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

作　　者：Yu Wen Shichun Lun Yuxue Jiao Wei Zhang Tianyu Hu Ting Liu Fan Yang Jie Tang Bing Zhang William R.Bishai Li-Fang Yu 

机构地区：[1]Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China [2]Center for Tuberculosis Research,Department of Medicine,Division of Infectious Disease,Johns Hopkins School of Medicine,Baltimore,MD,21231-1044,United States [3]Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [4]Shanghai Key Laboratory of Green Chemistry and Chemical Process,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China

出　　处：《Chinese Chemical Letters》2024年第3期326-331,共6页中国化学快报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.82073706 and 22107031);funded in part with Federal funds from the National Institutes of Health and National Institute of Allergy and Infectious Diseases,Department of Health and Human Services(No.AI155602)。

摘　　要：Inhibition of mycobacterial membrane protein large 3(MmpL3)thereby affecting the mycolic acid biosynthetic 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.Comprehensive 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)=0.03–0.13μg/mL]and the clinical isolates of multidrug resistance(MDR)and extensive drug resistance(XDR)tuberculosis(MIC=0.06–1.0μg/mL).Moreover,compounds 21 and 28 showed neglectable cytotoxicity(IC_(50)≥32μg/mL)to the mammalian Vero cells and favorable physicochemical and pharmacokinetic 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.

关 键 词：TUBERCULOSIS MDR and XDR-TB MmpL3 inhibitor 1 2 4-Triazole Structure-based drug design 

分 类 号：TQ460.1[化学工程—制药化工]