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

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

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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.

TuberculosisMDR and XDR-TBMmpL3 inhibitor1,2,4-TriazoleStructure-based drug design

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

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Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China

Center for Tuberculosis Research,Department of Medicine,Division of Infectious Disease,Johns Hopkins School of Medicine,Baltimore,MD,21231-1044,United States

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China

Shanghai Key Laboratory of Green Chemistry and Chemical Process,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China

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国家自然科学基金国家自然科学基金National Institutes of Health and National Institute of Allergy and Infectious Diseases,Department of Health and Human Servi

8207370622107031AI155602

2024

10.1016/j.cclet.2023.108464

中国化学快报(英文版)
中国化学会

中国化学快报(英文版)

CSTPCD
影响因子：0.771
ISSN：1001-8417
年,卷(期)：2024.35(3)
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