Empirical and molecular docking-based screening of heterocyclic compounds to identify potential acetylcholinesterase inhibitors to treat Alzheimer’s disease and its histology | ||
| Egyptian Pharmaceutical Journal | ||
| Volume 22, Issue 4, October 2023, Pages 659-675 PDF (3.05 M) | ||
| Authors | ||
| Zamzam Alhuwaymil; Zuhair M. Mohammedsaleh; Mamdoh S. Moawadh; Zaid Bassfar; Waheeb S. Aggad; Basal Sulaiman M. Alkhudhairy; Hailah M. Almohaimeed; Manal E. Alosaimi; Mona H. Soliman | ||
| 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. | ||
| Keywords | ||
| Alzheimer’s diseases; Heterocyclic compounds; neurofibrillary tangles; Neuroinflammation; neuronal loss | ||
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