Novel isoxazoline-linked 1,3,4-thiadiazole hybrids as anticancer agents: Design, synthesis, biological evaluation, molecular docking, and molecular dynamics simulation.

In the current study, natural (R)-carvone was utilized as a starting material for the efficient synthesis of two series of isoxazoline derivatives bearing the 1,3,4-thiadiazole moiety. The new compounds were obtained in good yields and were characterized by H and C NMR and HRMS analysis. The newly synthesized monoterpenic isoxazoline 1,3,4-thiadiazole and their thiosemicarbazone intermediate derivatives were evaluated for their anticancer activity in four cancer cell lines (HT-1080, A-549, MCF-7, and MDA-MB-231). Most of the synthesized compounds exhibited moderate to high anticancer effects. Compound 13c showed the highest anticancer activity with IC values ranging from 19.33 ± 1.81 to 34.81 ± 3.03 µM. Further investigation revealed that compounds 12e and 13c could inhibit the cell growth of HT-1080 and MCF-7 cells by inducing apoptosis through caspase-3/7 activation. The apoptotic effect was accompanied by an S phase and G2/M cell cycle arrest for 13c and 12e, respectively. Compounds 12e and 13c were assessed in silico using molecular docking and molecular dynamics. We found that compound 13c is moderately active against the caspase-3 protein, which triggers apoptosis via intrinsic and extrinsic routes, making compound 13c a promising candidate to activate the proapoptotic protein (caspase-3).