: Acetylcholinesterase (AchE), hydrolase enzyme, regulates the hydrolysis of acetylcholine neurotransmitter in the neurons. AchE is found majorly in the central nervous system at the site of cholinergic neurotransmission. It is involved in the pathophysiology of Alzheimer’s disease-causing dementia, cognitive impairment, behavioral and psychological symptoms. Recent findings involved the inhibition of AchE that could aid in the treatment of Alzheimer's. Many drugs of different classes being analyzed in the clinical trials and examined for their potency. Drugs that are used in the treatment of Alzheimer’s disease are donepezil, galantamine, tacrine, rivastigmine shows major adverse effects. To overcome this, researchers work on novel drugs to elicit inhibition. This review comprises the many hybrids and non-hybrid forms of heteroaromatic and non-heteroaromatic compounds that were designed and evaluated for AchE inhibition by Ellman’s method of assay. These novel compounds may assist the future perspectives in the discovery of novel moieties against Alzheimer’s disease by the inhibition of AchE.

The Quantitative Structural Activity Relationship among 49 reported compounds containing chalcone derivatives as an acetylcholinesterase inhibitor. The acetylcholinesterase enzyme is the major leading threat to neurodegenerative disorders. The 2D QSAR study was done using QSARINS software. Model 2 was obtained as the best model with an r2 value of 0.9398. The OECD principles were used to validate the model. The applicability domain of the model resulted in zero outliers. Based on the results of the QSAR study, 10 novel ligands possessing chalcones fused with quinoxaline were drawn. These 10 novel ligands showed class 5 toxicity, which was predicted using PROTOX II software. The ADME properties were also screened using preADMET. Molecular docking was performed between the 10 ligands and the acetylcholinesterase enzyme (PDB ID: 4EY7) using Autodock 4.0 softaware. 2D visualisation of drug interactions was also discussed. Compounds 4 and 5 with substitution of p-chloro and 2-bromo respectively demonstrated active binding to the catalytic anionic site and the peripheral anionic site, respectively. These results were compared with those of the standard drug, donepezil.