Abstract:
: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 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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Singh A,Sharma S,Arora S,Attri S,Kaur P,Kaur Gulati H,Bhagat K,Kumar N,Singh H,Vir Singh J,Mohinder Singh Bedi Pdoi
10.1016/j.bmcl.2020.127477subject
Has Abstractpub_date
2020-10-15 00:00:00pages
127477issue
20eissn
0960-894Xissn
1464-3405pii
S0960-894X(20)30588-6journal_volume
30pub_type
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