Green One-Pot Synthesis of Thiazole Scaffolds Catalyzed by Reusable NiFe₂O₄ Nanoparticles: <i>In Silico</i> Binding Affinity and <i>In Vitro</i> Anticancer Activity Studies

A facile, green, one-pot multicomponent synthesis strategy was employed to fabricate novel thiazole scaffolds incorporating phthalazine, pyridazine, and pyrido-pyridazine derivatives (<b>4a</b>-<b>4o</b>). This synthetic route entailed the reaction of an α-halo carbonyl compound (<b>1</b>) with thiosemicarbazide (<b>2</b>) and various anhydrides (<b>3a</b>-<b>3o</b>), utilizing NiFe₂O₄ nanoparticles as a reusable catalyst in an ethanol:water (1:1) solvent system. The cytotoxicity of the synthesized compounds was meticulously assessed against three cancer cell lines, A375, HeLa, and MCF-7, employing IC₅₀ values (μM) as the benchmark, and compared to the reference drug erlotinib. Compound <b>4n</b> displayed remarkable efficacy against A375 (0.87 ± 0.31 μM), HeLa (1.38 ± 1.24 μM), and MCF-7 (1.13 ± 0.96 μM) cell lines, significantly surpassing erlotinib's IC₅₀ values. Additionally, compounds <b>4k</b>, <b>4l</b>, <b>4m</b>, and <b>4o</b> demonstrated notable cytotoxicity across all tested cell lines, indicating their potential as effective anticancer agents. <i>In silico</i> docking studies against Hsp82 and Hsp90 proteins indicated that ligands <b>4k</b>, <b>4m</b>, <b>4c</b>, <b>4j</b>, <b>4o</b>, and <b>4l</b> had superior binding affinities compared 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 human intestinal absorption, and low CYP inhibitory promiscuity. Structure-activity relationship analysis revealed that cyano and benzylidene substitutions significantly enhanced anticancer activity. Overall, the synthesized compounds, particularly <b>4n</b>, demonstrated high efficacy, favorable binding interactions, and promising pharmacokinetic profiles, making them strong candidates for further development as anticancer agents.