Empirical and molecular docking-based screening of heterocyclic compounds to identify potential acetylcholinesterase inhibitors to treat Alzheimer’s disease and its histology

Alhuwaymil, Zamzam; Mohammedsaleh, Zuhair M.; Moawadh, Mamdoh S.; Bassfar, Zaid; Aggad, Waheeb S.; Alkhudhairy, Basal Sulaiman M.; Almohaimeed, Hailah M.; Alosaimi, Manal E.; Soliman, Mona H.

Empirical and molecular docking-based screening of heterocyclic compounds to identify potential acetylcholinesterase inhibitors to treat Alzheimer’s disease and its histology

Authors

Abstract

Background
Alzheimer’s disease (AD) is characterized by neuropathological symptoms, there has been no proper cure in recent era. It was linked to a deficiency in the brain neurotransmitter acetylcholine. Acetylcholinesterase is an enzyme that breaks down acetylcholine to an inactive form and the death of cholinergic neurons.
Objective
Therefore, there is a crucial need to identify alternative compounds with potential anti-cholinesterase agents and minimal undesirable effects. Fluoroquinolones and benzimidazole-benzothiazole derivatives offer antimicrobial, anti-inflammatory, anti-oxidant, anti-diabetic, and anti-Alzheimer activities.
Materials and methods
A series of fluoroquinolones and benzimidazole-benzothiazole derivatives were evaluated against acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and toxicology ADMET models were used for in-silico studies in addition to in-vitro studies, Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15, and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1, TBAF-2, TBAF-3, TBAF-4, TBAF-5, TBAF-6, TBAF-7, TBAF-8, and TBAF-9) passed through the AChE inhibition assay and their IC values were calculated.
Results and conclusion
The compound 1-ethyl-6-fluoro-7-(4-(2-(4-nitrophenylamino)-2-oxoethyl)piperazin-1-yl) −4-oxo-1, 4 di-hydroquinoline-3-carboxylic acid and 2-((1H-benzo[d]imidazol-2-yl)methyl)-N’-(3-bromobenzyl)-4-hydroxy-2H-thiochromene-3-carbohydrazide 1, 1-dioxide (Z-9 and TBAF-6) showed the lowest IC values against AChE/BChE (0.37±0.02/2.93±0.03 μM and 0.638±0.001/1.31±0.01 μM, respectively) than the standard drug, donepezil (3.9±0.01/4.9±0.05 μM). During the in-vivo investigation, behavioral trials were performed to analyze the neuroprotective impact of Z-9 and TBAF-6 compounds on AD mouse models. Hematological and histopathological parameters revealed that compounds have a safer aptitude. However heterocyclic compounds dramatically corrected the loss of neurons, neuroinflammation, neurofibrillary tangles, and degenerative changes in the brain’s architecture. Also, Z-9 and TBAF-6 compounds improve behavioral and biochemical parameters hence treating neurodegenerative disorders effectively.

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