Design, synthesis, and biological evaluation of novel 4,5-diaryl-1,2,3-thiadiazole derivatives: anticancer activity and molecular docking studies

Abstract

Malignancies remain a major global health challenge. Microtubule-targeting agents (MTAs) have emerged as a significant therapeutic class, effectively suppressing cancer cell proliferation by interfering with the normal dynamics of microtubules. Combretastatin, particularly combretastatin A-4, is a natural compound with anti-angiogenic and anticancer properties that interacts with the colchicine-binding site at the α/β-tubulin interface. A new series of 4,5-diaryl-1,2,3-thiadiazole analogues, based on the SAR of combretastatin A-4, were designed and synthesized. The anticancer activity of the synthesized derivatives was assessed on human gastric adenocarcinoma (AGS), human colorectal adenocarcinoma (HT-29), human breast adenocarcinoma (MCF-7), and mouse embryo fibroblast (NIH3T3) cell lines by MTT assay, along with known drugs (paclitaxel and doxorubicin) as references. Among the synthesized compounds, compound 5g demonstrated the highest cytotoxic activity in most of the tested cell lines and exhibited superior cytotoxic effects against AGS and HT-29 cells compared with paclitaxel. Doxorubicin remained the most potent compound across all tested cell lines. Particularly, compounds 5d , 5f , and 5h exhibited high safety toward normal NIH-3T3 cells (IC₅₀ > 600 µM), with selective activity against some cancer cell lines. Docking studies showed that all compounds were predicted to bind within the colchicine-binding site of tubulin with more favorable predicted scores than combretastatin A-4. Molecular dynamics supported complex stability, with 5i showing greater stability than 5d . Compound 5g emerged as a promising potential tubulin inhibitor, requiring further experimental and in vivo validation.