Evaluation of the inhibitory activity of (aza)isoindolinone-type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis.
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.
Laboratoire de Chimie de Coordination (LCC), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 4, France.|INPT, Université Paul Sabatier, Université de Toulouse, Toulouse, Cedex 4, France.|Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 9, France.|LSPCMIB, Université Paul Sabatier, Université de Toulouse, Toulouse, France.
Aurélien
A
Chollet
Laboratoire de Chimie de Coordination (LCC), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 4, France.|INPT, Université Paul Sabatier, Université de Toulouse, Toulouse, Cedex 4, France.
Jean-Luc
JL
Stigliani
Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani', Pavia, Italy.
Maria Rosalia
MR
Pasca
Dipartimento di Biologia e Biotecnologie 'Lazzaro Spallanzani', Pavia, Italy.
Giorgia
G
Mori
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique (SPCMIB), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 9, France.|LSPCMIB, Université Paul Sabatier, Université de Toulouse, Toulouse, France.
Christian
C
Lherbet
Institut de Pharmacologie et de Biologie Structurale (IPBS), Centre National de la Recherche Scientifique (CNRS), Toulouse, France.|IPBS, Université Paul Sabatier, Université de Toulouse, Toulouse, France.
Patricia
P
Constant
Institut de Pharmacologie et de Biologie Structurale (IPBS), Centre National de la Recherche Scientifique (CNRS), Toulouse, France.|IPBS, Université Paul Sabatier, Université de Toulouse, Toulouse, France.
Annaïk
A
Quémard
Laboratoire de Chimie de Coordination (LCC), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 4, France.|INPT, Université Paul Sabatier, Université de Toulouse, Toulouse, Cedex 4, France.
Jean
J
Bernadou
Laboratoire de Chimie de Coordination (LCC), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 4, France.|INPT, Université Paul Sabatier, Université de Toulouse, Toulouse, Cedex 4, France.
Geneviève
G
Pratviel
Laboratoire de Chimie de Coordination (LCC), Centre National de la Recherche Scientifique (CNRS), Toulouse, Cedex 4, France. vania.bernardes-genisson@lcc-toulouse.fr.|INPT, Université Paul Sabatier, Université de Toulouse, Toulouse, Cedex 4, France. vania.bernardes-genisson@lcc-toulouse.fr.
Vania
V
Bernardes-Génisson
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000995:Antitubercular Agents; D001426:Bacterial Proteins; C110621:Isoindol-1-one; D054833:Isoindoles; D009171:Mycolic Acids; D011994:Recombinant Proteins; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)

Mycobacterium tuberculosis
; (aza)isoindolinone; InhA inhibition; docking; mycolic acid biosynthesis; structure-activity relationship