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

Abstract

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

Keywords:

• (R)-Carvone
• cancer
• thiazolidinone
• molecular docking
• virtual screening
• cytotoxic activity

Data availability statements

The datasets that were generated and analyzed in the present research are available from the corresponding author.

Acknowledgements

The authors extend their appreciation to the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia, for funding this research work through project number (IF2/PSAU/2022/03/21595).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia (project number: IF2/PSAU/2022/03/21595)