Bioorganic and medicinal chemistry letters (2020)
Update date:2022-08-28
Topics:
Arora, Saroj
Attri, Shivani
Bhagat, Kavita
Kaur Gulati, Harmandeep
Kaur, Prabhjot
Kumar, Nitish
Mohinder Singh Bedi, Preet
Sharma, Sahil
Singh, Atamjit
Singh, Harbinder
Vir Singh, Jatinder
A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC50 = 0.059 μΜ) with mixed type inhibition scenario. Structure-activity relationship revealed that three-carbon alkyl chain connecting coumarin and triazole is well tolerable for inhibitory potential. Hybrids obtained from 4-hydroxycoumarin and 1-benzotriazole were most potent AChE inhibitors. The inhibitory potential of all compounds against butyrylcholinesterase was also evaluated but all showed negligible activity suggesting that the hybrid molecules are selective AChE inhibitors. 13b (most potent AChE inhibitor) also showed copper-induced Aβ1-42 aggregation inhibition (34.26% at 50 μΜ) and chelating properties for metal ions (Cu2+, Fe2+, and Zn2+) involved in AD pathogenesis along with DNA protective potential against degenerative actions of [rad]OH radicals. Molecular modelling studies confirm the potential of 13b in blocking both PAS and CAS of AChE. In addition, interactions of 13b with Aβ1-42 monomer are also streamlined. Therefore, hybrid 13b can act as an effective hit lead molecule for further development of selective AChE inhibitors as multifunctional anti-Alzheimer's agents.
View MoreContact:021-50278900
Address:No.6,Room 201 ,Lane 299,bisheng road ,shanghai ,china
Jinan Hongfangde Pharmatech Co.,Ltd
Contact:86-531-88870908
Address:F Bldg. West Unit North Area of Univ. Tech. Garden Xinyu Rd. Jinan New & High Tech Industry Development Zone Shandong, China
Jiaozuo Zhongwen Trading Coporation Limited
Contact:+86 0391-3553810
Address:East Renmin Road
Chengdu Gelipu Biotechnology Co., Ltd.
website:http://www.glp-china.com
Contact:86-28-82610909
Address:chegndu
Hefei TNJ chemical industry co.,ltd
website:https://www.tnjchem.com
Contact:+86-551-65418695
Address:B911 Xincheng Business Center, Qianshan Road, Hefei Anhui China
Doi:10.1055/s-0032-1317963
(2013)Doi:10.1016/0375-9601(95)00118-M
(1995)Doi:10.1016/j.jorganchem.2014.12.010
(2015)Doi:10.1021/ja00747a051
(1971)Doi:10.3390/molecules24091725
(2019)Doi:10.1021/op0502349
(2006)