Tags

Type your tag names separated by a space and hit enter

Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors.
Eur J Med Chem. 2017 Jun 16; 133:184-196.EJ

Abstract

A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced β-amyloid (Aβ) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of Aβ aggregation (53.7% at 20 μM) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and Aβ (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment.

Authors+Show Affiliations

Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China. Electronic address: xiesaisainanchang@hotmail.com.School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: dingyue-2001@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28388521

Citation

Lan, Jin-Shuai, et al. "Design, Synthesis and Biological Activity of Novel Donepezil Derivatives Bearing N-benzyl Pyridinium Moiety as Potent and Dual Binding Site Acetylcholinesterase Inhibitors." European Journal of Medicinal Chemistry, vol. 133, 2017, pp. 184-196.
Lan JS, Zhang T, Liu Y, et al. Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors. Eur J Med Chem. 2017;133:184-196.
Lan, J. S., Zhang, T., Liu, Y., Yang, J., Xie, S. S., Liu, J., Miao, Z. Y., & Ding, Y. (2017). Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors. European Journal of Medicinal Chemistry, 133, 184-196. https://doi.org/10.1016/j.ejmech.2017.02.045
Lan JS, et al. Design, Synthesis and Biological Activity of Novel Donepezil Derivatives Bearing N-benzyl Pyridinium Moiety as Potent and Dual Binding Site Acetylcholinesterase Inhibitors. Eur J Med Chem. 2017 Jun 16;133:184-196. PubMed PMID: 28388521.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and biological activity of novel donepezil derivatives bearing N-benzyl pyridinium moiety as potent and dual binding site acetylcholinesterase inhibitors. AU - Lan,Jin-Shuai, AU - Zhang,Tong, AU - Liu,Yun, AU - Yang,Jing, AU - Xie,Sai-Sai, AU - Liu,Jing, AU - Miao,Ze-Yang, AU - Ding,Yue, Y1 - 2017/03/23/ PY - 2016/12/05/received PY - 2017/02/16/revised PY - 2017/02/17/accepted PY - 2017/4/8/pubmed PY - 2017/9/14/medline PY - 2017/4/8/entrez KW - Acetylcholinesterase inhibitors antioxidant KW - Alzheimer's disease KW - Benzylpyridinium KW - Donepezil KW - Neuroprotection KW - β-Amyloid aggregation SP - 184 EP - 196 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 133 N2 - A series of new donepezil derivatives were designed synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase and self-induced β-amyloid (Aβ) aggregation, and moderate antioxidant activity. Especially, compound 5b presented the greatest ability to inhibit cholinesterase (IC50, 1.9 nM for eeAChE and 0.8 nM for hAChE), good inhibition of Aβ aggregation (53.7% at 20 μM) and good antioxidant activity (0.54 trolox equivalents). Kinetic and molecular modeling studies indicated that compound 5b was a mixed-type inhibitor, binding simultaneously to the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, compound 5b could reduce PC12 cells death induced by oxidative stress and Aβ (1-42). Moreover, in vivo experiments showed that compound 5b was nontoxic and tolerated at doses up to 2000 mg/kg. These results suggested that compound 5b might be an excellent multifunctional agent for AD treatment. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/28388521/Design_synthesis_and_biological_activity_of_novel_donepezil_derivatives_bearing_N_benzyl_pyridinium_moiety_as_potent_and_dual_binding_site_acetylcholinesterase_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(17)30118-6 DB - PRIME DP - Unbound Medicine ER -