Acetylcholinesterase Inhibitory Potential and ADMET Analysis and Molecular Docking Studies of Coumarin and Benzohydrazide Derivatives in Alzheimer's Disease

Alzheimer's disease (AD), a prevalent type of dementia, is an irreversible, progressive, neurodegenerative, age-related brain disease. It can be fatal and is characterized by acute behavioral abnormalities, including a decline in memory and cognitive abilities. AD is closely linked to acetylcholinesterase (AChEs), which degrade acetylcholine (ACh). By inhibiting AChE, the synaptic acetylcholine (ACh) level in the brain increases, reducing the symptoms of AD. Identifying more potent natural AChEIs is crucial for preventing the effects of AD. In this study, 28 coumarin and five benzohydrazide derivatives were examined against AChE using the microplate assay technique. The findings showed that, in comparison to the reference drug (IC 50 = 0.04 ± 0.001 µM), two coumarin derivatives, compounds (CMP) 9 and 22, were effective inhibitors of AChE, with IC 50 values of 354 ± 0.125 µM and 430 ± 0.01 µM, respectively. The two strong coumarin derivatives were subjected to molecular docking and ADMET analysis against human acetylcholinesterase, and CMP 9 and 22 showed excellent binding affinities with minimal energy values (-13 and -11.4 kcal/mol). The two strong derivatives, CMP 9 and 22, are promising leads in the quest for effective AD medications because of their significant interactions with key residues in the AChE active site. Furthermore, animal model-and cell line-based verification is necessary to identify the long-term efficacy of these lead compounds.