Abstract
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 μg/mL]and the clinical isolates of multidrug resistance(MDR)and extensive drug resis-tance(XDR)tuberculosis(MIC=0.06-1.O μg/mL).Moreover,compounds 21 and 28 showed neglectable cytotoxicity(IC50 ≥ 32 μg/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.
基金项目
国家自然科学基金(82073706)
国家自然科学基金(22107031)
National Institutes of Health and National Institute of Allergy and Infectious Diseases,Department of Health and Human Servi(AI155602)
NETL
NSTL
万方数据