Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Asir, Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2024 Mar;28(6):2522-2537. doi: 10.26355/eurrev_202403_35759.
Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter 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 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. 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 toxicology 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.
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 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 neuroprotective 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.
This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole-benzothiazole) compounds improve behavioral and biochemical parameters, thus treating neurodegenerative disorders effectively.
阿尔茨海默病（AD）通过神经病理学症状来确定，目前还没有有效的治疗方法。大脑神经递质乙酰胆碱的缺乏与阿尔茨海默病的病因有关。乙酰胆碱酯酶是一种将乙酰胆碱分解为无活性形式的酶，导致胆碱能神经元死亡。传统的治疗方法虽然被使用，但效果较差。因此，迫切需要找到具有潜在抗乙酰胆碱酯酶作用且不良反应最小的替代化合物。
氟喹诺酮类和苯并咪唑-苯并噻唑衍生物具有抗菌、抗炎、抗氧化、抗糖尿病和抗阿尔茨海默病的活性。为了增强乙酰胆碱酯酶抑制剂的化学组合，评估了多种氟喹诺酮类和苯并咪唑-苯并噻唑化合物对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）的抑制作用。为此，使用分子对接和吸附、分布、代谢、排泄和毒理学 ADMET 模型对 AChE 和 BChE 酶进行了计算机模拟研究，以研究化合物可能的结合机制和类药性。还通过体外试验验证了对接杂环化合物对 AChE 和 BChE 酶的抑制作用。氟喹诺酮类（Z、Z3、Z4、Z6、Z8、Z12、Z15 和 Z9）和苯并咪唑-苯并噻唑化合物（TBIS-16、TBAF-1 至 9）通过了 AChE 抑制试验，计算了它们的 IC50 值。
化合物 1-乙基-6-氟-7-（4-（2-（4-硝基苯氨基）-2-氧代乙基）哌嗪-1-基）-4-氧代-1,4-二氢喹啉-3-羧酸和 2-（（1H-苯并[d]咪唑-2-基）甲基）-N'-(3-溴苄基）-4-羟基-2H-硫代色烯-3-甲脒 1,1-二氧化物（Z-9 和 TBAF-6）对 AChE/BChE 的最低 IC50 值（分别为 0.37±0.02/2.93±0.03 µM 和 0.638±0.001/1.31±0.01 µM）低于标准药物多奈哌齐（3.9±0.01/4.9±0.05 µM）。在体内研究中，进行了行为试验以分析 Z-9 和 TBAF-6 化合物对 AD 小鼠模型的神经保护作用。用 Z-9 和 TBAF-6 化合物治疗的组的认知行为优于标准药物。
本研究发现，Z-9（氟喹诺酮类）和 TBAF-6（苯并咪唑-苯并噻唑）化合物改善了行为和生化参数，从而有效治疗神经退行性疾病。
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