Design, Synthesis, and Biological Evaluation of Benzimidazol-2-One Hybrids as Potential Anti-Alzheimer's Disease Agents
DRUG DEVELOPMENT RESEARCH, cilt.87, ss.1-26, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 87
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/ddr.70369
- Dergi Adı: DRUG DEVELOPMENT RESEARCH
- Derginin Tarandığı İndeksler: Academic Search Ultimate (EBSCO), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Biomedical Reference Collection: Corporate Edition (EBSCO), Health Research Premium Collection (ProQuest), Scopus, Science Citation Index Expanded (SCI-EXPANDED), BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE
- Sayfa Sayıları: ss.1-26
- Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
- İstanbul Medipol Üniversitesi Adresli: Evet
Özet
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.