Synthesis, Antioxidant Activity, In Silico Evaluation, and Cytotoxicity of Novel Polyphenolic–Methyliden–Hydrazono–Thiazole Derivatives

Novel thiazolyl–polyphenolic derivatives were designed and synthesized to investigate the influence of aromatic substituents on antioxidant activity, molecular properties, and cytotoxicity. Eight derivatives (E1–E8) were synthesized by a Hantzsch reaction and their structures were confirmed by MS, FT-IR, and 1H/13C NMR spectroscopy. Antioxidant activity was evaluated using DPPH, ABTS, TAC, RP, FRAP, and CUPRAC assays. The experimental results were supported by DFT calculations and SwissADME prediction, while cytotoxicity was evaluated against A549 lung adenocarcinoma cells and normal BJ fibroblasts. The antioxidant activity depended on the nature of the aromatic substituent. Compound E5 showed a superior antioxidant profile, presenting the highest DPPH radical scavenging activity and the strongest reducing power in the RP assay. The theoretical calculations supported these findings, showing favorable HOMO energy and low O–H bond dissociation energy values. Compound E6 showed the highest activity in the CUPRAC assay and exhibited the strongest cytotoxic activity against A549 cells together with the highest selectivity index. All synthesized compounds complied with Lipinski’s rule of five. Overall, the results show that the electronic properties of the aromatic substituent strongly influence both the antioxidant and cytotoxic activities of this series. These compounds may represent useful scaffolds for further development of antioxidant and anticancer agents.