New oxadiazole and pyrazoline derivatives as anti-proliferative agents targeting EGFR-TK: design, synthesis,...

Two new series of oxadiazole and pyrazoline derivatives were designed and synthesized as promising EGFR-TK inhibitors. The in vitro antiproliferative activity was studied against three human cancer cell lines; HCT116, HepG-2 and MCF7 using MTT assay. Compound 10c showed the most potent anticancer activity against all cancer cell lines, with IC₅₀ range of 1.82 to 5.55 μM, while proving safe towards normal cells WI-38 (IC₅₀ = 41.17 μM) compared to the reference drug doxorubicin (IC₅₀ = 6.72 μM). The most active candidates 5a, 9b, 10a, 10b and 10c were further assessed for their EGFR-TK inhibition. The best of which, compounds 5a and 10b showed IC₅₀ of 0.09 and 0.16 μM respectively compared to gefitinib (IC₅₀ = 0.04 μM). Further investigation against other EGFR family members, showed that 5a displayed good activities against HER3 and HER4 with IC₅₀ values 0.18 and 0.37 µM, respectively compared to gefitinib (IC₅₀ = 0.35 and 0.58 µM, respectively). Furthermore, 5a was evaluated for cell cycle distribution and apoptotic induction on HepG-2 cells. It induced mitochondrial apoptotic pathway and increased accumulation of ROS. Molecular docking study came in agreement with the biological results. Compounds 5a and 10b showed promising drug-likeness with good physicochemical properties.