Synthesis, docking study, and in-vitro anti-cancer evaluation of new triazole derivatives of flufenamic acid

Abstract The new triazole compounds derived from the parent flufenamic acid (FLU) were synthesized by a conventional method. The molecular-docking study of the synthesized compounds(s) against EGFR kinase revealed that such compounds occupied the critical site of EGFR kinase pocket with good positioning. Compound 8 exhibited cytotoxic activity against MCF-7 breast cancer cells (GI50 0.78 µM), and not against A549 lung cancer cells or normal cells, and this toxic effect was due to induction of the intrinsic apoptotic pathway. Moreover compound 8 showed an inhibitory effect against EGFR kinase. Novel compounds were synthesized and confirmed by spectroscopic analysis, including AT-IR, 1HNMRS and CHNS. Compound 8 apoptosis induction was evident by fragmented nuclei after DAPI staining and smeared DNA by agarose gel electrophoresis. Additionally, treating MCF-7 cells with compound 8 resulted in an increment in the level of caspase 9 mRNA level, and its activation. Moreover, compound 8-treated MCF-7 cells showed enhanced cytochrome-c release from the mitochondria to cytosol indicating an induction for the intrinsic apoptotic pathway. Finally, compound 8 showed comparable EGFR kinase inhibitory activity (3.4 µM) to erlotinib (1.22 µM), which was matched by the molecular docking studies that showed that the target compounds may be considered as potential inhibitors of EGFR kinase.