A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed as multifunctional agents for the treatment of Alzheimer’s disease (AD). The designed compounds were synthesized by using standardized series of azide-alkyne Cu-catalyzed 1,4-cycloaddition reactions in good to moderate yield which were further characterized by using 1H and 13C NMR. 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. Compound 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.

New coumarin-benzotriazole based hybrid molecules as multitargeting agents for the treatment of Alzheimer's disease

ACS Fall 2021

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