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

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

Research output: Contribution to journalArticlepeer-review


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) = 0.03–0.13 μg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 μg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 μg/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.

Original languageEnglish (US)
Article number108464
JournalChinese Chemical Letters
Issue number3
StatePublished - Mar 2024


  • 1,2,4-Triazole
  • MDR and XDR-TB
  • MmpL3 inhibitor
  • Structure-based drug design
  • Tuberculosis

ASJC Scopus subject areas

  • General Chemistry


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