A Coumarin-Donepezil Hybrid as a Blood-Brain Barrier Permeable Dual Cholinesterase Inhibitor: Isolation, Synthetic Modifications, and Biological Evaluation of Natural Coumarins.

Plants have immensely contributed to the drug discovery for neurodegenerative diseases. Herein, we undertook the phytochemical investigation of Nardostachys jatamansi (D.Don) DC. rhizomes followed by semisynthetic modifications to discover cholinesterase (ChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. The 8-acetyl-7-hydroxycoumarin isolated from the bioactive extract moderately inhibits acetylcholinesterase (AChE) and BACE-1 with IC ₅₀ values of 22.1 and 17.7 μM, respectively. The semisynthetic trifluoromethyl substituted coumarin chalcone display a 5-fold improvement in BACE-1 inhibition (IC ₅₀ 3.3 μM). Another semisynthetic derivative, a coumarin-donepezil hybrid, exhibits dual inhibition of both ChEs with IC ₅₀ values of 1.22 and 3.09 μM, respectively. Molecular modeling and enzyme kinetics revealed that the coumarin-donepezil hybrid is a non-competitive inhibitor of AChE. It crosses the blood-brain barrier and also inhibits Aβ self-aggregation. The results presented herein warrant a detailed investigation of the coumarin-donepezil hybrid in preclinical models of Alzheimer's disease.
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