL,Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires(2017), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Alkylation, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, malaria, Pharmaceutical Science, Schistosomiasis, Drug resistance, Heme, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 010402 general chemistry, 01 natural sciences, Plasmodium, Article, Analytical Chemistry, lcsh:QD241-441, Antimalarials, lcsh:Organic chemistry, schistosomiasis, Drug Discovery, parasitic diseases, Ic50 values, medicine, Animals, Humans, radical chemistry, Physical and Theoretical Chemistry, heme, alkylation, Schistosoma, Biological evaluation, Anthelmintics, biology, 010405 organic chemistry, Organic Chemistry, Radical chemistry, Biological activity, Schistosoma mansoni, Alkoxyamine, biology.organism_classification, medicine.disease, 3. Good health, 0104 chemical sciences, Malaria, Chemistry (miscellaneous), Molecular Medicine, alkoxyamine
Abstract: Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.
Published: 2020
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11. Nucleopolypeptides with DNA-triggered α helix-to-β sheet transition

Author: Jean-Luc Stigliani, Colin Bonduelle, Geneviève Pratviel, Michel Nguyen, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Circular dichroism, Stereochemistry, Beta sheet, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Protein Structure, Secondary, Catalysis, Nucleobase, chemistry.chemical_compound, Materials Chemistry, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Nucleotide, Protein secondary structure, chemistry.chemical_classification, Chemistry, Circular Dichroism, Metals and Alloys, DNA, General Chemistry, Polymer, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Helix, Ceramics and Composites, Peptides, 0210 nano-technology
Abstract: International audience; Synthetic polypeptides are versatile polymers outstandingly relevant to prepare bioinspired materials. In this work, we present a new class of smart polypeptide polymers, called nucleopolypeptides, having lateral chains functionalized with thymidine nucleobases. Structural studies performed by circular dichroism have revealed that the secondary structure of the polymers was influenced by nucleotide interaction and DNA sequence variation affording a selective helix-to-beta sheet transition with oligo(AAAAA)6.
Published: 2017
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12. Involvement of Pazopanib and Sunitinib Aldehyde Reactive Metabolites in Toxicity and Drug-Drug Interactions

Author: Marie-Noëlle, Paludetto, Jean-Luc, Stigliani, Anne, Robert, Vania, Bernardes-Génisson, Etienne, Chatelut, Florent, Puisset, and Cécile, Arellano
Subjects: Aldehydes, Sulfonamides, Indazoles, Angiogenesis Inhibitors, Serum Albumin, Human, Recombinant Proteins, Molecular Docking Simulation, Pyrimidines, Microsomes, Liver, Sunitinib, Cytochrome P-450 CYP3A, Humans, Drug Interactions, Protein Kinase Inhibitors
Abstract: Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.
Published: 2019

13. G-Quadruplex binding optimization by gold( iii ) insertion into the center of a porphyrin

Author: Geneviève Pratviel, Jean-Luc Stigliani, Emmanuelle Mothes-Martin, Patrick Calsou, Aurore De Rache, Jean-Louis Mergny, Samir Amrane, Coralie Modeste, Dennis Gomez, Angélique Pipier, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institute of Biophysics ASCR [Brno, Czech Republic], Cancéropole Grand Sud-Ouest (2016-E-10), Ligue Régionale contre le Cancer, comité de Dordogne, SYMBIT project (reg. no.CZ.02.1.01/0.0/0.0/15_003/0000477), ANR-12-BSV8-0008,QUARPDIEMS,Synthèse et évaluation cellulaire de ligands spécifiques de G-quadruplexes dérivés de porphyrines et salens(2012), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Gulli, Marie-Hélène, BLANC - Synthèse et évaluation cellulaire de ligands spécifiques de G-quadruplexes dérivés de porphyrines et salens - - QUARPDIEMS2012 - ANR-12-BSV8-0008 - BLANC - VALID, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], 010402 general chemistry, 01 natural sciences, Quantum mechanics, Ion, Quadruplex, Inorganic Chemistry, chemistry.chemical_compound, Gold iii, polycyclic compounds, heterocyclic compounds, [CHIM.COOR]Chemical Sciences/Coordination chemistry, ComputingMilieux_MISCELLANEOUS, G quadruplex binding, 010405 organic chemistry, Cationic polymerization, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Combinatorial chemistry, Porphyrin, 0104 chemical sciences, chemistry, Stacking, Nucleic acid, Gold-porphyrin, Selectivity, DNA, Drug DNA interactions
Abstract: International audience; Porphyrins represent a valuable class of ligands for G-quadruplex nucleic acids. Herein, we evaluate the binding of cationic porphyrins metallated with gold(iii) to G-quadruplex DNA and we compare it with other porphyrin derivatives. The G-quadruplex stabilization capacity and the selectivity of the various porphyrins were evaluated by biophysical and biochemical assays. The porphyrins were also tested as inhibitors of telomerase. It clearly appeared that the insertion of gold(iii) ion in the center of the porphyrin increases the binding affinity of the porphyrin for the G-quadruplex target. Together with modelling studies, it is possible to propose that the insertion of the square planar gold(iii) ion adds an extra positive charge on the complex and decreases the electron density in the porphyrin aromatic macrocycle, both properties being in favour of stronger electrostatic and π-staking interactions.
Published: 2019
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14. Synthesis, oxidation potential and anti-mycobacterial activity of isoniazid and analogues: insights into the molecular isoniazid activation mechanism

Author: Céline Deraeve, Giorgia Mori, Jean-Luc Stigliani, Alix Sournia-Saquet, Julie Laborde, Lea Lecoq, Beatrice Silvia Orena, Geneviève Pratviel, Vania Bernardes-Génisson, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, and University of Pavia
Subjects: Tuberculosis, Drug resistance, 010402 general chemistry, medicine.disease_cause, 01 natural sciences, Mycobacterium tuberculosis, chemistry.chemical_compound, medicine, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Heme, chemistry.chemical_classification, Mutation, biology, 010405 organic chemistry, Activator (genetics), Chemistry, Isoniazid, General Chemistry, biochemical phenomena, metabolism, and nutrition, respiratory system, bacterial infections and mycoses, biology.organism_classification, medicine.disease, 0104 chemical sciences, 3. Good health, Enzyme, Biochemistry, medicine.drug
Abstract: International audience; Tuberculosis (TB) is one of the leading causes of death due to infectious diseases. Among the specific drugs currently employed to treat tuberculosis, isoniazid (INH), a pro-drug, attracts a great interest. However, Mycobacterium tuberculosis (MTB) clinical isolates resistant to INH are significantly increasing thus compromising the efficiency of TB-treatment. Concerning the mechanism of resistance to INH, it is nowadays well established that it mainly results from mutations in the katG genes encoding for INH enzymatic activator. Recently, it was proposed that mutation in katG induces differences in heme or side chain redox potential so that the enzyme loses its ability to oxidize INH to radical species. In this work, we synthesized and selected a series of INH analogues for a study of their oxidation potential and evaluation of their anti-TB efficiency toward MTB wild-type and drug resistant strains. On the contrary to what was postulated, no correlation exists between the easier oxidation of a molecule and its anti-MTB activity toward resistant strains. Based on experimental data and theoretical calculations, we proposed an activation mechanism for INH and analogues based on a one-electron oxidation step of the hydrazyl function at the proximal nitrogen followed by a radical transposition to the distal nitrogen, which then induces a β-homolytic cleavage of the C(=O)-N bond to afford diazene and the isonicotinoyl radical species.
Published: 2016
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15. Ionic Polypeptide Polymers with Unusual β-Sheet Stability

Author: Geneviève Pratviel, Jean-Luc Stigliani, Colin Bonduelle, Christian Bijani, Pierre Verhaeghe, Michel Nguyen, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Models, Molecular, Polymers and Plastics, Polymers, Beta sheet, Ionic bonding, Bioengineering, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Biomaterials, Protein structure, Polymer chemistry, Materials Chemistry, Side chain, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Solubility, chemistry.chemical_classification, Ions, Aqueous solution, Molecular Structure, Water, Polymer, DNA, Hydrogen-Ion Concentration, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Amino acid, chemistry, Protein Conformation, beta-Strand, 0210 nano-technology, Peptides
Abstract: International audience; Incorporating charged amino acid side chains in polypeptide polymer backbones to improve solubility usually leads to reduced secondary structuring. Here we show that highly water soluble (>15 mg.mL–1) β-sheets can be obtained via nucleotide monophosphate grafting onto simple poly(γ-propargyl-L-glutamate) backbone. This synthetic methodology has been applied to the synthesis of thymidine-based nucleopolypeptides presenting stable β-sheet conformation in aqueous solutions with pH values comprised between 4 and 8. These polymeric analogues of nucleoproteins exhibited selective interaction with simple DNA sequences displaying adenine.
Published: 2018
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16. Novel 8-nitroquinolin-2(1 H )-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

Author: Susan Wyllie, Julien Pedron, Alain Moreau, Alix Sournia-Saquet, Pierre Verhaeghe, Bertrand Courtioux, Sébastien Hutter, Michèle Laget, Emmanuelle Mothes, Lucie Paloque, Clotilde Boudot, Alan H. Fairlamb, Sandra Bourgeade-Delmas, Laure Vendier, Geneviève Pratviel, Alexis Valentin, Elisa Boutet-Robinet, Nadine Azas, Jean-Luc Stigliani, LCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, France, Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Contaminants & Stress Cellulaire (ToxAlim-COMICS), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), The Wellcome Trust Centre for Anti-Infectives Research [Dundee, Scotland] (WCAIR), University of Dundee, Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: 0301 basic medicine, Trypanosoma, Cell Survival, Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, Antiprotozoal Agents, Trypanosoma brucei, 01 natural sciences, Redox, Article, Ames test, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Parasitic Sensitivity Tests, Drug Discovery, parasitic diseases, medicine, Electrochemistry, Humans, Kinetoplastida, Leishmania infantum, Cytotoxicity, Anti-kinetoplastids, Pharmacology, Leishmania, Dose-Response Relationship, Drug, Molecular Structure, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, Nitroquinolines, Electrochemical Techniques, Hep G2 Cells, General Medicine, 8-Nitroquinolin-2(1H)-one, Nitroreductases, biology.organism_classification, Combinatorial chemistry, 0104 chemical sciences, 030104 developmental biology, Intramolecular force, Lactam, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pharmacophore
Abstract: International audience; To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above -0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.
Published: 2018
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17. 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a] pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Author: Maxime D. Crozet, Alan H. Fairlamb, Geneviève Pratviel, Alexis Valentin, Pascal Rathelot, Alix Sournia-Saquet, Clotilde Boudot, Anita Cohen, Patrice Vanelle, Julien Pedron, Jean-Luc Stigliani, Sandra Bourgeade-Delmas, Susan Wyllie, Pierre Verhaeghe, Nadine Azas, Caroline Castera-Ducros, Cyril Fersing, Alain Moreau, Sébastien Hutter, Nicolas Primas, Bertrand Courtioux, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Department of Biochemistry, Medical Sciences Institute, Dundee University, Dundee, Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), and Université de Toulouse (UT)
Subjects: Models, Molecular, 0301 basic medicine, SARs, Redox potentials, HepG2 cytotoxicity, Crystallography, X-Ray, MESH: Parasitic Sensitivity Tests, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Parasitic Sensitivity Tests, In vitro activity, Drug Discovery, Nitroheterocycles, Moiety, MESH: Trypanocidal Agents, Imidazo[1, Leishmania, 2-a]pyridine, Molecular Structure, MESH: Drug Screening Assays, Antitumor, Hep G2 Cells, General Medicine, Trypanocidal Agents, 3. Good health, MESH: Nitroreductases, MESH: Cell Survival, Imidazo[1,2-a]pyridine, Pharmacophore, MESH: Models, Molecular, Trypanosoma, MESH: Cell Line, Tumor, Cell Survival, Stereochemistry, Antiparasitic, medicine.drug_class, Trypanosoma brucei brucei, 030106 microbiology, MESH: Molecular Structure, Substituent, Antineoplastic Agents, MESH: Hep G2 Cells, Article, Structure-Activity Relationship, 03 medical and health sciences, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Humans, Amastigote, Cell Proliferation, Pharmacology, MESH: Humans, MESH: Leishmania donovani, Dose-Response Relationship, Drug, Aryl, Organic Chemistry, MESH: Trypanosoma brucei brucei, Nitroreductases, MESH: Crystallography, X-Ray, 030104 developmental biology, chemistry, Nitro, Suzuki-Miyaura cross-coupling reaction, MESH: Antineoplastic Agents, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Drug Screening Assays, Antitumor, Leishmania donovani, Fexinidazole
Abstract: International audience; Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.
Published: 2018
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18. Smart Poly(imidazoyl-l-lysine): Synthesis and Reversible Helix-to-Coil Transition at Neutral pH

Author: Bonduelle, Estefania Piedra-Arroni, Fatma Makni, Laura Severac, Jean-Luc Stigliani, Geneviève Pratviel, and Colin
Subjects: food and beverages, smart polypeptides, imidazole-containing polymers, helix-to-coil transition, poly(lysine), pH-responsive
Abstract: Polypeptide polymers can adopt natural protein secondary structures such as α-helices or β-sheets, and this unique feature is at the origin of some intriguing physico–chemical properties. In this work, we present how side chain imidazoylation of a poly(l-lysine) scaffold affords the preparation of poly(histidine) counterparts exhibiting α-helix conformation. This structuring behavior is reversible and can be controlled by means of pH and or temperature changes.
Published: 2017
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19. Smart Poly(imidazoyl-l-lysine): Synthesis and Reversible Helix-to-Coil Transition at Neutral pH

Author: Estefania Piedra-Arroni, Fatma Makni, Laura Severac, Jean-Luc Stigliani, Geneviève Pratviel, Colin Bonduelle, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: lcsh:QD241-441, Imidazole-containing polymers, lcsh:Organic chemistry, Helix-to-coil transition, food and beverages, Smart polypeptides, Poly(lysine), [CHIM.COOR]Chemical Sciences/Coordination chemistry, Article, pH-responsive
Abstract: International audience; Polypeptide polymers can adopt natural protein secondary structures such as α-helices or β-sheets, and this unique feature is at the origin of some intriguing physico–chemical properties. In this work, we present how side chain imidazoylation of a poly(l-lysine) scaffold affords the preparation of poly(histidine) counterparts exhibiting α-helix conformation. This structuring behavior is reversible and can be controlled by means of pH and or temperature changes.
Published: 2017
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20. Structures of the copper and zinc complexes of PBT2, a chelating agent evaluated as potential drug for neurodegenerative diseases

Author: Michel Nguyen, Jean-Luc Stigliani, Laure Vendier, Bernard Meunier, Anne Robert, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Department of Chemical Engineering, Guangdong University of Technology, and Guangdong University of Technology
Subjects: chemistry.chemical_classification, Denticity, 010405 organic chemistry, Stereochemistry, Clioquinol, chemistry.chemical_element, Zinc, 010402 general chemistry, 01 natural sciences, Copper, 0104 chemical sciences, 3. Good health, Coordination complex, Inorganic Chemistry, Metal, chemistry, visual_art, medicine, visual_art.visual_art_medium, Chelation, [CHIM.COOR]Chemical Sciences/Coordination chemistry, PBT2, medicine.drug
Abstract: International audience; Clioquinol and PBT2, based on a 8-hydroxyquinoline scaffold, have been proposed as drugs able to treat the disruption of metal homeostasis in neurodegenerative diseases, especially Alzheimer's disease (AD). They are believed to reduce metal–amyloid (Aβ) interactions and regulate redox homeostasis in AD brains. Therefore, the understanding of the molecular aspects of metal chelation by 8-hydroxyquinolines is clearly important for the development of future metal chelators as putative drugs. Despite this, literature data on these aspects are rather limited. We report herein the stoichiometries and structures of the copper(II) and zinc(II) complexes of PBT2. The reported data indicate that the coordination chemistry of PBT2 is characterized by high versatility and a lack of metal selectivity. For each metal, several complexes can co-exist, and the copper complexes differ from their zinc analogues. The structures of the PBT2 complexes are significantly different to those reported for complexes of clioquinol, the prototype of this series. As PBT2 can be a bi- or tridentate ligand, different complexes can be formed with copper, including ternary complexes PBT2–Cu–X. The versatile structures of the metal complexes of PBT2 in vivo, especially in the brains of AD patients, should be dependent on competitive ligands, including amyloids. This feature might be a limitation for an efficient extraction of copper from amyloids.
Published: 2017
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21. ChemInform Abstract: Synthesis, Oxidation Potential and anti-Mycobacterial Activity of Isoniazid and Analogues: Insights into the Molecular Isoniazid Activation Mechanism

Author: Jean-Luc Stigliani, Vania Bernardes-Génisson, Beatrice Silvia Orena, Geneviève Pratviel, Lea Lecoq, Céline Deraeve, Giorgia Mori, Alix Sournia-Saquet, and Julie Laborde
Subjects: chemistry.chemical_classification, Mutation, Tuberculosis, biology, Activator (genetics), Stereochemistry, Isoniazid, General Medicine, Drug resistance, biochemical phenomena, metabolism, and nutrition, respiratory system, bacterial infections and mycoses, biology.organism_classification, medicine.disease, medicine.disease_cause, Mycobacterium tuberculosis, chemistry.chemical_compound, Enzyme, chemistry, Biochemistry, medicine, Heme, medicine.drug
Abstract: Tuberculosis (TB) is one of the leading causes of death due to infectious diseases. Among the specific drugs currently employed to treat tuberculosis, isoniazid (INH), a pro-drug, attracts a great interest. However, Mycobacterium tuberculosis (MTB) clinical isolates resistant to INH are significantly increasing thus compromising the efficiency of TB-treatment. Concerning the mechanism of resistance to INH, it is nowadays well established that it mainly results from mutations in the katG genes encoding for INH enzymatic activator. Recently, it was proposed that mutation in katG induces differences in heme or side chain redox potential so that the enzyme loses its ability to oxidize INH to radical species. In this work, we synthesized and selected a series of INH analogues for a study of their oxidation potential and evaluation of their anti-TB efficiency toward MTB wild-type and drug resistant strains. On the contrary to what was postulated, no correlation exists between the easier oxidation of a molecule and its anti-MTB activity toward resistant strains. Based on experimental data and theoretical calculations, we proposed an activation mechanism for INH and analogues based on a one-electron oxidation step of the hydrazyl function at the proximal nitrogen followed by a radical transposition to the distal nitrogen, which then induces a b-homolytic cleavage of the C(=O)-N bond to afford diazene and the isonicotinoyl radical species.
Published: 2016
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22. Evaluation of the inhibitory activity of (aza)isoindolinone-type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis

Author: Jean-Luc Stigliani, Vania Bernardes-Génisson, Maria Rosalia Pasca, Geneviève Pratviel, Giorgia Mori, Jean Bernadou, Annaïk Quémard, Christian Lherbet, Patricia Constant, Aurélien Chollet, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani' = Department of Biology and Biotechnology [Univ di Pavia] (DBB UNIPV), Università degli Studi di Pavia = University of Pavia (UNIPV), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Antitubercular Agents, Reductase, Isoindoles, 010402 general chemistry, 01 natural sciences, Biochemistry, law.invention, Mycobacterium tuberculosis, (aza)isoindolinone, mycolic acid biosynthesis, Structure-Activity Relationship, Bacterial Proteins, law, Drug Discovery, Structure–activity relationship, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Binding site, Pharmacology, Binding Sites, biology, 010405 organic chemistry, Chemistry, INHA, Organic Chemistry, biology.organism_classification, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), In vitro, Recombinant Proteins, 0104 chemical sciences, 3. Good health, Protein Structure, Tertiary, Molecular Docking Simulation, Mycolic Acids, Docking (molecular), docking, Recombinant DNA, Molecular Medicine, InhA inhibition, Thermodynamics
Abstract: International audience; Inhibitors of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA) are considered as potential promising therapeutics for the treatment of tuberculosis. Previously, we reported that azaisoindolinone-type compounds displayed, in vitro, inhibitory activity toward InhA. Herein, we describe chemical modifications of azaisoindolinone scaffold, the synthesis of 15 new compounds and their evaluations toward the in vitro InhA activity. Based on these results, a structure-InhA inhibitory activity relationship analysis and a molecular docking study, using the conformation of InhA found in the 2H7M crystal structure, were carried out to predict a possible mode of interaction of the best (aza)isoindolinone-type inhibitors with InhA in vitro. Then, the work was extended toward evaluations of these compounds against Mycobacterium tuberculosis (Mtb) growth, and finally, some of them were also investigated in respect of their ability to inhibit mycolic acid biosynthesis inside mycobacteria. Although, some azaisoindolinones were able to inhibit InhA activity and Mtb growth in vitro, they did not inhibit the mycolic acid biosynthesis inside Mtb.
Published: 2016
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23. Comparison of the Reactivity of Antimalarial 1,2,4,5-Tetraoxanes with 1,2,4-Trioxolanes in the Presence of Ferrous Iron Salts, Heme, and Ferrous Iron Salts/Phosphatidylcholine

Author: James Chadwick, B. Kevin Park, Fatima Bousejra-El Garah, James L. Maggs, Paul M. O'Neill, Jean-Luc Stigliani, Sant Muangnoicharoen, Michael H. L. Wong, Richard Amewu, and Stephen A. Ward
Subjects: Models, Molecular, Alkylation, Plasmodium berghei, Plasmodium falciparum, Stereoisomerism, Heme, Peroxide, Ferrous, Antimalarials, Structure-Activity Relationship, chemistry.chemical_compound, Parasitic Sensitivity Tests, Phosphatidylcholine, Drug Discovery, Organic chemistry, Spiro Compounds, Tetraoxanes, Ferrous Compounds, Porphyrin, Combinatorial chemistry, Peroxides, chemistry, Phosphatidylcholines, Molecular Medicine
Abstract: Dispiro-1,2,4,5-tetraoxanes and 1,2,4-trioxolanes represent attractive classes of synthetic antimalarial peroxides due to their structural simplicity, good stability, and impressive antimalarial activity. We investigated the reactivity of a series of potent amide functionalized tetraoxanes with Fe(II)gluconate, FeSO(4), FeSO(4)/TEMPO, FeSO(4)/phosphatidylcholine, and heme to gain knowledge of their potential mechanism of bioactivation and to compare the results with the corresponding 1,2,4-trioxolanes. Spin-trapping experiments demonstrate that Fe(II)-mediated peroxide activation of tetraoxanes produces primary and secondary C-radical intermediates. Reaction of tetraoxanes and trioxolanes with phosphatidylcholine, a predominant unsaturated lipid present in the parasite digestive vacuole membrane, under Fenton reaction conditions showed that both endoperoxides share a common reactivity in terms of phospholipid oxidation that differs with that of artemisinin. Significantly, when tetraoxanes undergo bioactivation in the presence of heme, only the secondary C-centered radical is observed, which smoothly produces regioisomeric drug derived-heme adducts. The ability of these tetraoxanes to alkylate the porphyrin ring was also confirmed with Fe(II)TPP and Mn(II)TPP, and docking studies were performed to rationalize the regioselectivity observed in the alkylation process. The efficient process of heme alkylation and extensive lipid peroxidation observed here may play a role in the mechanism of action of these two important classes of synthetic endoperoxide antimalarial.
Published: 2011
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24. Synthesis and antimalarial activity of new atovaquone derivatives

Author: Genevieve Baziard-Mouysset, Henri Vial, Maynadier Marjorie, Salome El Hage, Michèle Ane, Marc Payard, and Jean-Luc Stigliani
Subjects: Stereochemistry, Plasmodium falciparum, Pharmacology, Chemical synthesis, Antimalarials, Structure-Activity Relationship, Parasitic Sensitivity Tests, Chloroquine, parasitic diseases, Drug Discovery, medicine, Structure–activity relationship, Malaria, Falciparum, Atovaquone, Quinine, biology, Chemistry, Organic Chemistry, Biological activity, General Medicine, Antimicrobial, biology.organism_classification, medicine.drug
Abstract: In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC(50) values in the range of 1.25-50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.
Published: 2009
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25. Binding of the tautomeric forms of isoniazid-NAD adducts to the active site of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA): A theoretical approach

Author: Jean Bernadou, Vania Bernardes-Génisson, Jean-Luc Stigliani, Tamara Delaine, Philippe Arnaud, and Bernard Meunier
Subjects: Models, Molecular, ONIOM, Stereochemistry, Crystallography, X-Ray, Adduct, Isomerism, Catalytic Domain, Isoniazid, Materials Chemistry, Computer Simulation, Physical and Theoretical Chemistry, Spectroscopy, biology, Chemistry, Ligand, INHA, Active site, Mycobacterium tuberculosis, AutoDock, NAD, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), Computer Graphics and Computer-Aided Design, Tautomer, Protein Structure, Tertiary, Docking (molecular), biology.protein, Protein Binding
Abstract: The front-line antituberculosis drug isoniazid (INH) inhibits InhA, the NADH-dependent fatty acid biosynthesis enoyl ACP-reductase from Mycobacterium tuberculosis, via formation of covalent adducts with NAD (INH-NAD adducts). While ring tautomers were found the main species formed in solution, only the 4S chain INH-NAD tautomer was evidenced in the crystallized InhA:INH-NAD complex. In this study we attempted to explore the modes of interaction and energy binding of the different isomers placed in the active site of InhA with the help of various molecular modelling techniques. Ligand and enzyme models were generated with the help of the Vega ZZ program package. Resulting ligands were then docked into the InhA active site individually using computational automated docking package AUTODOCK 3.0.5. The more relevant docked conformations were then used to compute the interaction energy between the ligands and the InhA cavity. The AM1 Hamiltonian and the QM/MM ONIOM methodologies were used and the results compared. The various tautomers were found docked in almost the same place where INH-NAD was present as predicted by earlier X-ray crystallographic studies. However, some changes of ligand conformation and of the interactions ligand-protein were evidenced. The lower binding energy was observed for the 4S chain adduct that probably represents the effective active form of the INH-NAD adducts, as compared to the 4R epimer. The two 4S,7R and 4R,7S ring tautomers show intermediate and similar binding energies contrasting with their different experimental inhibitory potency on InhA. As a possible explanation based on calculated conformations, we formulated the hypothesis of an initial binding of the two ring tautomers to InhA followed by opening of only the ring hemiamidal 4S,7R tautomer (possibly catalyzed by Tyr158 phenolate basic group) to give the 4S chain INH-NAD tight-binding inhibitor. The predictions of ligand-protein interactions at the molecular level can be of primary importance in elucidating the mechanisms of action of isoniazid and InhA-related resistances, in identifying the effective mycobactericidal entities and, in further step, in the design of a new generation of antitubercular drugs.
Published: 2008
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26. Ring–Chain Tautomerism of Simplified Analogues of Isoniazid–NAD(P) Adducts: an Experimental and Theoretical Study

Author: Jean-Luc Stigliani, Vania Bernardes-Génisson, Bernard Meunier, Jean Bernadou, Heinz Gornitzka, and Tamara Delaine
Subjects: Solvent, chemistry.chemical_compound, chemistry, Stereochemistry, Organic Chemistry, Pyridine, Substituent, Molecular orbital, Pyridinium, Physical and Theoretical Chemistry, Ring (chemistry), Tautomer, Adduct
Abstract: Simplified analogues of oxidized and reduced isoniazid–NAD(P) adducts were prepared to study their behaviour with regard to ring–chain tautomeric isomerism in solution. In DMSO, the oxidized analogues (pyridinium salts) and the corresponding 1,2-dihydropyridine-reduced compounds were found to exist exclusively in the ring (cyclic hemiamidal) form. In contrast, the 1,4-dihydropyridine-reduced analogues were present in the ring and/or chain forms depending on the nature of the aromatic substituent. The 1,4-dihydropyridines (Ar = Ph, 3Cl-Py) are, in solution, preferentially in the keto–amide chain form, whereas the pyridine analogue (Ar = Py), which is the closest model of the isoniazid–NAD(P) adduct, exists as ring (major) and chain (minor) tautomers in equilibrium. The ratio of the tautomeric forms involved in the equilibrium of this system is also influenced by the polarity of the solvent with a shift towards the ring tautomer when the polarity of the solvent is increased. Complementary computational studies were performed by using quantum chemical calculations (B3LYP/6-31G**) and frontier molecular orbital analysis, which allowed the key structural factors involved in the ring–chain tautomerism equilibrium to be discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Published: 2007
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27. Cationic porphyrin - anionic surfactant mixtures for the promotion of self-organized 1:4 ion pair in water with strong aggregation properties

Author: Geneviève Pratviel, Jean-Luc Stigliani, Muriel Blanzat, Vincent Pradines, Isabelle Rico-Lattes, Christian Bijani, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: chemistry.chemical_classification, Anions, Aqueous solution, Porphyrins, Proton Magnetic Resonance Spectroscopy, Supramolecular chemistry, Cationic polymerization, Chemical modification, Water, Micelle, Porphyrin, Atomic and Molecular Physics, and Optics, chemistry.chemical_compound, Surface-Active Agents, chemistry, Pulmonary surfactant, Microscopy, Electron, Transmission, Cations, Polymer chemistry, Organic chemistry, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Physical and Theoretical Chemistry, Alkyl
Abstract: International audience; We performed a systematic study on the spectroscopic and aggregation properties of stoichiometric mixtures (1:4) of the tetracationic meso-tetrakis(4-N-methylpyridinium)porphyrin (H2TMPyP) and three sodium alkylsulfate surfactants (tetradecyl, hexadecyl, and octadecylsulfate) in an aqueous solution. The objective was to build a supramolecular aggregate, which would favor the internalization of tetracationic porphyrins in cells without chemical modification of the structure of the porphyrin. We show that stoichiometric H2TMPyP/alkylsulfate (1:4) mixtures lead to the formation of large hollow spherical aggregates (60–160 nm). The TEM images show that the membrane of these aggregates are composed of smaller aggregates, which are probably rod-like micelles. These rod-like micelles have a hydrophobic core composed of the alkyl chains of the alkylsulfate surfactant, whereas the charged surface corresponds to the tetracationic porphyrins.
Published: 2015
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28. Synthesis,antimicrobial activity and physico-chemical properties of some n-alkyldimethylbenzylammonium halides

Author: Salomé El Hage, Christine Roques, Jean-Luc Stigliani, Geneviève Baziard, Barbora Lajoie, Aurélie Furiga-Chusseau, Centre National de la Recherche Scientifique - CNRS (FRANCE), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Laboratoire de génie chimique [ancien site de Basso-Cambo] (LGC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique de Toulouse - INPT (FRANCE), Laboratoire de Génie Chimique (LGC), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Health, Toxicology and Mutagenesis, Biomedical Engineering, 02 engineering and technology, Antimicrobial activity, 010402 general chemistry, medicine.disease_cause, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Microbiology, Benzalkonium chloride, [CHIM.GENI]Chemical Sciences/Chemical engineering, Quaternization, Artificial Intelligence, Enterococcus hirae, Lipophilicity, medicine, Génie chimique, [CHIM.COOR]Chemical Sciences/Coordination chemistry, General Pharmacology, Toxicology and Pharmaceutics, Candida albicans, Escherichia coli, General Immunology and Microbiology, biology, Chemistry, General Neuroscience, Aspergillus niger, General Medicine, Quaternary ammonium salts, 021001 nanoscience & nanotechnology, biology.organism_classification, Antimicrobial, 0104 chemical sciences, Ingénierie biomédicale, Staphylococcus aureus, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, General Agricultural and Biological Sciences, Antibacterial activity, medicine.drug, Nuclear chemistry
Abstract: International audience; Quaternary ammonium salts (chloride, bromide and iodide; QUATs) with n-alkyl chain lengths between C8 and C18 have been synthesized under optimized experimental conditions. These compounds were tested in vitro for antimicrobial activity against representative bacterial strains (Staphylococcus aureus CIP 4.83, Enterococcus hirae CIP 5855, Pseudomonas aeruginosa CIP 82118, Escherichia coli CIP 53126, Mycobacterium smegmatis CIP 7326) and fungal species (Aspergillus niger ATCC 16404, Candida albicans IP 118079, Trichophyton interdigitale IP 146583). While these compounds showed moderate antifungal activity, several of them (particularly C14-I−) may be considered as highly potential antibacterial agents against S. aureus, E. hirae and E. coli with MIC values lower than that of commercial benzalkonium chloride and ciprofloxacin used as standards. The relationship between the lipophilicity and the antibacterial activity of the tested QUATs was quantified by a multiple linear regression method.
Published: 2014
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29. Antipoliovirus Structure−Activity Relationships of Some Aporphine Alkaloids

Author: M. Amoros, L. Girre, Joël Boustie, Jarbas Montanha, Marc Payard, and Jean-Luc Stigliani
Subjects: Models, Molecular, Aporphines, Stereochemistry, Pharmaceutical Science, Herpesvirus 1, Human, Virus Replication, Antiviral Agents, Methylenedioxy, Analytical Chemistry, Structure-Activity Relationship, chemistry.chemical_compound, Alkaloids, Cytopathogenic Effect, Viral, Chlorocebus aethiops, Drug Discovery, Animals, Humans, Structure–activity relationship, Moiety, Aporphine, Isoquinoline, Vero Cells, Pharmacology, Chemistry, Tetrahydroisoquinoline, Alkaloid, Organic Chemistry, Poliovirus, Complementary and alternative medicine, Molecular Medicine
Abstract: A series of 18 aporphinoids have been tested in vitro against human poliovirus. The aporphines (+)-glaucine fumarate (1), (+)-N-methyllaurotetanine (4), (+)-isoboldine (7), and (-)-nuciferine, HCl (10) were found to be active with selectivity indices > 14. The nature of the 1, 2-substituents of the isoquinoline moiety appeared to be critical for antipoliovirus activity. An SAR study demonstrated the importance of a methoxyl group at C-2 on the tetrahydroisoquinoline ring for the induction of antipoliovirus activity. Molecular modeling of some compounds in this series revealed the close similarities between the three-dimensional conformational features of the inactive 1,2-substituted derivatives (+)-boldine (6) and (+)-laurolitsine (5) with derivatives containing the 1,2-(methylenedioxy) moiety, which were generally found to be inactive as exemplified by (+)-cassythicine (9).
Published: 1998
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30. Synthesis and in vitro bronchospasmolytic activity of 8-aryl, heteroaryl or arylalkyl theophyllines

Author: C. Tournaire, Charles Advenier, Jean-Luc Stigliani, Marc Payard, A. Rached, J. C. Yavo, Genevieve Baziard-Mouysset, and S Younes
Subjects: Pharmacology, Bicyclic molecule, Stereochemistry, Aryl, Organic Chemistry, General Medicine, Chemical synthesis, In vitro, Bronchospasm, chemistry.chemical_compound, chemistry, Drug Discovery, medicine, Theophylline, medicine.symptom, Histamine, Acetylcholine, medicine.drug
Abstract: Summary Twenty-four 8-aryl- or 8-heteroaryl-substituted theophyllines have been synthesized. The substituents are aromatic rings and heterocycles likely to induce an antiallergic effect or a spasmolytic activity. In vitro evaluation of the bronchospasm caused by acetylcholine or histamine shows an interesting activity for half of the compounds. Among them, the furanic 111s and 2-chlorophenyl IIIi derivatives are, for instance, four times more active than theophylline.
Published: 1995
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31. Synthesis and calcium antagonistic activity of diethyl styrylbenzylphosphonates

Author: J Tisne-Versailles, G. Tchani, R Bonnafous, S Younes, Genevieve Baziard-Mouysset, Marc Payard, and Jean-Luc Stigliani
Subjects: Pharmacology, Fostedil, Ester derivatives, Organic Chemistry, Antagonist, chemistry.chemical_element, Biological activity, General Medicine, Calcium, In vitro, chemistry.chemical_compound, chemistry, Drug Discovery, Fluorine, Organic chemistry, Antagonism
Abstract: Twenty-three new phosphonic ester derivatives of stilbene exhibiting structural analogies with fostedil are described. Examination of calcium antagonism showed that this activity could not be increased by introducing electron-withdrawing, electron-releasing or lipophilic substituents. Only compounds containing fluorine at the 2 or 4 positions exhibited similar activity to the model.
Published: 1994
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32. Inhibitory effects on platelet aggregation and cyclic AMP phosphodiesterase of azaindolizine-type compounds

Author: Jean-Luc Stigliani, Gérard Grassy, Jacques Szefner, Jean-Pierre Chapat, Yves Adam, J. C. Teulade, and A. Gueiffier
Subjects: chemistry.chemical_classification, biology, Platelet aggregation, Chemistry, Process Chemistry and Technology, Phosphodiesterase, Biological activity, Inhibitory postsynaptic potential, Computer Science Applications, Analytical Chemistry, chemistry.chemical_compound, Enzyme, Biochemistry, Enzyme inhibitor, biology.protein, Platelet, Arachidonic acid, Spectroscopy, Software
Abstract: Grassy, G., Stigliani, J.-L., Szefner, J., Gueiffier, A., Teulade, J.-C., Chapat, J.-P. and Adam, Y., 1993. Inhibitory effects on platelet aggregation and cyclic AMP phosphodiesterase of azaindolizine-type compounds. Structure-activity relationships and molecular modelling. Chemometrics and Intelligent Laboratory Systems, 20: 71–84. This paper deals with the synthesis and biological activities of aryl-2 imidazo[1,2-a]pyridines and pyridines. These compounds are valued as inhibitors of cyclic AMP phosphodiesterase (PDE) derived from beef heart and as inhibitors of human platelet aggregation. The most attractive in this series, compounds 13a and 15a, are ten times more potent than aspirin on arachidonic acid induced platelet aggregation. They also exhibit significant activity as inhibitors of phosphodiesterase. Analysis of these azaindolizine-type compounds by molecular modelling techniques suggests spatial and electronic similarities with other classes of PDE inhibitors.
Published: 1993
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33. Synthesis and pharmacological study of new calcium antagonists, analogues of cinnarizine and flunarizine

Author: G Baziard-Mouysset, J Tisne-Versailles, Jean-Luc Stigliani, S Younes, R Bonnafous, G de Saqui-Sannes, and M. Payard
Subjects: Pharmacology, Cinnarizine, Stereochemistry, Organic Chemistry, Antagonist, chemistry.chemical_element, Biological activity, General Medicine, Calcium, Phosphonate, In vitro, chemistry.chemical_compound, chemistry, Drug Discovery, medicine, Moiety, Flunarizine, medicine.drug
Abstract: Several phosphonic diethyl esters were synthesized and their calcium antagonistic activity evaluated in vitro. The diethyl phosphonate group was condensed on substituted [diphenylmethyl], [(2-benzofuranyl)phenylmethyl], [(4-(diphenylmethyl-1-piperazinyl) methyl], [4 (4-diphenylmethyl-1-piperazinyl methyl) phenylmethyl], and [4-(3-phenyl-2-propenyl)-1-piperazinyl methyl] groups. Despite the presence of the diethyl phosphonate moiety and the benzhydrylpiperazinyl group, both present in potent calcium antagonist structures, only 1 of the 19 synthesized compounds exhibited a calcium antagonistic profile.
Published: 1993
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34. Synthesis and calcium antagonistic activity of a series of diethyl benzofuryl, benzothienyl and benzogammapyronyl benzylphosphonates

Author: R Bonnafous, Jean-Luc Stigliani, G Baziard-Mouysset, G. Tchani, J Tisne-Versailles, and M. Payard
Subjects: Pharmacology, Fostedil, Bicyclic molecule, Chemistry, Stereochemistry, organic chemicals, Organic Chemistry, Benzothiophene, chemistry.chemical_element, Biological activity, General Medicine, Calcium, Phosphonate, chemistry.chemical_compound, Drug Discovery, Chromone, heterocyclic compounds, Benzofuran
Abstract: In this work we present about 15 original heterocyclic diethyl benzylphosphonate analogues of fostedil, in which we have varied the nature of the heterocycle, the substituents or the phosphonic group, or even the position of this latter. Three diethyl 4-(2-benzofuryl) benzyl phosphonates exhibited slightly higher calcium antagonism than the control. Solely substitution with a fluorine atom was able to maintain activity, whereas the other modifications always decreased it.
Published: 1993
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35. ChemInform Abstract: Synthesis and in vitro Bronchospasmolytic Activity of 8-Aryl, Heteroaryl or Arylalkyl Theophyllines

Author: Jean-Luc Stigliani, Charles Advenier, C. Tournaire, Marc Payard, J. C. Yavo, A. Rached, Genevieve Baziard-Mouysset, and S Younes
Subjects: Aryl, Aromaticity, General Medicine, Medicinal chemistry, In vitro, Bronchospasm, chemistry.chemical_compound, chemistry, medicine, Purine derivative, Theophylline, medicine.symptom, Histamine, Acetylcholine, medicine.drug
Abstract: Summary Twenty-four 8-aryl- or 8-heteroaryl-substituted theophyllines have been synthesized. The substituents are aromatic rings and heterocycles likely to induce an antiallergic effect or a spasmolytic activity. In vitro evaluation of the bronchospasm caused by acetylcholine or histamine shows an interesting activity for half of the compounds. Among them, the furanic 111s and 2-chlorophenyl IIIi derivatives are, for instance, four times more active than theophylline.
Published: 2010
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36. ChemInform Abstract: Study of the Reactivity of Nitriles Towards Diazomethane: Synthesis and Structural Study of N-Methyl-v-triazoles

Author: M. Payard, A. Carpy, G Baziard-Mouysset, Jean-Luc Stigliani, G. Commenges, and S. Danoun
Subjects: chemistry.chemical_compound, Chemistry, Diazomethane, Triazole derivatives, Organic chemistry, Reactivity (chemistry), General Medicine
Published: 2010
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37. Évaluation de l'activité inhibitrice calcique d'une série de benzylphosphonates de diéthyle

Author: J. Bellan, J Tisne-Versailles, Jean-Luc Stigliani, R Bonnafous, M. Payard, G Baziard-Mouysset, G. Grassy, G. Tchani, and S Younes
Subjects: Pharmacology, Fostedil, chemistry.chemical_compound, chemistry, Organic Chemistry, Drug Discovery, General Medicine, Medicinal chemistry
Abstract: Resume Les proprietes inhibitrices calciques d'une serie de 39 benzylphosphonates de diethyle diversement substitues, analogues du Fostedil, ont eteevaluees. Seuls 6 composes presentent une certaine activite, celle-ci reste cependant beaucoup plus faible que celle du temoin. Le criblage sur l'aorte de lapin s'avere plus selectif que celui pratique sur le muscle atrial gauche de cobaye. Une approche de relations structure-activite met en evidence une certaine influence de la lipophilie et de la presence de deux cycles aromatiques conjugues et separes par une distance optimale. Aucun effet electronique du aux substituants n'a pu etre demontre.
Published: 1992
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38. Reconnaissance de forme et structure moléculaire: étude comparative de quelques voies d'approche appliquées à l'étude du pouvoir carcinogène d'hydrocarbures aromatiques polybenzéniques

Author: G. Grassy, Monique Bonnafous, and Jean-Luc Stigliani
Subjects: Pharmacology, Chemistry, Organic Chemistry, Drug Discovery, General Medicine, Molecular biology
Abstract: Resume Dans le cadre d'une etude comparative des techniques simples de reconnaissance de forme du graphe moleculaire, nous avons teste l'efficacite previsionnelle de 5 types de descripteurs structuraux. Dans ce but, une prevision de l'activite carcinogene d'hydrocarbures aromatiques polybenzeniques a ete effectuee sur la base d'une analyse discriminante.
Published: 1990
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39. Design and synthesis of novel imidazoline derivatives with potent antihyperglycemic activity in a rat model of type 2 diabetes

Author: Jean Luc Stigliani, Salomé El Hage, Marc Payard, Jean-Guy Bizot-Espiard, Louis Crane, Daniel-Henri Caignard, Jean-Michel Léger, Labssita Youssef, Alain Ktorza, Maria Anastassiadou, and Pierre Renard
Subjects: Blood Glucose, Male, Models, Molecular, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Imidazoline receptor, Crystallography, X-Ray, Biochemistry, Chemical synthesis, Streptozocin, chemistry.chemical_compound, Structure-Activity Relationship, In vivo, Oral administration, Drug Discovery, medicine, Animals, Hypoglycemic Agents, Rats, Wistar, Molecular Biology, Glucose tolerance test, medicine.diagnostic_test, Molecular Structure, Chemistry, Organic Chemistry, Imidazoles, Biological activity, Streptozotocin, Rats, Disease Models, Animal, Diabetes Mellitus, Type 2, Drug Design, Benzyl group, Molecular Medicine, Cattle, Rabbits, medicine.drug
Abstract: Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I1/I2 binding sites for several substituted aryl imidazolines. Among these compounds, 2-(α-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties. It was then chosen as lead compound. Thirty-six new derivatives were synthesized by replacing the cyclohexyl/benzyl group by various cyclic systems or the imidazoline ring by isosteric heterocycles. These compounds were evaluated in vivo for their antihyperglycemic activity using an oral glucose tolerance test (OGTT) in a rat model of type-2 diabetes obtained by giving a single intravenous (iv) injection of a low dose of streptozotocin to rats (STZ rats) and in normal rats. Nine compounds with an imidazoline moiety, possibly substituted by a methyl group, had a potent effect on the glucose tolerance in normal or STZ-diabetic rats, after an oral (po) administration of the test compound at a dose of 30 or 10 mg kg−1, without any hypoglycemia. Replacement of the imidazoline ring by isosteric heterocycles resulted in a total loss of activity.
Published: 2006

40. Reactions of Some ortho and para Halogenated Aromatic Nitriles with Ethylenediamine: Selective Synthesis of Imidazolines

Author: Maria Anastassiadou, Marc Payard, Jean-Luc Stigliani, Genevieve Baziard-Mouysset, and Louis Crane
Subjects: chemistry.chemical_classification, Nucleophilic addition, Nitrile, Chemistry, Organic Chemistry, Ethylenediamine, General Medicine, Biochemistry, Medicinal chemistry, chemistry.chemical_compound, Nucleophilic aromatic substitution, Drug Discovery, Nucleophilic substitution, Organic chemistry, Acid hydrolysis, Reactivity (chemistry), Thioamide
Abstract: The reaction of ethylenediamine (EDA) with ortho and/or para halogenated benzonitriles did not lead to the imidazolines expected: a competitive aromatic nucleophilic substitution (SNAr) was observed instead. The selective synthesis of these imidazolines was performed by nucleophilic addition of EDA to thiobenzamide derivatives. The difference in reactivity between the nitrile and thioamide derivatives was estimated by a frontier orbital approach at the RHF/6-31G** level which predicted a greater reactivity of substituted thiobenzamides towards the nucleophilic addition of EDA.
Published: 2004
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41. Evidence that nicotine acetylcholine receptors are not the main targets of cotinine toxicity

Author: Jean-Luc Stigliani, Omar Riah, Genevieve Baziard-Mouysset, Jean-Claude Dousset, Younes Belahsen, and Philippe Courriere
Subjects: Male, Nicotine, Time Factors, Metabolite, Respiratory Tract Diseases, Hexamethonium Compounds, Pharmacology, Receptors, Nicotinic, Toxicology, Lethal Dose 50, chemistry.chemical_compound, Mice, medicine, Animals, Drug Interactions, Nicotinic Agonists, Cotinine, Acetylcholine receptor, Alkaloid, Body Weight, General Medicine, Organ Size, Rats, Nicotinic agonist, chemistry, Toxicity, Hexamethonium, Female, medicine.drug
Abstract: The toxicity of nicotine, cotinine and their mixtures was studied in Mus musculus mice as well their effects on growth after repetitive administration to young mice. The affinity constants of the two alkaloids for the nicotinic acetylcholine receptors (nAChRs) of Torpedo and rat brain membranes were determined. The administration of these alkaloids produced distinct symptoms of intoxication. Nicotine was 100-fold more toxic than cotinine and 10-fold more rapid than cotinine at producing respiratory arrest. The affinity of nicotine for both subtypes of nAChRs was >100-fold higher than that of cotinine. Repetitive administrations of nicotine caused weight loss, whereas that of cotinine caused weight gain (P
Published: 1999

42. SYNTHESIS AND PROTOZOOCIDAL ACTIVITY OF NEW 1,4-NAPHTHOQUINONES

Author: Marc Payard, Christian Bories, Jean-Michel Léger, Philippe M. Loiseau, Jean-Luc Stigliani, Michèle Αné-Margail, Genevieve Baziard-Mouysset, Xavier Canron, Saïda Danoun, and Henri Vial
Subjects: Chemistry, Organic Chemistry, Organic chemistry
Published: 1999
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43. ADDITION OF DIAZOMETHANE TO 3 AND 4-NITROPHTHALODINITRILES

Author: Mohamed Selkti, Marc Payard, Saïda Danoun, Bernard Viossat, Jean-Luc Stigliani, Alain Tomas, and Genevieve Baziard-Mouysse
Subjects: chemistry.chemical_compound, chemistry, Diazomethane, Organic Chemistry, Organic chemistry
Published: 1998
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44. Inside Cover: Docking Studies of Structurally Diverse Antimalarial Drugs Targeting PfATP6: No Correlation between in silico Binding Affinity and in vitro Antimalarial Activity. (ChemMedChem 9/2009)

Author: Anne Robert, Fatima Bousejra-El Garah, Jean-Luc Stigliani, Frederic Cosledan, and Bernard Meunier
Subjects: Pharmacology, Molecular model, Chemistry, In silico, Organic Chemistry, Biochemistry, Combinatorial chemistry, In vitro, Docking (molecular), Drug Discovery, medicine, Molecular Medicine, Antimalarial Agent, General Pharmacology, Toxicology and Pharmaceutics, Artemisinin, medicine.drug
Published: 2009
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45. Ligands de structures G-quadruplex d'acides nucléiques : modélisation, synthèse et activité antivirale

Author: Rundstadler, Tiffany, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier - Toulouse III, Geneviève Pratviel, and Jean-Luc Stigliani
Subjects: Porphyrin, ARN, G-quadruplex, Porphyrine, ADN, HIV-1, RNA, [CHIM.COOR]Chemical Sciences/Coordination chemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA, Alchemical free energy
Abstract: Guanine-rich DNA and RNA sequences are capable of folding into non-canonic, four-stranded G-quadruplex structures referred to as G4. They are involved in the fundamental processes of life (transcription, translation, etc.). Due to their original structure they may be targeted by small molecules, or ligands, in order to tune their biological function. Indeed, G-quadruplex structures have received particular attention as potential pharmacological targets for the treatment of cancer or viral infections. It is worth noting that the G4 sequences of HIV-1 virus genome are highly conserved regions and thus correspond to attractive target. Porphyrins are known as excellent G4 ligands. Some porphyrin derivatives bearing several cationic charges and a central gold(III) metal ion show a noticeable antiviral activity against HIV-1 virus. Besides, their activity correlates with their affinity for viral G4s in vitro. The work was devoted, in a first part, to the preparation of a porphyrin-biotin conjugate of the most active porphyrin against HIV-1 in order to better understand its mechanism of action and to identify the targeted viral G4s responsible for the inhibition of viral replication by the porphyrin. The design/synthesis of such a biotinylated conjugate implied the preparation of a library of porphyrin derivatives that were subjected to a structure/activity study for their capacity of recognition of viral G4s. The resulting best porphyrin-biotin conjugate allowed the pull-down of HIV-1 RNA from infected cells in vitro. This result demonstrates the efficiency of the porphyrin-biotin conjugate to trap viral G4-folded RNA and confirms the importance of such structures in HIV-1 replication cycle. In the second part of the thesis, molecular modeling was used on the one hand, to explore the structure/activity relationship of already available porphyrin derivatives, and on the other hand, to propose new porphyrins endowed with higher affinity for G4s and as a consequence, better antiviral activity. We performed interaction free energy calculations with the Alchemical Binding Free Energy method based on successive molecular dynamic simulations. In a first step, we validated the method with existing porphyrins and a HIV-1 virus G4 sequence of known structure. Then, the method was applied to original fluoro- and nitro-porphyrin derivatives. The data allow us to propose some new porphyrins with potential higher affinity for G4 with respect to the best antiviral porphyrin taken as a reference compound.; Les séquences d'acides nucléiques riches en guanines peuvent former des structures non canoniques d'ADN ou d'ARN par repliements à 4 brins appelées G-quadruplex (G4). Ces structures particulières interviennent comme régulateurs dans les processus fondamentaux du vivant (transcription, traduction, etc.). De par leur structure originale les G4s peuvent être ciblés par des petites molécules, ou ligands, de façon à interférer avec leur fonction biologique. Les G4s ont notamment fait l'objet d'une attention particulière comme cible pharmacologique pour le traitement du cancer ou des infections virales. Il est à noter que dans le génome du virus VIH-1 les séquences de G4s se trouvent particulièrement bien conservées et constituent donc des cibles privilégiées. Les porphyrines sont connues pour être d'excellents ligands de G4. Certains dérivés de porphyrines portant plusieurs charges cationiques et présentant un coeur métallé par de l'or(III) possèdent une activité antivirale remarquable contre le virus VIH-1 qui de plus, se corrèle avec leur capacité à se lier in vitro à des G4s présents dans le génome du VIH-1. Le travail de thèse a consisté dans une première partie à préparer un dérivé biotinylé de la porphyrine la plus active sur le VIH-1 pour mieux comprendre son mécanisme d'action biologique et identifier les G4s cibles responsables de l'inhibition de la réplication virale par cette molécule. L'élaboration de ce dérivé biotinylé, a donné lieu à la synthèse d'une librairie de molécules qui ont fait l'objet d'une étude de relation structure/activité pour le ciblage des G4s. Le composé biotinylé ainsi optimisé a permis d'isoler de l'ARN du VIH-1 à partir de cellules infectées in vitro. Ce résultat démontre l'efficacité du composé porphyrine-biotine à séquestrer des ARNs viraux structurés en G-quadruplex et confirme donc l'existence de G4s essentiels à la réplication dans le génome de VIH-1. Dans une deuxième partie, la modélisation moléculaire est mise à profit afin, d'une part de compléter les études de relation structure/activité effectuées sur les porphyrines déjà synthétisées et d'autre part d'orienter la synthèse vers de nouvelles porphyrines dont l'affinité pour les G4s viraux et en conséquence, l'activité antivirale seraient meilleures. Nous avons pour cela effectué des calculs d'énergie libre d'interaction en appliquant la méthode de transformation alchimique, qui est basée sur un ensemble de simulations de dynamique moléculaire. La méthode a été dans un premier temps validée par la détermination des énergies libres d'interaction entre les porphyrines expérimentales et un G-quadruplex de VIH-1 dont la structure est décrite. Elle a ensuite été mise oeuvre sur une librairie originale de porphyrines fluorées et/ou nitrées. Ces résultats théoriques nous permettent de proposer de nouveaux dérivés de porphyrines potentiellement plus affins pour les G4s par comparaison avec la meilleure porphyrine antivirale prise comme référence.
Published: 2021

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