Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis

Tetiana Matviiuk; Jan Madacki; Giorgia Mori; Beatrice Silvia Orena; Christophe Menendez; Andrii Kysil; Christiane André-Barrès; Frédéric Rodriguez; Jana Korduláková; Sonia Mallet-Ladeira; Zoia Voitenko; Maria Rosalia Pasca; Christian Lherbet; Michel Baltas

doi:10.1016/j.ejmech.2016.07.028

Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis

Eur J Med Chem. 2016 Nov 10:123:462-475. doi: 10.1016/j.ejmech.2016.07.028. Epub 2016 Jul 16.

Authors

Affiliations

¹ Taras Shevchenko National University of Kyiv, Department of Chemistry, 64 Str. Volodymyrska, Kyiv, 01033, Ukraine; CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, UMR-5068, 118 Route de Narbonne, F-31062, Toulouse cedex 9, France; Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, 118 route de Narbonne, F-31062, Toulouse cedex 9, France.
² Department of Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynskádolina Ch-1, 842 15, Bratislava, Slovakia.
³ University of Pavia, Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", via Ferrata 1, 27100, Pavia, Italy.
⁴ CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, UMR-5068, 118 Route de Narbonne, F-31062, Toulouse cedex 9, France; Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, 118 route de Narbonne, F-31062, Toulouse cedex 9, France.
⁵ Taras Shevchenko National University of Kyiv, Department of Chemistry, 64 Str. Volodymyrska, Kyiv, 01033, Ukraine.
⁶ Université de Toulouse, UPS, Service Commun Rayons X, ICT-FR2599, 118 Route de Narbonne, F-31062, Toulouse cedex 09, France.
⁷ CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, UMR-5068, 118 Route de Narbonne, F-31062, Toulouse cedex 9, France; Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, 118 route de Narbonne, F-31062, Toulouse cedex 9, France. Electronic address: christian.lherbet@itav.fr.
⁸ CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, UMR-5068, 118 Route de Narbonne, F-31062, Toulouse cedex 9, France; Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, 118 route de Narbonne, F-31062, Toulouse cedex 9, France. Electronic address: baltas@chimie.ups-tlse.fr.

PMID: 27490025
DOI: 10.1016/j.ejmech.2016.07.028

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.

Keywords: InhA; Inhibition; Mycobacterium tuberculosis; Pyrrolidine; Pyrrolidinone; Synthesis.

MeSH terms

Antitubercular Agents / chemistry
Antitubercular Agents / metabolism
Antitubercular Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / chemistry
Bacterial Proteins / metabolism
Drug Design*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Escherichia coli / drug effects
Membrane Transport Proteins / metabolism
Microbial Sensitivity Tests
Molecular Docking Simulation
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / metabolism
Oxidoreductases / antagonists & inhibitors*
Oxidoreductases / chemistry
Oxidoreductases / metabolism
Protein Conformation
Pyrrolidines / chemistry*
Pyrrolidines / metabolism
Pyrrolidines / pharmacology*
Pyrrolidinones / chemistry*
Pyrrolidinones / metabolism
Pyrrolidinones / pharmacology*
Structure-Activity Relationship

Substances

Antitubercular Agents
Bacterial Proteins
Enzyme Inhibitors
Membrane Transport Proteins
MmpL3 protein, Mycobacterium tuberculosis
Pyrrolidines
Pyrrolidinones
Oxidoreductases
InhA protein, Mycobacterium