Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents

摘要

Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosyn-thetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehen-sive structure-activity relationship exploration resulted in the identification of compounds 21 and 28 , which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03-0.13 mu g/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug re-sistance (XDR) tuberculosis (MIC = 0.06-1.0 mu g/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 >= 32 mu g/mL) to the mammalian Vero cells and favorable physicochemical and pharma-cokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay.

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