Design, Synthesis, and Biological Evaluation of Benzimidazol-2-One Hybrids as Potential Anti-Alzheimer's Disease Agents.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which single-target therapies often provide insufficient benefit, motivating the development of multi-target-directed ligands (MTDLs). In this study, a novel series of benzimidazolone-based hybrids incorporating piperazine, coumarin, and triazole moieties was designed, synthesized, and evaluated for inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase-B (MAO-B), as well as antioxidant potential via on-line HPLC-based assays. Structures were confirmed by 1H-NMR, 13C-NMR (APT), and elemental analysis. Several compounds showed notable, micromolar-range inhibitory activity, though less potent than the reference drugs. Kinetic analysis showed that the leading compounds inhibited their respective enzymes via a mixed-type mechanism. Compound 1 showed the strongest AChE inhibition (IC50 = 0.777 ± 0.014 µM), compound 9b the highest BChE inhibition (IC50 = 0.659 ± 0.005 µM), and compound 9c the most potent MAO-B inhibition (IC50 = 2.431 ± 0.003 µM). Compound 8a showed the highest CUPRAC copper-reducing capacity, while 7c displayed the strongest DPPH radical-scavenging activity. Liposomal formulations of 4c, 7c, and 8a exhibited enhanced antioxidant responses relative to their free forms. In silico ADME predictions (SwissADME) indicated favorable drug-likeness and blood-brain barrier permeation for the compact scaffold (compound 1) and the piperazine-based hybrids, whereas the larger bis-conjugated derivatives were limited by high polarity and molecular weight. Overall, these benzimidazolone-based hybrids represent promising multi-target candidates for AD drug development.