Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase and COX for Treatment of Alzheimer's Disease.

Q3 Psychology

Central nervous system agents in medicinal chemistry Pub Date : 2022-01-01 DOI:10.2174/1871524922666220428134001

Sukhvir Kaur, Richa Minhas, Shivam Mishra, Birpal Kaur, Yogita Bansal, Gulshan Bansal

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引用次数: 1

Abstract

Background: A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues.

Objective: The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models.

Methods: The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, ¹H-NMR, ¹³C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation.

Results: Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil.

Conclusion: The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.

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苯并咪唑抑制乙酰胆碱酯酶和COX治疗阿尔茨海默病的设计、合成和评价

背景:乙酰胆碱酯酶(AChE)抑制剂和非甾体抗炎药(NSAID)作为鸡尾酒药物同时服用，已被证明对AD患者有显著的保护作用。但它的专利依从性差，药效学和药代动力学问题。目的:本研究旨在设计和合成一种既能抑制乙酰胆碱酯酶又能抗炎的杂化分子，以减缓AD的进展。合成的分子将在体外和体内模型中进行评估。方法:本研究通过苯并咪唑将布洛芬或萘普生与不同的二取代胺(AChE抑制剂药效团)偶联，得到IB01-IB05和NP01-NP05两个系列化合物。通过FTIR、1H-NMR、13C-NMR和ms对合成的化合物进行了表征，并对化合物进行了体外AChE抑制和COX抑制活性评价。取活性最高的化合物进行体内评价。结果:与NP01-NP05相比，IB01-IB05系列化合物具有更强的抗氧化活性。采用东莨菪碱致健忘症模型，选择体外评价最强的化合物IB04在体内评价其记忆恢复活性。它以剂量依赖的方式显著逆转东莨菪碱诱导的变化(即逃避潜伏期、靶象限平均停留时间、脑乙酰胆碱酯酶活性和氧化应激)。与多奈哌齐相比，8 mg/kg剂量的IB04在降低AD表现方面显着有效。结论:利用布洛芬和吡咯烷基的苯并咪唑复合物可能为开发抗AD的多效新化合物提供了模板。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Central nervous system agents in medicinal chemistry Psychology-Neuropsychology and Physiological Psychology

CiteScore

2.10

自引率

0.00%

发文量

期刊介绍： Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Containing a series of timely in-depth reviews written by leaders in the field covering a range of current topics, Central Nervous System Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in the field.