Pyridine-based glycosides bearing 1,2,4-triazole and their 1,3,4-oxadiazole analogues as potential EGFR and CDK-2 inhibitors: Design, synthesis, antiproliferative activity and in silico studies

The increasing toxicity of recently developed anticancer medications is seen as a serious problem that stems from the variety of targets involved; as a result, more research on these phenomena is necessary. In the present work, a novel class of pyridine-based glycosides with a 1,2,4-triazole core and their 1,3,4-oxadiazolyl counterparts with distinct sugar segments are designed and synthesized. The afforded products were studied for their cytotoxicity behavior against a number of cell lines of human cancer. Pyridine-based glycosides 14 and 21 revealed excellent anticancer activity against HepG-2 and MCF-7 cell lines (IC50 = 10.6, 12.8 mu M against HepG-2 and 8.3, 9.8 mu M against MCF-7, respectively). The inhibitory investigation of the latter promising candidates was further examined in against CDK-2/cyclin A2 kinases and EGFR. The 1,2,4-triazole glycoside-based pyridine system and its oxadiazolyl analog were approximately equipotent with the reference erlotinib in the inhibitory activity against EGFR. On the other hand, the pyridine-1,3,4-oxadiazole product 21 explored a higher potency and sensitivity (half the potency of roscovitine) against CDK-2/cyclin A2 than its pyridine-1,2,4-triazole analogue 14. In an effort to understand its mode of action, it was also investigated how oxadiazolyl-glycoside 21 affected the induction of apoptosis and cell cycle arrest. Furthermore, it increased the MCF-7 cells' p53 and, Bax levels. To further obtain a clear justification and acquire knowledge of the binding nature and affinities of the potent compounds and their targeted enzymes, a molecular docking investigation was simulated. This promotes the deployment of the compounds as effective leads for future investigations in anticancer research.