title: Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth.
abstract: A series of fluorene-based derivatives was synthesized and evaluated for inhibiting both InhA and Mycobacterium tuberculosis growth. These compounds were inspired by the previously reported Genz-10850 molecule, a good InhA inhibitor, but with a poor activity against M. tuberculosis growth. Structure-activity relationships were performed by introducing the following chemical modifications: 1) the piperazine ring; 2) the amide group; 3) the aryl moiety; and 4) the fluorene moiety. Among these new derivatives, one of them was more effective against both the InhA activity and mycobacterial growth, compared to the hit compound. Docking studies were also performed to rationalize activities of these derivatives. Furthermore, we showed for the first time that efflux pump inhibitors potentiated the efficacy of Genz-10850 (GEQ) derivatives against M. tuberculosis growth, demonstrating that these compounds could be substrates of some efflux pumps.
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France; Université de Toulouse, Université Paul Sabatier, LSPCMIB, F-31077, Toulouse, France; Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique (CNRS), 205, Route de Narbonne, BP 44099, F-31077, Toulouse, Cedex 4, France; Université de Toulouse, Université Paul Sabatier, INPT, F-31077, Toulouse, Cedex 4, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Chollet
authors.affiliation: Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", University of Pavia, via Ferrata 1, 27100, Pavia, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mori
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France; Université de Toulouse, Université Paul Sabatier, LSPCMIB, F-31077, Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Menendez
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France; Université de Toulouse, Université Paul Sabatier, LSPCMIB, F-31077, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rodriguez
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France; Université de Toulouse, Université Paul Sabatier, LSPCMIB, F-31077, Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fabing
authors.affiliation: Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", University of Pavia, via Ferrata 1, 27100, Pavia, Italy.
authors.forename: Maria Rosalia
authors.initials: MR
authors.lastname: Pasca
authors.affiliation: Department of Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynská dolina Ch-1, 842 15, Bratislava, Slovakia.
authors.forename: Jan
authors.initials: J
authors.lastname: Madacki
authors.affiliation: Department of Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynská dolina Ch-1, 842 15, Bratislava, Slovakia.
authors.forename: Jana
authors.initials: J
authors.lastname: Korduláková
authors.affiliation: Département Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 Route de Narbonne, BP 64182, 31077, Toulouse, France; Université de Toulouse, Université Paul Sabatier, IPBS, 31077, Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Constant
authors.affiliation: Département Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 Route de Narbonne, BP 64182, 31077, Toulouse, France; Université de Toulouse, Université Paul Sabatier, IPBS, 31077, Toulouse, France.
authors.forename: Annaïk
authors.initials: A
authors.lastname: Quémard
authors.affiliation: Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique (CNRS), 205, Route de Narbonne, BP 44099, F-31077, Toulouse, Cedex 4, France; Université de Toulouse, Université Paul Sabatier, INPT, F-31077, Toulouse, Cedex 4, France.
authors.forename: Vania
authors.initials: V
authors.lastname: Bernardes-Génisson
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France; Université de Toulouse, Université Paul Sabatier, LSPCMIB, F-31077, Toulouse, France. Electronic address: lherbet@chimie.ups-tlse.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Lherbet
authors.affiliation: Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France; Université de Toulouse, Université Paul Sabatier, LSPCMIB, F-31077, Toulouse, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Baltas
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C475580:GENZ10850; D007211:Indoles; D010879:Piperazines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: Efflux pumps; InhA; Inhibitors; Medicinal chemistry; Mycobacterium tuberculosis