Organic Chemistry (CPC) Division-II, Indian Institute of Chemical Technology, Hyderabad-500607, India.
J Med Chem. 2012 Apr 26;55(8):3911-22. doi: 10.1021/jm300125e. Epub 2012 Apr 9.
A molecular hybridization approach is an emerging structural modification tool to design new molecules with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one molecular platform to prepare various novel clubbed 1,2,3-triazole hybrids using click chemistry. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogues revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Two of the most potent M. tuberculosis inhibitors 13h and 13q with MIC = 0.78 μg/mL (∼1.9 μM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of molecular hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections.
分子杂交方法是一种新兴的结构修饰工具，可用于设计具有改善的药效性质的新分子。在这项研究中，将基于 1,2,3-三唑的结核分枝杆菌抑制剂和基于合成及天然产物的三环（咔唑、二苯并[b,d]呋喃和二苯并[b,d]噻吩）抗分枝杆菌剂整合到一个分子平台中，使用点击化学制备各种新型的棒状 1,2,3-三唑杂合体。新类似物的结构-活性关系和对结核分枝杆菌 H37Rv 菌株的体外活性表明，顺序为：二苯并[b,d]噻吩>二苯并[b,d]呋喃>9-甲基-9H-咔唑系列。两种最有效的结核分枝杆菌抑制剂 13h 和 13q 的 MIC = 0.78 μg/mL（约 1.9 μM），对四种不同的人癌细胞系显示出低细胞毒性和高选择性指数（50-255）。这些结果共同提供了分子杂交的重要性以及开发基于三唑棒状二苯并[b,d]噻吩的先导候选物以治疗分枝杆菌感染的潜力。
