A library of 1,4-dihydropyridine-based 1,2,3-triazol derivatives has been designed, synthesized, and evaluated their cytotoxic potential on colorectal adenocarcinoma (Caco-2) cell lines. All compounds were characterized and identified based on their 1H and 13C NMR (Nuclear Magnetic Resonance) spectroscopic data. Furthermore, molecular docking of best anticancer hits with target proteins (protein kinase CK2α, tankyrase1, and tankyrase2) has been performed. Our results implicated that most of these compounds have significant antiproliferative activity with IC50 values between 0.63 ± 0.05 and 5.68 ± 0.14 µM. Moreover, the mechanism of action of most active compounds 13ab' and 13ad' suggested that they induce cell death through apoptosis in the late apoptotic phase as well as dead phase, and they could promote cell cycle arrest at the G2/M phase. Furthermore, the molecular docking study illustrated that 13ad' possesses better binding interaction with the catalytic residues of target proteins involved in cell proliferation and antiapoptotic pathways. Based on our in vitro and in silico study, 13ad' was found to be a highly effective anti-cancerous compound. The present data indicate that dihydropyridine-linked 1,2,3-triazole conjugates can be generated as potent anticancer agents.
Keywords: apoptosis; cheminformatics; click chemistry; cytotoxicity; green synthesis; protein kinase; tankyrase.