Design, Synthesis, and in vitro Evaluation of Derivatives of Quinoxaline-2- One as a Myeloperoxidase Modulator Using in silico Methods

Q2 Pharmacology, Toxicology and Pharmaceutics
Dakshinesh Parameswaran, Saravanan Thangavelu, Jubie Selvaraj, Selvinthanuja Chellappa, L. Vivekanandan, R. Veerasamy, Prabha Thangavelu
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引用次数: 0

Abstract

Our study aimed to design, synthesis, and in vitro evaluation of derivatives of quinoxaline-2-one as a myeloperoxidase modulator using in silico methods. In some pathological situations, the overproduction of oxidising agents also results in oxidative damage to host cell proteins and DNA, which induces abnormal expression of inflammatory cytokines and chemokines. A recently discovered biomarker of inflammation is myeloperoxidase. Various inflammatory conditions cause the release of this enzyme into the extracellular environment. Our study aimed to design, synthesis, and in vitro evaluation of derivatives of quinoxaline-2-one as a myeloperoxidase modulator using in silico methods. A series of quinoxaline-2-one derivatives was synthesised and characterised by various analytical techniques. Further, to confirm and explore the molecular mechanism, an in silico docking study against the myeloperoxidase enzyme was performed (PDB ID: 1DNU). The compounds Q1, Q2, and Q5 showed better antioxidant activity in the DPPH assay, whereas the nitric oxide scavenging assay showed the compounds Q2, Q4, and Q5 had significant activity when compared to the standard IC50 value (28.8 µg/ml). Beside, the anti-inflammatory studies showed the compounds Q1, Q3, and Q5 showed better inhibition (89.79%) when compared to the standard drug aceclofenac (85.37%) at 1000 µg/ml concentration. The top three ligands for myeloperoxidase (PDB ID: 1DNU) with the highest scores in activity were found as Q2, Q1, and Q5, with scores of -13.2838, -12.5841, and -11.6906 Kcal/mol, respectively. The compounds were efficiently bound to the myeloperoxidase active site with arene-arene, arene-cation, hydrogen bonding, and etc. interactions. By introducing the various heterocyclic rings and deactivating and activating groups, we may produce a newer class of candidates for many infectious diseases. Thus, from the computational studies carried out, we may obtain hints for optimising the molecular selectivity of the quinoxaline-2-one derivatives to provide help in the design of new compounds for effective myeloperoxidase enzyme modulators. However, further pharmacokinetics, pharmacodynamics, preclinical, and clinical studies permit the design of the new agents without undesirable interactions. Nil
利用硅学方法设计、合成和体外评估作为髓过氧化物酶调节剂的喹喔啉-2-酮衍生物
我们的研究旨在利用硅学方法设计、合成和体外评估作为髓过氧化物酶调节剂的喹喔啉-2-酮的衍生物。 在某些病理情况下,氧化剂的过度产生也会导致宿主细胞蛋白质和 DNA 的氧化损伤,从而诱发炎症细胞因子和趋化因子的异常表达。最近发现的一种炎症生物标志物是髓过氧化物酶。各种炎症条件都会导致这种酶释放到细胞外环境中。 我们的研究旨在利用硅学方法设计、合成和体外评估作为髓过氧化物酶调节剂的喹喔啉-2-酮的衍生物。 我们合成了一系列喹喔啉-2-酮衍生物,并通过各种分析技术对其进行了表征。此外,为了证实和探索其分子机制,还针对髓过氧化物酶(PDB ID:1DNU)进行了硅学对接研究。 化合物 Q1、Q2 和 Q5 在 DPPH 试验中显示出更好的抗氧化活性,而一氧化氮清除试验显示,与标准 IC50 值(28.8 µg/ml)相比,化合物 Q2、Q4 和 Q5 具有显著的活性。此外,抗炎研究表明,在 1000 µg/ml 浓度下,与标准药物醋氯芬酸(85.37%)相比,化合物 Q1、Q3 和 Q5 显示出更好的抑制效果(89.79%)。髓过氧化物酶(PDB ID:1DNU)活性得分最高的前三个配体为 Q2、Q1 和 Q5,得分分别为 -13.2838、-12.5841 和 -11.6906 Kcal/mol。这些化合物通过炔-炔、炔-阳离子、氢键等相互作用与髓过氧化物酶活性位点有效结合。 通过引入各种杂环以及失活和活化基团,我们可能会产生一类新的候选化合物,用于治疗多种传染性疾病。因此,从已进行的计算研究中,我们可以获得优化喹喔啉-2-酮衍生物分子选择性的提示,为设计有效的髓过氧化物酶调节剂的新化合物提供帮助。不过,还需要进一步开展药代动力学、药效学、临床前和临床研究,才能设计出没有不良相互作用的新制剂。 无
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来源期刊
Current Bioactive Compounds
Current Bioactive Compounds Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)
CiteScore
1.90
自引率
0.00%
发文量
112
期刊介绍: The journal aims to provide comprehensive review articles on new bioactive compounds with proven activities in various biological screenings and pharmacological models with a special emphasis on stereoeselective synthesis. The aim is to provide a valuable information source of bioactive compounds synthesized or isolated, which can be used for further development of pharmaceuticals by industry and academia. The journal should prove to be essential reading for pharmacologists, natural product chemists and medicinal chemists who wish to be kept informed and up-to-date with the most important developments on new bioactive compounds of natural or synthetic origin, including their stereoeselective synthesis.
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