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

ABSTRACT

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 ¹ H‐NMR, ¹³ C‐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 (IC ₅₀  = 0.777 ± 0.014 µM), compound 9b the highest BChE inhibition (IC ₅₀  = 0.659 ± 0.005 µM), and compound 9c the most potent MAO‐B inhibition (IC ₅₀  = 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.