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1. Evaluation of heteroatom-rich derivatives as antitubercular agents with InhA inhibition properties

Author

Christian Lherbet, Mohamed Amari, Beatrice Silvia Orena, Frédéric Rodriguez, Mokhtar Fodili, Nadji Belkheiri, Bachar Rébat Moulkrere, Nathalie Saffon-Merceron, Giorgia Mori, Pascal Hoffmann, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, chemistry.chemical_classification, biology, 010405 organic chemistry, Chemistry, Stereochemistry, INHA, Organic Chemistry, Heteroatom, Fatty Acid Biosynthesis Pathway, Pharmacology toxicology, biology.organism_classification, 01 natural sciences, 3. Good health, 0104 chemical sciences, Mycobacterium tuberculosis, 03 medical and health sciences, 030104 developmental biology, Enzyme, Docking (molecular), [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, ComputingMilieux_MISCELLANEOUS
Abstract

Two series of heterocyclic compounds derived from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (DHA) and 2-acetylbutyrolactone have been synthesized and characterized. The compounds were evaluated for their activities against Mycobacterium tuberculosis strain, and as inhibitors of InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. Among the tested compounds, one DHA derivative, compound 2, showed promising activity against both mycobacteria and InhA. Docking studies were also carried out and give some new structure-activity trends compatible with current structural knowledge.

Published
2018
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2. Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis

Author

Tetiana Matviiuk, Christian Lherbet, Michel Baltas, Andrii I. Kysil, Christophe Menendez, Maria Rosalia Pasca, Frédéric Rodriguez, Beatrice Silvia Orena, Giorgia Mori, Zoia Voitenko, Jan Madacki, Christiane André-Barrès, Sonia Mallet-Ladeira, Jana Korduláková, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Comenius University in Bratislava, Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, University of Pavia, Taras Shevchenko National University of Kyiv, and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, Pyrrolidines, Stereochemistry, Protein Conformation, Antitubercular Agents, Drug Evaluation, Preclinical, Microbial Sensitivity Tests, 01 natural sciences, Pyrrolidine, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Bacterial Proteins, Drug Discovery, Escherichia coli, [CHIM]Chemical Sciences, Enzyme Inhibitors, Mode of action, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, 010405 organic chemistry, INHA, Organic Chemistry, Membrane Transport Proteins, General Medicine, biology.organism_classification, Pyrrolidinones, 0104 chemical sciences, 3. Good health, Molecular Docking Simulation, 030104 developmental biology, chemistry, Biochemistry, Drug Design, Oxidoreductases
Abstract

A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 μM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.

Published
2016
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3. Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity

Author

Michel Baltas, Valérie Lobjois, Serhii Krykun, Damien Veau, Christian Lherbet, Giorgia Mori, Céline Frongia, Beatrice Silvia Orena, Stefan Chassaing, Maria Rosalia Pasca, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-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 des Technologies Avancées en sciences du Vivant (ITAV), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 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)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Tuberculosis, medicine.drug_class, Stereochemistry, Cell Survival, Antitubercular Agents, Microbial Sensitivity Tests, Antimycobacterial, 01 natural sciences, Biochemistry, Mycobacterium tuberculosis, chemistry.chemical_compound, Minimum inhibitory concentration, Drug Discovery, Drug Resistance, Bacterial, medicine, Humans, [CHIM]Chemical Sciences, General Pharmacology, Toxicology and Pharmaceutics, Cytotoxicity, Cell survival, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, 010405 organic chemistry, Organic Chemistry, biology.organism_classification, medicine.disease, HCT116 Cells, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, Hydralazine Hydrochloride, Cinnamates, Molecular Medicine, Phthalazines, Organic synthesis
Abstract

Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug-resistant TB. Herein we explored the potential of an alternative class of molecules as anti-TB agents. Thus, a series of novel 3-substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis (M.tb) H37 Rv strain with minimum inhibitory concentration (MIC) values10 μg mL(-1) , whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC50100 μm). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug-resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine-based derivatives promising leads for further development.

Published
2016
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4. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

Author

Ana Luisa de Jesus Lopes Ribeiro, Maria Rosalia Pasca, Laurent R. Chiarelli, Giulia Degiacomi, Nathalie Barilone, Marco Fondi, Vadim Makarov, Leonardo B. Marino, Riccardo Manganelli, Marco Bellinzoni, Giuseppe Zanoni, Stewart T. Cole, Francesca Boldrin, Renato Fani, Alessio Porta, Giorgia Mori, Alain R. Baulard, Ruben C. Hartkoorn, Giovanna Riccardi, Jaroslav Blaško, Luiz Pedro S. de Carvalho, Pedro M. Alzari, Zuzana Svetlíková, Ivana Centárová, Elena Kazakova, Sean Ekins, Alexander Lepioshkin, Katarína Mikušová, Marta Esposito, University of Pavia, Russian Academy of Sciences [Moscow] (RAS), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Padova, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Collaborative Drug Discovery, The Francis Crick Institute [London], Universidade Estadual Paulista Júlio de Mesquita Filho = São Paulo State University (UNESP), Comenius University in Bratislava, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), The research leading to these results received funding mainly from the European Community's Seventh Framework Program (Grant 260872). Additional funding was from the Slovak Research and Development Agency (Contract No. DO7RP-0015-11), the Francis Crick Institute which receives core funding from Cancer Research UK, the UK Medical Research Council (MC_UP_A253_1111), and the Wellcome Trust. The CDD TB database was funded by the Bill and Melinda Gates Foundation (Grant no. 49852). L.B.M. receives partial support from the FAPESP (2011/21232-1), CNPq (140079/2013-0), and CAPES PDSE (99999.003125/2014-09) programs., European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Università degli Studi di Pavia = University of Pavia (UNIPV), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi di Padova = University of Padua (Unipd), and Università degli Studi di Firenze = University of Florence (UniFI)

Subjects
Models, Molecular, MESH: Mycobacterium tuberculosis, MESH: Carbon-Nitrogen Ligases, Protein Conformation, Mutant, Clinical Biochemistry, Antitubercular Agents, Drug Evaluation, Preclinical, MESH: Drug Design, Biochemistry, Activation, Metabolic, Mice, chemistry.chemical_compound, MESH: Protein Conformation, Drug Discovery, Carbon-Nitrogen Ligases, MESH: Animals, CTP synthetase, MESH: Bacterial Proteins, chemistry.chemical_classification, 0303 health sciences, MESH: Microbial Sensitivity Tests, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Hep G2 Cells, General Medicine, MESH: Thiophenes, 3. Good health, Drug Discovery3003 Pharmaceutical Science, Molecular Biology, Molecular Medicine, Pharmacology, MESH: Drug Evaluation, Preclinical, Oxidoreductases, MESH: Models, Molecular, MESH: Activation, Metabolic, MESH: High-Throughput Screening Assays, Phenotypic screening, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Drug design, MESH: Hep G2 Cells, Microbial Sensitivity Tests, Thiophenes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Mycobacterium tuberculosis, 03 medical and health sciences, Bacterial Proteins, [CHIM.CRIS]Chemical Sciences/Cristallography, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Oxidoreductases, Gene, MESH: Mice, 030304 developmental biology, DNA ligase, MESH: Humans, 030306 microbiology, biology.organism_classification, MESH: Antitubercular Agents, High-Throughput Screening Assays, chemistry, Drug Design, biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], DNA
Abstract

Summary To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target., Graphical Abstract, Highlights • Two compounds activated by EthA kill M. tuberculosis through PyrG inhibition • EthA metabolite is active against PyrG and M. tuberculosis growth • Definition of the mechanism of activation and validation of PyrG as a new drug target, CTP synthetase PyrG, essential in Mycobacterium tuberculosis, could represent a new potential drug target. With a multidisciplinary approach, Mori et al. identify two compounds killing growing and dormant mycobacteria through PyrG inhibition, and define their mechanism of action.

Published
2015
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5. Pyridine-3,4-dicarboximide as starting material for the total synthesis of the natural product eupolauramine and its isomer iso-eupolauramine endowed with anti-tubercular activities

Author

Vania Bernardes-Génisson, Céline Deraeve, Giorgia Mori, Gildas Perdigão, Maria Rosalia Pasca, Geneviève Pratviel, 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), Dipartimento di Biologia e Biotecnologie ‘Lazzaro Spallanzani’, University of Pavia, and University of Pavia

Subjects
Natural product, 010405 organic chemistry, Chemistry, Stereochemistry, Organic Chemistry, Total synthesis, 010402 general chemistry, 01 natural sciences, Biochemistry, Combinatorial chemistry, 0104 chemical sciences, 3. Good health, chemistry.chemical_compound, Yield (chemistry), Drug Discovery, Pyridine, Lactam, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Anti tubercular, Eupolauramine
Abstract

A direct and convenient synthetic pathway for preparation of the key intermediate aza-isoindolinone 4a/4b, which could be ready obtained from pyridine-3,4-dicarboximide was described. This approach was valorized in the total synthesis of the natural product eupolauramine 7b and in the first synthesis of the position analog iso-eupolauramine 7a, which was obtained after 6 steps in an overall yield of 13%. The developed strategy represents the first synthetic approach employing a starting material already embedding the pyridine and the lactam cycles (cycles D and C, respectively) of the azaphenanthrene lactam framework. These compounds, mainly the new non-natural product, showed a good inhibitory activity against Mycobacterium tuberculosis growth. (C) 2015 Elsevier Ltd. All rights reserved.

Published
2015
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6. Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium tuberculosis

Author

Michel Baltas, Christian Lherbet, Frédéric Rodriguez, Giorgia Mori, Brigitte Guidetti, Zoia Voitenko, Maria Rosalia Pasca, Tetiana Matviiuk, Marian V. Gorichko, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-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, Dipartimento di Biologia e Biotecnologie, Università degli Studi di Pavia, and Taras Shevchenko National University of Kyiv

Subjects
Models, Molecular, Pyrrolidines, Stereochemistry, Antitubercular Agents, Microbial Sensitivity Tests, Pyrrolidine, Catalysis, Mycobacterium tuberculosis, Structure-Activity Relationship, chemistry.chemical_compound, Bacterial Proteins, Succinimide, Drug Discovery, Humans, Tuberculosis, Structure–activity relationship, [CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, Chemistry, INHA, Organic Chemistry, General Medicine, biology.organism_classification, 3. Good health, Mycobacterium tuberculosis H37Rv, Michael reaction, Oxidoreductases
Abstract

In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA.

Published
2014
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