title: Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase.
abstract: A series of novel 2-aminobenzimidazole derivatives were synthesized under microwave irradiation. Their biological activities were evaluated on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A number of the 2-aminobenzimidazole derivatives showed good inhibitory activities to AChE and BuChE. Among them, compounds 9, 12 and 13 were found to be >25-fold more selective for BuChE than AChE. No evidence of cytotoxicity was observed by MTT assay in PC12 cells or HepG2 cells exposed to 100μM of the compounds. Molecular modeling studies indicate that the benzimidazole moiety of compounds 9, 12 and 13 forms a face-to-face π-π stacking interaction in a 'sandwich' form with the indole ring of Trp82 (4.09Å) in the active gorge, and compounds 12 and 13 form a hydrogen bond with His438 at the catalytic site of BuChE. In addition, compounds 12 and 13 fit well into the hydrophobic pocket formed by Ala328, Trp430 and Tyr332 of BuChE. Our data suggest the 2-aminobenzimidazole drugs as promising new selective inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
authors.forename: Jinmei
authors.initials: J
authors.lastname: Zhu
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Wu
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Li
authors.forename: Gui-Sheng
authors.initials: GS
authors.lastname: Wu
authors.forename: Shan
authors.initials: S
authors.lastname: Xie
authors.forename: Qian-Nan
authors.initials: QN
authors.lastname: Hu
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.forename: Huai-Rong
authors.initials: HR
authors.lastname: Luo
authors.forename: Xuechuan
authors.initials: X
authors.lastname: Hong
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
chemical_list: D001562:Benzimidazoles; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase