Design, Synthesis, and Biological Evaluation of Novel Heterocyclic Derivatives of 2,4-Thiazolidine Dione as Anti-Cancer Agents

Abstract

This study explores the development of novel 2,4-thiazolidinedione derivatives as potential anticancer agents. We report the synthesis of 15 novel analogs utilizing a strategic approach focused on intermediate diversification. Key intermediates, (Z)-5-([1,1′-biphenyl]-4-ylmethylene)thiazolidine-2,4-dione 5a and (Z)-5-(benzo[1,3]dioxol-5-ylmethylene)thiazolidine-2,4-dione 5b, were synthesized via Knoevenagel condensation and acetal formation reactions, respectively. Subsequent N-alkylation reactions provided a platform for introducing diverse functionalities and exploring structure–activity relationships to optimize the medicinal chemistry profile of these novel compounds. The synthesized compounds were tested against various human cancer cell lines, including for breast (MCF-7, MDA-MB-453), lung (A549), and prostate (PC-3) cancers, using an MTT assay. Compounds 8c and 10g emerged as particularly promising, exhibiting activity against all tested cell lines with IC₅₀ values between 3.41 ± 0.51 and 40 μM. These compounds also induced apoptosis, suggesting that they inhibit cell proliferation through this cell death pathway. Moreover, relative molecular docking studies provided evidence that compound 8c likely functions by intercalating with DNA.