Potential acetylcholinesterase inhibitors to treat Alzheimer’s disease

Abstract. – OBJECTIVE: Alzheimer’s disease (AD) is identified by neuropathological symp- toms, and there is now no effective treatment for the condition. A lack of the brain neurotransmit- ter acetylcholine has been related to the etiology of Alzheimer’s disease. Acetylcholinesterase is
an enzyme that breaks down acetylcholine to an inactive form and causes the death of cholinergic neurons. Conventional treatments were used but had less effectiveness. Therefore, there is a cru- cial need to identify alternative compounds with potential anti-cholinesterase agents and minimal
undesirable effects.
MATERIALS AND METHODS: Fluoroquinolones and benzimidazolebenzothiazole derivatives offer antimicrobial, anti inflammatory, anti-oxidant, anti-diabetic, and antiAlzheimer activities.To enhance the chemical portfolio of cholinesterase inhibitors, a variety of fluoroquinolones and benzimidazole-benzothiazole compounds were evaluated against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and oxicolo
gy ADMET models were used for in-silico studies for both AChE and BChE enzymes to investigate possible binding mechanisms and drug-likeness of the compounds. The inhibitory effect of docked heterocyclic compounds was also verified in vitro against AChE and BChE enzymes. Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15,and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1 to 9) passed through the AChE inhibition assay and their IC50 values were calculated. RESULTS: The compound 1-ethyl-6 fluo
ro-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 IC50 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 neuropro-
tective impact of Z-9 and TBAF-6 compounds on AD mouse models. The groups treated with Z-9 and TBAF-6 compounds had better cognitive behavior than the standard drug. CONCLUSIONS: This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole-benzothiazole) compounds improve behavioral and biochemical parameters, thus treating
neurodegenerative disorders effectively.