Synthesis of novel (R)-carvone-tagged thiazolidinone as anticancer leads: characterization, in vitro antiproliferative evaluation and in silico studies

This work describes the successful synthesis of a series of three novel thiazolidinone-carvone-O-alkyl hybrids through a two-step approach involving heterocyclization and O-alkylation reactions. Comprehensive structural characterization of the obtained products was achieved using NMR and HRMS spectroscopic techniques. This study assessed in vitro antiproliferative activity of synthesized thiazolidinone-carvone-O-alkyl hybrids (5a–c) against various human cancer cell lines, viz. HT-1080 (fibrosarcoma), A-549 (lung cancer), MCF-7 (breast cancer) and MDA-MB-231 (breast cancer). MTT assay revealed promising results for compounds 5b and 5c, demonstrating good antiproliferative activity against A-549 and MCF-7 cell lines comparable to the positive control, Doxorubicin. Compound 5a, harbouring an O-acetoxy group, displayed limited anticancer activity against MCF-7 and MDA-MB-231 cells, with IC₅₀ values of 69.33 ± 0.42 µM and >100 µM, respectively. Docking results confirmed that the compounds 5a–c binds at the active site of p21 with docking scores −2.0, −4.8, and −7.0 kcal/mol, respectively. Compound 5a-c also showed good binding potential against Bcl2 protein with docking score of −4.9, −6.0, −5.5 kcal/mol, respectively. Furthermore, binding energy analysis and dynamics simulation studies of compounds towards p21 and Bcl2 yielded promising results. In PAK4 assay, compound 5c showed comparable potency (IC₅₀ 6.76 µM) with the standard control UC2288 (IC₅₀ 6.40 µM), while in BCL-2 TR-FRET assay, 5c exhibited good inhibition (IC₅₀ 1.78 µM) as compared to Venetoclax (IC₅₀ 0.016 µM). In conclusion, compounds 5a-c could be used as a structural framework for the discovery of novel therapeutics to combat different types of cancer. Communicated by Ramaswamy H. Sarma.