Synthesis of novel ()-carvone-tagged thiazolidinone as anticancer leads: characterization, antiproliferative evaluation and 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 antiproliferative activity of synthesized thiazolidinone-carvone-O-alkyl hybrids () 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 and , demonstrating good antiproliferative activity against A-549 and MCF-7 cell lines comparable to the positive control, Doxorubicin. Compound , harbouring an O-acetoxy group, displayed limited anticancer activity against MCF-7 and MDA-MB-231 cells, with IC values of 69.33 ± 0.42 µM and >100 µM, respectively. Docking results confirmed that the compounds binds at the active site of p21 with docking scores -2.0, -4.8, and -7.0 kcal/mol, respectively. Compound 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 showed comparable potency (IC 6.76 µM) with the standard control UC2288 (IC 6.40 µM), while in BCL-2 TR-FRET assay, exhibited good inhibition (IC 1.78 µM) as compared to Venetoclax (IC 0.016 µM). In conclusion, compounds could be used as a structural framework for the discovery of novel therapeutics to combat different types of cancer.Communicated by Ramaswamy H. Sarma.