Alzheimer’s Disease Drug Design by Synthesis, Characterization, Enzyme Inhibition, In Silico, SAR Analysis and MM-GBSA Analysis of Schiff Bases Derivatives

IF 3.2 4区 工程技术 Q2 CHEMISTRY, MULTIDISCIPLINARY
Halis Karatas, İlayda Bersu Kul, Meltem Aydin, Burak Tüzün, Parham Taslimi, Zülbiye Kokbudak
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引用次数: 0

Abstract

Schiff bases, azomethine group containing compounds, form a significant class in pharmaceutical and medicinal chemistry with biologic applications. In this study, two new Schiff base molecules (7 and 9) were synthesized from the condensation reaction of 1-amino-5-(4-methylbenzoyl)-4-p-tolylpyrimidin-2(1H)-one (Z1) with 3-chlorobenzaldehyde and 3-fluorobenzaldehydes in good yields (76–75%). The synthesized Schiff bases were completely characterized by IR, NMR and LC–MS. Moreover, both synthesized compounds were evaluated against acetylcholinesterase and butyrylcholinesterase as two important targets in the treatment of Alzheimer’s disease. Approximately, both new compounds were more potent than positive control tacrine against these studied enzymes. Cholinesterase enzyme inhibition is a widely used treatment approach for a variety of mental illnesses. Through the inhibition of the acetylcholinesterase enzyme, which hydrolyzes acetylcholine, cholinesterase inhibitors directly improve cholinergic transmission. Using the SAR (structure–activity relationship) approach to connect different functional groups, the influence of this synthesized molecule on the activity was examined. The investigated compounds were then structurally characterized at the levels of B3LYP, HF, and M062X/6–31+G(d,p). Using maps of molecular electrostatic potential (MEP), the active sites of the compounds under study were identified. In the end, our focus was on evaluating the drug’s potential as an inhibitor against the Alzheimer’s disease, specifically targeting the Alzheimer’s disease protein, that are Acetylcholinesterase (AChE) (PDB ID: 1OCE, 1QTI, and 4M0E) and Butyrylcholinesterase (BChE) (PDB ID: 6R6V and 2WSL). The binding free energy is computed using MM/GBSA techniques. ADME/T characteristics were investigated to see whether these compounds could be potential drugs.

阿尔茨海默病药物设计:希夫碱衍生物的合成、表征、酶抑制、硅、SAR分析和MM-GBSA分析
希夫碱是一种含亚甲基的化合物,在药物化学和药物化学中具有重要的生物应用。本文以1-氨基-5-(4-甲基苯甲酰)-4-对-甲基嘧啶-2(1H)- 1 (Z1)为原料,与3-氯苯甲醛和3-氟苯醛缩合反应合成了两个新的希夫碱分子(7和9),产率为76 ~ 75%。合成的席夫碱通过IR、NMR和LC-MS进行了完整的表征。此外,两种合成的化合物对乙酰胆碱酯酶和丁基胆碱酯酶作为治疗阿尔茨海默病的两个重要靶点进行了评价。大约,这两种新化合物对这些酶的作用都比阳性对照他克林更有效。胆碱酯酶抑制是一种广泛应用于多种精神疾病的治疗方法。胆碱酯酶抑制剂通过抑制水解乙酰胆碱的乙酰胆碱酯酶,直接改善胆碱能的传递。采用构效关系法连接不同官能团,考察了合成的分子对活性的影响。然后在B3LYP, HF和M062X/ 6-31 +G水平上对所研究的化合物进行结构表征(d,p)。利用分子静电势图(MEP),确定了所研究化合物的活性位点。最后,我们的重点是评估该药物作为阿尔茨海默病抑制剂的潜力,特别是针对阿尔茨海默病蛋白,乙酰胆碱酯酶(AChE) (PDB ID: 1OCE, 1QTI和4M0E)和丁基胆碱酯酶(BChE) (PDB ID: 6R6V和2WSL)。结合自由能的计算采用MM/GBSA技术。研究了ADME/T特性,以确定这些化合物是否可能成为潜在的药物。
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
Korean Journal of Chemical Engineering
Korean Journal of Chemical Engineering 工程技术-工程:化工
CiteScore
4.60
自引率
11.10%
发文量
310
审稿时长
4.7 months
期刊介绍: The Korean Journal of Chemical Engineering provides a global forum for the dissemination of research in chemical engineering. The Journal publishes significant research results obtained in the Asia-Pacific region, and simultaneously introduces recent technical progress made in other areas of the world to this region. Submitted research papers must be of potential industrial significance and specifically concerned with chemical engineering. The editors will give preference to papers having a clearly stated practical scope and applicability in the areas of chemical engineering, and to those where new theoretical concepts are supported by new experimental details. The Journal also regularly publishes featured reviews on emerging and industrially important subjects of chemical engineering as well as selected papers presented at international conferences on the subjects.
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