Green One-Pot Synthesis\nof Thiazole Scaffolds Catalyzed\nby Reusable NiFe<sub>2</sub>O<sub>4</sub> Nanoparticles: <i>In\nSilico</i> Binding Affinity and <i>In Vitro</i> Anticancer\nActivity Studies

A facile, green, one-pot multicomponent synthesis strategy\nwas\nemployed to fabricate novel thiazole scaffolds incorporating phthalazine,\npyridazine, and pyrido-pyridazine derivatives (<b>4a</b>–<b>4o</b>). This synthetic route entailed the reaction of an α-halo\ncarbonyl compound (<b>1</b>) with thiosemicarbazide (<b>2</b>) and various anhydrides (<b>3a</b>–<b>3o</b>),\nutilizing NiFe<sub>2</sub>O<sub>4</sub> nanoparticles as a reusable\ncatalyst in an ethanol:water (1:1) solvent system. The cytotoxicity\nof the synthesized compounds was meticulously assessed against three\ncancer cell lines, A375, HeLa, and MCF-7, employing IC<sub>50</sub> values (μM) as the benchmark, and compared to the reference\ndrug erlotinib. Compound <b>4n</b> displayed remarkable efficacy\nagainst A375 (0.87 ± 0.31 μM), HeLa (1.38 ± 1.24 μM),\nand MCF-7 (1.13 ± 0.96 μM) cell lines, significantly surpassing\nerlotinib’s IC<sub>50</sub> values. Additionally, compounds <b>4k</b>, <b>4l</b>, <b>4m</b>, and <b>4o</b> demonstrated\nnotable cytotoxicity across all tested cell lines, indicating their\npotential as effective anticancer agents. <i>In silico</i> docking studies against Hsp82 and Hsp90 proteins indicated that\nligands <b>4k</b>, <b>4m</b>, <b>4c</b>, <b>4j</b>, <b>4o</b>, and <b>4l</b> had superior binding affinities\ncompared to erlotinib. ADME analysis showed that compounds <b>4n</b>, <b>4j</b>, <b>4l</b>, <b>4m</b>, and <b>4o</b> had favorable pharmacokinetic profiles, including nontoxicity, high\nhuman intestinal absorption, and low CYP inhibitory promiscuity. Structure–activity\nrelationship analysis revealed that cyano and benzylidene substitutions\nsignificantly enhanced anticancer activity. Overall, the synthesized\ncompounds, particularly <b>4n</b>, demonstrated high efficacy,\nfavorable binding interactions, and promising pharmacokinetic profiles,\nmaking them strong candidates for further development as anticancer\nagents.