Synthesis of novel 4-methylthiocoumarin and comparison with conventional coumarin derivative as a multi-target-directed ligand in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder characterized by cognitive deficit and memory loss. The pathological feature of the disease involves β-amyloid senile plaques, reduced levels of acetylcholine neurotransmitter, oxidative stress and neurofibrillary tangles formation within the brain of AD patients. The present study aims to screen the inhibitory activity of newly synthesized and existing novel 4-methylthiocoumarin derivative against acetylcholinesterase, butyrylcholinesterase, BACE1, β-amyloid aggregation and oxidative stress involved in the AD pathogenesis. The in vitro assays used in this study were Ellman's assay, FRET assays, Thioflavin T, transmission electron microscopy, circular dichroism, FRAP, and TEAC. Molecular docking and dynamics studies were performed to correlate the results. C3 and C7 (thiocoumarin derivatives) were found to be the most potent inhibitors of acetylcholinesterase (IC50-5.63 µM) and butyrylcholinesterase (IC50-3.40 µM) using Ellman's assays. Enzyme kinetic studies showed that C3 and C7 compounds followed by the mixed mode of inhibition using LB plot. C3 also moderately inhibited the BACE1 using FRET assay. C3 inhibited the fibrillization of β-amyloid peptides in a concentration-dependent manner as observed by Thioflavin T, TEM studies and Circular dichroism data. Molecular modeling studies were performed to understand the probable mode of binding of C3 and C7 in the binding pocket of acetylcholinesterase, butyrylcholinesterase, BACE1 and amyloid β peptides. This indicates the important role of hydrophobic interactions between C3 and acetylcholinesterase. C3 also exhibited significant antioxidant potential by FRAP and TEAC assays. Hence, C3 might serve as a promising lead for developing novel multi target-directed ligand for the treatment of AD. © King Abdulaziz City for Science and Technology 2020.