A Review on Recent Development of Novel Heterocycles as Acetylcholinesterase Inhibitor for the Treatment of Alzheimer’s Disease

Abstract

Abstract: Alzheimer's Disease (AD), affecting a large population worldwide, is characterized by the old population's loss of memory and learning ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed to treat AD, including naturally-derived inhibitors, synthetic analogs, and hybrids. Acetylcholinesterase (AChE) has obtained a re-newed interest as a therapeutic target in Alzheimer's disease (AD) due to increased neural cells' function by increasing the concentration of acetylcholine. In this review, we reported the recent de-velopment of novel heterocyclic compounds such as coumarin-benzotriazole hybrids, carbazole de-rivatives, tacrine conjugates, N-benzyl-piperidine-aryl-acyl hydrazones hybrid, spiropyrazoline de-rivatives, coumarin-dithiocarbamate hybrids, etc., as AChE inhibitors for the treatment of Alz-heimer disease. All the bioactive compounds show an effect on different cells and interact simulta-neously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE with a nar-row range of IC50 values from 0.4 nm to 88.21 μm using Ellman’s in vitro AChE assay method and show high BBB permeability in vitro. In addition, the in vitro fluorescence assay study using Am-plex Red assay kits revealed that all the compounds could inhibit self-induced β-amyloid (Aβ) ag-gregation with the highest inhibition range from 31.4 to 82%. Furthermore, most of the compounds show a low toxicity profile during in vivo studies. The results suggest that all the compounds consti-tute promising leads for the AChE targeted approach for Alzheimer’s disease.