Towards novel thiazolidine-2,4-diones. Synthesis, anticancer activity, DFT, and molecular docking

Two series of 3-substituted (Z)-5-(3,4,5-trimethoxybenzylidene)thiazolidine-2,4-dione derivatives were designed, synthesized, and evaluated for their anticancer potential. The first series (9a-f) incorporates carbamate moieties, whereas the second series (10a-e and 11a,b) contains urea functionalities. The synthetic route involved hydrolysis of the ester 4 into the corresponding acid 6, followed by conversion to the acid azide intermediate 8, and subsequent Curtius rearrangement in the presence of alcohols or amines to afford the target compounds. The antiproliferative activity of the synthesized derivatives was assessed against a panel of human cancer cell lines (MCF-7, MDA-MB-231, A2780, A2780cis, and K562), as well as the non-tumorigenic HaCaT cell line, using cisplatin as a reference drug. Several derivatives demonstrated promising cytotoxicity; in particular, the six compounds (9c, 9e, 9f, 10a, 10b, and 10c) exhibited IC50 values below 20 µM. Notably, compounds 9c, 9e, 10a, and 10b showed pronounced selectivity toward the aggressive triple-negative breast cancer MDA-MB-231 cell line, underscoring this scaffold as a promising platform for anticancer drug development. The urea derivatives 10a and 10b demonstrated superior activity compared with the carbamate analogues 9c and 9e. Compound 10b exhibited the highest activity (IC50 = 6.02±0.91 µM) and appeared as an MDA-MB-231 hit compound. Computational investigations, including DFT calculations and molecular docking, supported the experimental findings and suggested a multitarget mechanism of action.