Indole ring linked thiazolidone hybrid molecules as potent tubulin inhibitors

Tubulin inhibitors are a prominent class of antineoplastic agents for cancer therapy, with many established drugs originating from plant-derived compounds such as vinca alkaloids and taxanes. A new series of twenty-four 5-(substituted) benzylidene-2-{[2-(3H-indol-3-yl)ethyl]imino}-3-phenyl-1,3-thiazolidin-4-one derivatives (1−24) was synthesized based on assuming that it would inhibit tubulin polymerization, successfully. To assess their biological potential these derivatives were subjected to a comprehensive screening including cytotoxic activity using various cancer cell lines, cell death studies, cell motility and migration analysis, assessment of the compounds' ability to inhibit tubulin polymerization, and computational analysis. Out of the twenty-four synthesized compounds, specifically compounds 8, 10, 15, 21, and 23 demonstrated a desirable selective cytotoxic effect against the MCF7 cancer cell line compared to the healthy epithelial counterparts. Mechanistic studies confirmed that these five active compounds functioned as tubulin polymerization inhibitors, exhibiting an inhibitory mechanism similar to that of vinblastine. Computational analyses strongly supported these findings, demonstrating that the five active compounds possessed a high affinity binding to the tubulin structure. Compound 15 was identified as the most potent derivative, causing significant cell cycle arrest and inducing a distinct apoptotic effect in MCF7 cells. 2-{[2-(3H-indol-3-yl)ethyl]imino}-3-phenyl-5-[(3-hydroxy-4-methoxy phenyl)methylidene]-1,3-thiazolidin-4-one (15) represents a novel chemical series targeting microtubules. This compound emerged as a promising potential hit molecule due to its selective cytotoxicity against MCF7 cells, potent vinblastine-like tubulin polymerization inhibition. • Novel indole-thiazolidine hybrid molecules synthesized as anticancer agents. • The five compounds exerted antiproliferative action on MCF7 cells, selectively. • Compounds inhibitory actions on tubulin polymerization supported by computational analysis. • Tubulin polymerization was defected upon compound 15 treatment which caused apoptosis. • Compound 15 possessing 3-hydroxy-5-methoxy emerged as a potential hit molecule.