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

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.