Natural product produced by plants has been the backbone for numerous anticancer agents. In the present work, natural bioactive thymol based 1,2,3-triazole hybrids have been synthesized and evaluated for anticancer activity in MCF-7 and MDA-MB-231 cancer cells. The synthesized molecules displayed desired pharmacokinetic predictions for an orally available drug. Among the synthesized hybrids, compound 4-((2-isopropyl-5-methylphenoxy)methyl)-1-o-tolyl-1H-1,2,3-triazole (10) was the most potent (IC 6.17 μM) showing comparable cytotoxity to tamoxifen (IC 5.62 μM) and 3.2 fold inhibition to 5-fluorouracil (IC 20.09 μM) against MCF-7 cancer cells. Whereas against MDA-MB-231 cancer cells, compound 10 (IC 10.52 μM) and 3-(4-((2-isopropyl-5-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (12) (IC 11.41 μM) displayed 1.42 and 1.3 fold inhibition, respectively to tamoxifen (IC 15.01 μM) whereas 2.4 fold and 2.2 activity to 5-Florouracil (IC 25.31 μM). Furthermore, 10 and 12 significantly inhibited thymidylate synthase enzyme with 2.4 and 1.26 fold activity to standard drug, Pemetrexed (IC 5.39 μM) suggesting their mode of action as thymidylate synthase inhibitors. Cell cycle arrest and annexin V induced apoptosis study of compound 10 showed cell cycle arrest at the G2/M phase and induction of apoptosis in MCF-7 cells. The molecular docking was accomplished onto thymidylate synthase (TS) protein. The active compounds exhibited promising binding interactions and binding affinities into active sites. Finally, density functional theory (DFT) calculations including chemical reactivity and molecular electrostatic potential (MEP) have been performed to confirm the data obtained from docking and biological experiments. The results from this study inferred that compound 10 could be served as a lead molecule for the treatment of breast cancer.
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