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Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase.
Bioorg Med Chem. 2013 Jul 15; 21(14):4218-24.BM

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+Show Affiliations

Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23719283

Citation

Zhu, Jinmei, et al. "Synthesis, Biological Evaluation and Molecular Modeling of Substituted 2-aminobenzimidazoles as Novel Inhibitors of Acetylcholinesterase and Butyrylcholinesterase." Bioorganic & Medicinal Chemistry, vol. 21, no. 14, 2013, pp. 4218-24.
Zhu J, Wu CF, Li X, et al. Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg Med Chem. 2013;21(14):4218-24.
Zhu, J., Wu, C. F., Li, X., Wu, G. S., Xie, S., Hu, Q. N., Deng, Z., Zhu, M. X., Luo, H. R., & Hong, X. (2013). Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorganic & Medicinal Chemistry, 21(14), 4218-24. https://doi.org/10.1016/j.bmc.2013.05.001
Zhu J, et al. Synthesis, Biological Evaluation and Molecular Modeling of Substituted 2-aminobenzimidazoles as Novel Inhibitors of Acetylcholinesterase and Butyrylcholinesterase. Bioorg Med Chem. 2013 Jul 15;21(14):4218-24. PubMed PMID: 23719283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. AU - Zhu,Jinmei, AU - Wu,Chun-Feng, AU - Li,Xiaobing, AU - Wu,Gui-Sheng, AU - Xie,Shan, AU - Hu,Qian-Nan, AU - Deng,Zixin, AU - Zhu,Michael X, AU - Luo,Huai-Rong, AU - Hong,Xuechuan, Y1 - 2013/05/09/ PY - 2013/02/16/received PY - 2013/05/01/revised PY - 2013/05/02/accepted PY - 2013/5/31/entrez PY - 2013/5/31/pubmed PY - 2014/1/22/medline SP - 4218 EP - 24 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 21 IS - 14 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/23719283/Synthesis_biological_evaluation_and_molecular_modeling_of_substituted_2_aminobenzimidazoles_as_novel_inhibitors_of_acetylcholinesterase_and_butyrylcholinesterase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(13)00423-9 DB - PRIME DP - Unbound Medicine ER -