Synthesis, SAR, and multi-target evaluation of isonicotinoyl hydrazones as potent MPO/AChE inhibitors and metal chelators for Alzheimer's disease.

Isonicotinoyl hydrazone derivatives (1-20) were synthesized and evaluated for their inhibitory activities against myeloperoxidase (MPO) and acetylcholinesterase (AChE), antioxidant activity, metal ion chelation, regulation of reactive oxygen species, and cytoprotective activity, with the aim of identifying multi-target therapeutic candidates for Alzheimer's disease. In this study, 9 exhibited a free radical scavenging activity of 93% and showed strong inhibitory effects against MPO and AChE, with inhibition rates of 90% and 73%, respectively. An in-depth structure-activity relationship analysis revealed that 9 possesses a favorable pharmacological balance between lipophilicity and electronic properties. Moreover, 9 effectively chelated Cu2⁺, Fe2⁺, Mg2⁺, and Zn2⁺ ions. It also reduced oxidative stress, significantly improved cell viability in neuronal damage models, and prevented cell death in a concentration-dependent manner. Furthermore, molecular docking studies demonstrated that 9 exhibits favorable binding affinities toward both target enzymes, providing a structural basis for its dual-target inhibitory activity and supporting the rationality of the structure-activity relationship analysis. Collectively, these results suggest that 9 represents a potential therapeutic candidate for the development of therapeutic agents for Alzheimer's disease.