Development of coumarin-inspired bifunctional hybrids as a new class of anti-Alzheimer's agents with potent efficacy.

Considering the multifactorial and complex nature of Alzheimer's disease and the requirement of an optimum multifunctional anti-Alzheimer's agent, a series of triazole tethered coumarin-eugenol hybrid molecules was designed as potential multifunctional anti-Alzheimer's agents using donepezil and a template. The designed hybrid molecules were synthesized a click chemistry approach and preliminarily screened for cholinesterase and Aβ aggregation inhibition. Among them, AS15 emerged as a selective inhibitor of AChE (IC = 0.047 μM) over butyrylcholinesterase (BuChE: IC ≥ 10 μM) with desired Aβ aggregation inhibition (72.21% at 50 μM) properties. In addition, AS15 showed protective effects against DNA damage caused by hydroxyl radicals originating from HO. Molecular docking and simulation studies confirmed the favorable interactions of AChE and the Aβ monomer desired for their inhibition. AS15 exhibited an LD value of 300 mg kg and showed significant improvements in memory and learning behavior in scopolamine-induced cognition impairment mouse-based animal models (Y-maze test and Morris water maze test) for behavioral analysis. Overall outcomes suggest AS15 as a potential preclinical multifunctional candidate for the management of Alzheimer's disease, and it serves as a promising lead for further development of potent and safer multifunctional anti-Alzheimer's agents.