2- Integrated experimental and computational insights into thiazolidine derivatives with potent cytotoxicity against PC-3 prostate cancer cells
Abstract In this study, a new series of 3-Acetyl-2-phenyl-5,5-dimethylthiazolidine-4-carbohydrazide (A1-8) was synthesized and comprehensively characterized by FT-IR, 1H/13C NMR, and mass spectrometry. The cytotoxic potential of the compounds was evaluated in vitro against PC-3 human prostate cancer cells using the MTT assay. Among the series, compounds A4 and A5, bearing 4-chlorophenyl and 4-bromophenyl groups, respectively, exhibited the most potent cytotoxicity with IC50 values of 50.65 ± 0.98 μg/mL and 50.03 ± 0.98 μg/mL, closely comparable to standard drugs Darolutamide (55.4 ± 0.9 μg/mL) and R-Bicalutamide (80.34 ± 0.89 μg/mL). In contrast, the least active compound A6 which incorporate 4-methylphenyl group exhibited an IC50 of 120 ± 0.83 μg/mL. Gene expression analysis confirmed that these compounds induced significant upregulation of tumor suppressor genes p53 and p21, indicating a mechanism of cell cycle arrest and apoptosis. Density Functional Theory (DFT), Molecular Electrostatic Potential (MEP), and frontier molecular orbital (FMO) analyses were conducted to elucidate structure–activity relationships and chemical reactivity. Molecular electrostatic potential (MEP) mapping highlighted key electrophilic and nucleophilic regions across the molecule surfaces. ADME predictions revealed that all compounds, except A3 and A8, possessed high gastrointestinal absorption and zero Lipinski rule violations, with bioavailability scores of 0.55. POM analysis identified two antitumor pharmacophore sites (Oδ−, Hδ+) with interaction distances in the range of 2.058–2.180 Å. Osiris property predictions confirmed no major toxicity alerts. Overall, compounds A4 and A5 emerge as promising leads with potent antiproliferative effects, favorable pharmacokinetics, and strong computational backing, meriting further investigation as anti-prostate cancer agents.