Design, synthesis, in silico studies, and apoptotic antiproliferative activity of novel thiazole-2-acetamide derivatives as tubulin polymerization inhibitors

The most effective antitubulin derivative was <b>10a</b>, exhibiting an IC₅₀ value of 2.69 μM. Subsequently, <b>10o</b> and <b>13d</b> exhibited IC₅₀ values of 3.62 μM and 3.68 μM, respectively. These compounds exhibited more potency than the reference combretastatin A-4, which displayed an IC₅₀ value of 8.33 μM. These compounds had no cytotoxic effects on normal cells, preserving over 85% cell viability at 50 μM. The antiproliferative experiment demonstrated that compounds <b>10a</b>, <b>10o</b>, and <b>13d</b> displayed significant activity against four cancer cell lines, with average GI₅₀ values of 6, 7, and 8 μM, equivalent to the reference's doxorubicin and sorafenib. Compounds 10a, 10o, and 13d were demonstrated to activate caspases 3, 9, and Bax, while down-regulating the anti-apoptotic protein Bcl2. Molecular docking studies demonstrated superior binding affinities for <b>10a</b> (-7.3 kcal/mol) at the colchicine binding site of tubulin, forming key hydrophobic and hydrogen bonding interactions that enhance its activity. ADMET analysis confirmed favorable drug-like properties, establishing these compounds as promising candidates for further development as anticancer agents targeting tubulin polymerization.