Synthesis of 2,4-Bis(trifluoromethyl)benzaldehyde Hybrid Thiosemicarbazones as Prolyl Oligopeptidase Inhibitors for Neurodegenerative Disorders and their In-silico Analysis.

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Anam Rubbab Pasha, Saeed Ullah, Sobia Ahsan Halim, Ajmal Khan, Javid Hussain, El-Kott Attalla F, Muhammad Moazzam Naseer, Waleed Eltantawy, Ahmed Al-Harrasi, Zahid Shafiq
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引用次数: 0

Abstract

Introduction: Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia.

Method: The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde- based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in-vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 μM).

Result: Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 μM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 μM) indicated competitive inhibition of the aforementioned enzyme.

Conclusion: Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

作为神经退行性疾病脯氨酰寡肽酶抑制剂的 2,4-双(三氟甲基)苯甲醛杂合硫代氨基甲酸唑的合成及其分子内分析。
简介脯氨酰特异性寡肽酶(POP)是大脑中高表达的酶之一,是治疗中枢神经系统疾病,特别是自闭症谱系障碍、精神分裂症、帕金森病、阿尔茨海默病和痴呆症的重要靶点:本研究旨在探讨 2,4-双(三氟甲基)苯甲醛硫代氨基甲酸盐作为 POP 抑制剂治疗上述疾病的可能性。研究采用了核磁共振、质谱和傅立叶变换红外光谱等多种技术对合成的化合物进行结构确认。经过体外评价,发现所有这些化合物都是持久性有机污染物酶的主要抑制剂(IC50= 10.14 - 41.73 μM):结果:化合物 3a 是该系列中活性最强的化合物(IC50 10.14 ± 0.72 μM)。对活性最强的 3a 的动力学研究(Ki =13.66 0.0012 μM)表明,该化合物对上述酶具有竞争性抑制作用:此外,分子对接显示,硫代氨基甲酰在这些分子与持久性有机污染物酶活性位点的结合过程中发挥了显著作用。
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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current 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.
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