In silico-guided synthesis and cytotoxic evaluation of novel thiazolidin-4-one derivatives on glioblastoma cell lines

Abstract This study presents the synthesis and characterization of two thiazolidin-4-one derivatives ( 7a and 7b ) and the in silico-guided biological evaluation of two novel thiazolidin-4-one derivatives, 7a and 7b for their cytotoxic activity against glioblastoma cells. The chemical structures of the synthesized compounds were confirmed using standard spectroscopic techniques, including FT-IR, 1 H/13 C-NMR, and HRMS.Cytotoxicity was evaluated in glioblastoma (U87-MG, LN229) and HEK293 reference cells. Compound 7a exhibited moderate cytotoxicity but showed no selectivity toward glioblastoma cells, whereas compound 7b was markedly more cytotoxic to HEK 293 cells than to either glioblastoma cell line, indicating limited tumor selectivity. To explore a potential mechanism of action, in silico studies were performed. A PASS (Prediction of Activity Spectra for Substances) analysis predicted MCL-1 (Myeloid Cell Leukemia-1) as the most probable biological target (Pa > 0.90), providing a hypothesis for further investigation. Molecular docking suggested that both compounds can interact to the MCL-1 site, with 7a (-7.7 kcal/mol) showing a slightly more favorable predicted docking score than 7b (-7.3 kcal/mol), though slightly weaker than the reference AMG 176 (-9.3 kcal/mol). ADMET profiling predicted favorable solubility, lipophilicity, and drug-likeness for both compounds. However these predictions also indicated low gastrointestinal absorption and lack of blood–brain barrier permeability, which is a major limitation for glioblastoma therapy. Molecular dynamics simulations provided additional support indicating the potential for stable binding of compound 7a within the MCL-1 active site.