Liu Chun-Xiu, Zhao Xin, Wang Lei, Yang Zai-Chang
College of Pharmacy, Guizhou University, Guiyang, 550025, PR China.
College of Pharmacy, Guizhou University, Guiyang, 550025, PR China; State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University, Guiyang, 550014, China.
Microb Pathog. 2022 Apr;165:105507. doi: 10.1016/j.micpath.2022.105507. Epub 2022 Mar 27.
Development of new drugs with novel mechanisms of action is required to combat the problem of drug-resistant Mycobacterium tuberculosis. The present investigation is aimed at combining two pharmacophores (quinoline or isoquinolines and thiosemicarbazide) to synthesize a series of compounds. Seven compounds were synthesized based on combination principle in this study. The compound 1-7 showed activities against M. tuberculosis HRv strain with MIC values rang from 2 to 8 μg/ml. Compound 5 exhibited remarkable antimycobacterial activity (MIC = 2 μg/ml), and was therefore selected for study of the mechanism of action. Molecular docking suggested initially that compound 5 could occupy the active site of KatG of M. tuberculosis. Furthermore compound 5 exhibited potent inhibitory effect on activity of KatG. RT-PCR finally displayed that compound 5 could up-regulate the transcription of katG of M. tuberculosis. Together, these studies reveal that compound 5 might be the inhibitor of KatG of Mycobacterium tuberculosis. One of the more significant findings to emerge from this study is that KatG of M.tuberculosis can be used as a putative novel target for new anti-tubercular drug design.
需要开发具有新型作用机制的新药来应对耐药结核分枝杆菌的问题。本研究旨在将两种药效基团（喹啉或异喹啉与硫代氨基脲）结合以合成一系列化合物。本研究基于组合原理合成了七种化合物。化合物1 - 7对结核分枝杆菌H37Rv菌株具有活性，MIC值范围为2至8μg/ml。化合物5表现出显著的抗分枝杆菌活性（MIC = 2μg/ml），因此被选用于作用机制研究。分子对接初步表明化合物5可占据结核分枝杆菌KatG的活性位点。此外，化合物5对KatG的活性表现出强效抑制作用。RT-PCR最终显示化合物5可上调结核分枝杆菌katG的转录。总之，这些研究表明化合物5可能是结核分枝杆菌KatG的抑制剂。本研究中出现的一个更重要的发现是，结核分枝杆菌的KatG可作为新型抗结核药物设计的假定新靶点。
