EGFR tyrosine kinase inhibitor: design, synthesis, characterization, biological evaluation, and molecular docking of novel 1,3,4-oxadiazole, thio-methyl, and 1,2,3-triazole hybrids

Concerning the structural analysis and optimization of various potential EGFR inhibitors. A series of heterocyclic compounds incorporating pyridine, 1,3,4-oxadiazole, thio-methyl, and 1,2,3-triazole were successfully synthesized via a click reaction 12–21, resulting in high yields. The synthesis process entailed the reaction of terminal alkynes, specifically 2-(prop-2-yn-1-ylthio)-5-(pyridin-4-yl)-1,3,4-oxadiazole 1 with various substituted aryl azides 2–11. The cytotoxic properties of the resulting derivatives were assessed against HCT-116, HePG-2, and MCF-7 cancer cell lines. Notably, Compound 19 displayed the highest activity among the tested compounds, with selectivity towards the tumor cells, yielding IC50 values of low micromolar level. Consequently, a series of biological assays were conducted to elucidate the potential mechanism of action of the most potent derivative. Compound 19 demonstrated considerable suppression of EGFR, with an IC50 value of 0.313 µM. This highly effective EGFR inhibitor, Compound 19, halted the HePG-2 cell cycle at the G0/G1 phase by triggering the apoptotic pathway. Moreover, molecular docking illustrated a distinctive interaction of compound 19 with the EGFR binding pocket. This work ultimately presents new derivatives of 1,3,4-oxadiazole, thio-methyl, and 1,2,3-triazole as potential cytotoxic agents and EGFR inhibitors, which should be the subject of further research in tumor therapy.