Design, synthesis, characterization and evaluation of 1,3,5-triazine-benzimidazole hybrids as multifunctional acetylcholinesterases inhibitors

• Published in: Journal of molecular structure 2022-06, Vol.1257, p.132498, Article 132498
• Main Authors: Wu, Wen-Long, Wen, Ze-Yu, Qian, Jing-Jing, Zou, Jing-Pei, Liu, Shan-Ming, Yang, Shun, Qin, Tian, Yang, Qun, Liu, Yu-Han, Liu, Wei-Wei, Wang, Jing, Shi, Li-Ying, Shi, Da-Hua
• Format: Article
• Language: English
• Subjects: 1,3,5-Triazine; Acetylcholinesterase; Alzheimer's disease; Benzimidazole; Inhibitor
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.132498

•Design and synthesis of 24 1,3,5-triazine-benzimidazole hybrids.•The new compounds were evaluated for acetylcholinesterases inhibitory activity and metal chelating property.•Docking study and in silico ADME physicochemical parameters of the novel compounds were determined.•Compound 9f revealed the highest acetylcholinesterases inhibitory activity and good metal chelating property. A series of hybrids of benzimidazole and 1,3,5-triazine were designed and synthesized and evaluated as multi-target agents for the treatment of Alzheimer's disease. 24 compounds were designed, synthesized and identified by NMR, IR, HRMS and single-crystal X-ray diffraction studies. The compound 6c had the crystal system of orthorhombic and the space group of P212121. The cholinesterase inhibitory activity of synthesized compounds was measured using colorimetric Ellman's method. Most 1,3,5-triazine-benzimidazole hybrids showed potent acetylcholinesterase-inhibition activities and weak butyrylcholinesterase inhibitory activities. Compound 9f possessed the best acetylcholinesterase inhibitory activity with the IC50 of 0.044 µM, which is better than donepezil (0.052 µM). Molecular docking and molecular dynamics simulations demonstrated that there is a stable interaction between compound 9f and acetylcholinesterase. Simultaneously, experiments have also proved that compound 9f has good metal chelating properties. ADMET in silico prediction results suggest the compound can pass through the blood-brain barrier well and have good drug similarity. So, compound 9f could be a multi-target agent for the treatment of Alzheimer's disease. [Display omitted]