2. Academic Validation
  3. Synthesis and evaluation of new 5-(1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole derivatives and their application as OXPHOS inhibitors

Synthesis and evaluation of new 5-(1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole derivatives and their application as OXPHOS inhibitors

  • Eur J Med Chem. 2025 Jun 25:297:117903. doi: 10.1016/j.ejmech.2025.117903.
Longcai Cao 1,  Han Yao 2,  Puzhuang Hou 1,  Yuanyuan Ren 2,  Haitao Zhi 2,  Xian Jia 1,  Xingshu Li 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2 Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research, Guangzhou Bay Area Institute of Biomedicine, Guangzhou 510990, PR China.
  • 3 Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research, Guangzhou Bay Area Institute of Biomedicine, Guangzhou 510990, PR China. Electronic address: lixsh@mail.sysu.edu.cn.
PMID: 40592181 DOI: 10.1016/j.ejmech.2025.117903
Abstract

Twenty new 5-(1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole derivatives were synthesized and evaluated as OXPHOS inhibitors against cancers. The anti-proliferation assay exhibited that most of the compounds possessed good to excellent inhibitory activity on PC9 non-small cell lung Cancer cells and Bxpc-3 pancreatic Cancer cells. Among them, the optimal compound 28c, provided 0.0123 μM of IC50 value on PC9 cells, 0.25 μM and 0.0173 μM of the IC50 values against Bxpc-3 cells in glucose and galactose medium, respectively. In PC9 xenograft nude mice, TGI of 28c is 74.4 % compared with 44.16 % of the reference IACS-010759 when oral administration at dosage of 7.5 mg/kg. Mechanism research showed that 28c can bind with respiratory chain complex I, modulate the levels of NADH, NAD+ et al. in PC9 cells, activate cellular ROS and down regulate NRF2 and cause DNA damage in tumor cells.

Keywords

Antitumor; Cellular ROS; NADH; OXPHOS inhibitor; Respiratory chain complex I.

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