期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 15, 期 2, 页码 626-640出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.10.064
关键词
tuberculosis; ring-substituted quinolines; synthesis; 3D-QSAR study; COMFA; COMSIA; HINT
Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC = 6.25 mu g/mL, 99% inhibition, Mycobacterium tuberculosis H37Rv) has led to two series of 4-(adamantan-1-yl)-2-substituted quinolines (Series 1-2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid N'-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs 7, 9, 20, and 21 displayed MIC of 3.125 mu g/mL. Further investigation of AQCH by its reaction with various aliphatic, aromatic, and heteroaromatic aldehydes led to the synthesis of 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidene hydrazides (Series 2). Analogs 42-44 and 48 have produced promising antimycobacterial activities (99% inhibition) at 3.125 mu g/mL against drug-sensitive M. tuberculosis H37Rv strain. The most potent analog 35 of the series produced 99% inhibition at 1.00 mu g/mL against drug-sensitive strain, and MIC of 3.125 mu g/mL against isoniazid-resistant TB strain. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by three methods-comparative molecular field analysis (CoMFA), CoMFA with inclusion of a hydropathy field (HINT), and comparative molecular similarity indices analysis (CoMSIA). Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a test set of molecules was the best for the CoMFA model generated with database alignment. Based on the CoMFA contours, we have tried to explain the structure-activity relationships of the compounds reported herein. (c) 2006 Elsevier Ltd. All rights reserved.
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