Substituted 3-R-2,8-Dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4] triazino [2,3-c]quinazoline-5a(6H)carboxylic Acids and their Salts - a Promising Class of Anti-inflammatory Agents.
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引用次数: 4
Abstract
Background: Computer-aided drug design is among the most effective methods of medicinal chemistry. The above mentioned approach is used for the purposeful search of antiinflammatory agents among quinazoline condensed derivatives.
Objective: The study aimed to conduct a purposeful synthesis of novel 3-R-2,8-dioxo-7,8-dihydro- 2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)carboxylic acids and their salts as promising anti-inflammatory agents, evaluate their structure by physicochemical methods and establish their anti-inflammatory activity.
Methods: The structures of target compounds were proposed due to their structure similarity to existing drugs and experimental agents with anti-inflammatory activities. The features of the synthesized compounds structures were evaluated by IR-, NMR spectroscopy and chromatography-mass spectrometry and discussed in detail. Probable molecular mechanisms of activity were predicted by molecular docking. The anti-inflammatory activity was determined by their ability to reduce the formalin- and carrageenan-induced paw edema in rats.
Results: It was found that the condensation of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)ones with 2-oxoglutaric acid yielded 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline- 5a(6H)carboxylic acids which may be considered as a promising anti-inflammatory agent. An in silico study showed that the obtained compounds revealed affinity to the molecular targets and corresponded to the drug-like criteria. Additionally docking study allowed to estimate the nature of interactions between synthesized compounds and molecular targets. The in vivo experiments showed that the obtained compounds demonstrated significant anti-inflammatory activity comparable or higher than the activity of the reference drug Diclofenac.
Conclusion: The developed and implemented search strategy of the anti-inflammatory agents was justified. 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline5a(6H)carboxylic acids possessed the anti-inflammatory activity and additional introduction of fluorine atoms in position 11 or 12 of the heterocyclic system led to amplification of this activity.
取代3- r -2,8-二氧基-7,8-二氢- 2h -吡咯[1,2-a][1,2,4]三嗪基[2,3-c]喹唑啉-5a(6H)羧酸及其盐类——一类有前景的抗炎剂。
背景:计算机辅助药物设计是药物化学中最有效的方法之一。上述方法用于在喹唑啉缩合衍生物中有目的地寻找抗炎药。目的:有目的地合成新型抗炎药3- r -2,8-二氧基-7,8-二氢- 2h -吡咯[1,2-a][1,2,4]三嗪基[2,3-c]喹唑啉-5a(6H)羧酸及其盐类，并通过理化方法评价其结构，建立其抗炎活性。方法:根据目标化合物的结构与现有抗炎药物和实验药物的结构相似，提出其结构。通过红外光谱、核磁共振光谱和质谱分析对合成的化合物结构进行了表征，并对其进行了详细的讨论。通过分子对接预测了活性的可能分子机制。抗炎活性是通过降低福尔马林和卡拉胶诱导的大鼠足跖水肿的能力来确定的。结果:3-(2-氨基苯基)-6- r -1,2,4-三嗪-5(2H)与2-氧己二酸缩合得到3- r -2,8-二氧基-7,8-二氢-2H-吡咯罗[1,2-a][1,2,4]三嗪基[2,3-c]喹唑啉- 5a(6H)羧酸，是一种很有前途的抗炎药。一项计算机研究表明，所获得的化合物显示出对分子靶标的亲和力，并符合药物样标准。此外，对接研究允许估计合成化合物与分子靶点之间相互作用的性质。体内实验表明，所获得的化合物具有显著的抗炎活性，与对照药物双氯芬酸的活性相当或更高。结论:制定并实施的抗炎药搜索策略是合理的。3- r -2,8-二氧基-7,8-二氢- 2h -吡咯[1,2-a][1,2,4]三嗪基[2,3-c]喹唑啉5a(6H)羧酸具有抗炎活性，并且在杂环体系的11或12位额外引入氟原子导致该活性扩增。
期刊介绍：
Anti-Inflammatory & Anti-Allergy 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 anti-inflammatory & anti-allergy agents. Publishing a series of timely in-depth reviews written by leaders in the field covering a range of current topics, Anti-Inflammatory & Anti-Allergy 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.
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