Chollet Aurélien, Stigliani Jean-Luc, Pasca Maria Rosalia, Mori Giorgia, Lherbet Christian, Constant Patricia, Quémard Annaïk, Bernadou Jean, Pratviel Geneviève, Bernardes-Génisson Vania
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.
Chem Biol Drug Des. 2016 Nov;88(5):740-755. doi: 10.1111/cbdd.12804. Epub 2016 Jul 16.
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.
结核分枝杆菌烯酰-ACP还原酶（InhA）抑制剂被认为是治疗结核病的潜在有前景的疗法。此前，我们报道了氮杂异吲哚啉酮类化合物在体外对InhA具有抑制活性。在此，我们描述了氮杂异吲哚啉酮骨架的化学修饰、15种新化合物的合成及其体外InhA活性评估。基于这些结果，利用2H7M晶体结构中发现的InhA构象进行了结构-InhA抑制活性关系分析和分子对接研究，以预测最佳（氮杂）异吲哚啉酮类抑制剂与InhA在体外可能的相互作用模式。然后，将工作扩展到评估这些化合物对结核分枝杆菌（Mtb）生长的影响，最后，还研究了其中一些化合物抑制分枝杆菌内分枝菌酸生物合成的能力。尽管一些氮杂异吲哚啉酮能够在体外抑制InhA活性和Mtb生长，但它们并未抑制Mtb内的分枝菌酸生物合成。
