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Evaluation of the inhibitory activity of (aza)isoindolinone‐type compounds: toward in vitro InhA action, Mycobacterium tuberculosis growth and mycolic acid biosynthesis
Author(s) -
Chollet Aurélien,
Stigliani JeanLuc,
Pasca Maria Rosalia,
Mori Giorgia,
Lherbet Christian,
Constant Patricia,
Quémard Annaïk,
Bernadou Jean,
Pratviel Geneviève,
BernardesGénisson Vania
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12804
Subject(s) - inha , mycobacterium tuberculosis , in vitro , biochemistry , mycolic acid , biosynthesis , chemistry , docking (animal) , tuberculosis , biology , enzyme , medicine , pathology , nursing
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.