Design, Synthesis, and <i>In Vitro</i> Cytotoxic Studies of Some Novel Arylidene-Hydrazinyl-Thiazoles as Anticancer and Apoptosis-Inducing Agents

Cancer, defined by uncontrolled cell growth, poses a significant global health challenge, necessitating the development of new anticancer drugs crucial to address drug resistance, side effects, and the need for combination therapies. The study presents the design, synthesis, and anticancer screening of a series of novel functionalized arylidene-hydrazinyl-thiazoles against various human cancer cell lines. The environmentally benign synthetic protocol involves the visible-light prompted, NBS-mediated domino reaction of thiosemicarbazide, heteroaryl aldehydes, and unsymmetrical 1,3-diketones. The regioselective organic transformation delivered the single regioisomeric product, characterized unambiguously through detailed 2D NMR spectral studies. In vitro cytotoxic studies revealed that the synthesized derivatives exhibited excellent cytotoxic potential against BxPC-3, MOLT-4, and MCF-7 cancer cell lines. Notably, compounds <b>4m</b>, <b>4n</b>, and <b>4r</b> showed significant cytotoxicity, reducing cell survival to 23.85-26.45% for BxPC-3, 30.08-33.30% for MOLT-4, and 44.40-47.63% for MCF-7 at a concentration of 10 μM. These compounds profoundly induced apoptosis, evidenced by increased caspase-3/7 activity, loss of mitochondrial membrane potential, and modulation of Bcl2 and Bax gene expression. Additionally, these compounds caused robust cell cycle arrest at the G₂/M phase by inhibiting tubulin polymerization, indicating their multifaceted impact on cancer cells.