Quinoline derivatives as potential anti-tubercular agents: Synthesis, molecular docking and mechanism of action

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 H37Rv 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. [Display omitted] •Compound 5 was a powerful anti-mycobacterial agent with low cytotoxicity to the Vero cell line.•Inhibition of KatG of Mycobacterium tuberculosis might be the mechanism of action of compounds 5 against Mtb H37Rv strain.•The KatG of M.tuberculosis can be used as a novel target for new anti-tubercular drug design.