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5+1-Heterocyclization as preparative approach for carboxy-containing triazolo[1,5-c]quinazolines with anti-inflammatory activity
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-01-11 , DOI: 10.1016/j.ejmech.2024.116137 Natalya Krasovska 1 , Galina Berest 2 , Igor Belenichev 2 , Hanna Severina 3 , Inna Nosulenko 2 , Oleksii Voskoboinik 4 , Sergiy Okovytyy 5 , Serhii Kovalenko 5
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-01-11 , DOI: 10.1016/j.ejmech.2024.116137 Natalya Krasovska 1 , Galina Berest 2 , Igor Belenichev 2 , Hanna Severina 3 , Inna Nosulenko 2 , Oleksii Voskoboinik 4 , Sergiy Okovytyy 5 , Serhii Kovalenko 5
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Present article is devoted to the purposeful search of novel anti-inflammatory agents among carboxyl-containing partially hydrogenated [1,2,4]triazolo[1,5]quinazolines and products of their tandem cyclization. It has been shown that target compound’s could be obtained interaction between [2-(3-R-1-1,2,4-triazol-5-yl)phenyl]amines and oxo-containing carboxylic acids and their esters of various structure. The structures of synthesized compounds were verified by appropriate methods, the features of NMR-spectra patterns were discussed as well. The low predicted toxicity of obtained compounds has been estimated using methods. In vivo study on the model of acute aseptic inflammation (carrageenan test) have been revealed that synthesized compounds expose anti-inflammatory activity in the range of 0.94–52.66%. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-]quinazolin-5-yl)benzoic acid has been identified as most active compound. Additionally, the effects of some (2-R-5,6-dihydro[1,2,4]triazolo[1,5-]quinazolin-5-yl)benzoic acids (compounds ) on the levels of key inflammatory markers have been estimated. It has been shown that studied compounds decrease the level of neutrophils, COX-2, nitrotyrosine, IL-1b, C-reactive protein and increase level of eNOS. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-]quinazolin-5-yl)benzoic acid () has been identified as compound with most expressed anti-inflammatory activity and significant effect on the levels of marker of inflammatory processes. Molecular docking study towards СОХ-1 and СОХ-2 has been conducted to substantiate possible mechanism of obtained compounds anti-inflammatory activity. It has been found that fixation of 4-(2-(ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-]quinazolin-5-yl)benzoic acid () molecule in active site of enzyme is outstandingly similar to the reference ligands. The essential value of carboxylic group for presence of anti-inflammatory activity has been estimated as result of SAR-analysis. It has been found that studied class of compounds is perspective for further structural modification aimed to the creation of novel anti-inflammatory agents.
中文翻译：
5+1-杂环化作为具有抗炎活性的含羧基三唑并[1,5-c]喹唑啉的制备方法
本文致力于在含羧基的部分氢化[1,2,4]三唑并[1,5]喹唑啉及其串联环化产物中有目的地寻找新型抗炎药。结果表明，[2-(3-R-1-1,2,4-三唑-5-基)苯基]胺与含氧羧酸及其各种结构的酯之间的相互作用可以获得目标化合物。通过适当的方法验证了合成化合物的结构，并讨论了NMR谱图的特征。已使用方法估计了所获得的化合物的低预测毒性。急性无菌炎症模型的体内研究（角叉菜胶试验）表明，合成化合物的抗炎活性在 0.94-52.66% 范围内。 4-(2-(乙氧基羰基)-5,6-二氢-[1,2,4]三唑并[1,5-]喹唑啉-5-基)苯甲酸已被确定为最活跃的化合物。此外，一些（2-R-5,6-二氢[1,2,4]三唑并[1,5-]喹唑啉-5-基）苯甲酸（化合物）对关键炎症标志物水平的影响已被证实估计的。研究表明，所研究的化合物可降低中性粒细胞、COX-2、硝基酪氨酸、IL-1b、C 反应蛋白的水平，并增加 eNOS 的水平。 4-(2-(乙氧基羰基)-5,6-二氢-[1,2,4]三唑并[1,5-]喹唑啉-5-基)苯甲酸()已被确定为具有最多表达抗炎作用的化合物活性并对炎症过程标志物水平产生显着影响。对СОХ-1和СОХ-2进行了分子对接研究，以证实所获得的化合物抗炎活性的可能机制。 已发现4-(2-(乙氧基羰基)-5,6-二氢-[1,2,4]三唑并[1,5-]喹唑啉-5-基)苯甲酸()分子在活性位点的固定酶的结构与参考配体非常相似。 SAR 分析的结果估计了羧基对于抗炎活性存在的基本价值。已经发现，所研究的一类化合物有望进一步进行结构修饰，以创造新型抗炎剂。
更新日期：2024-01-11
中文翻译：
5+1-杂环化作为具有抗炎活性的含羧基三唑并[1,5-c]喹唑啉的制备方法
本文致力于在含羧基的部分氢化[1,2,4]三唑并[1,5]喹唑啉及其串联环化产物中有目的地寻找新型抗炎药。结果表明，[2-(3-R-1-1,2,4-三唑-5-基)苯基]胺与含氧羧酸及其各种结构的酯之间的相互作用可以获得目标化合物。通过适当的方法验证了合成化合物的结构，并讨论了NMR谱图的特征。已使用方法估计了所获得的化合物的低预测毒性。急性无菌炎症模型的体内研究（角叉菜胶试验）表明，合成化合物的抗炎活性在 0.94-52.66% 范围内。 4-(2-(乙氧基羰基)-5,6-二氢-[1,2,4]三唑并[1,5-]喹唑啉-5-基)苯甲酸已被确定为最活跃的化合物。此外，一些（2-R-5,6-二氢[1,2,4]三唑并[1,5-]喹唑啉-5-基）苯甲酸（化合物）对关键炎症标志物水平的影响已被证实估计的。研究表明，所研究的化合物可降低中性粒细胞、COX-2、硝基酪氨酸、IL-1b、C 反应蛋白的水平，并增加 eNOS 的水平。 4-(2-(乙氧基羰基)-5,6-二氢-[1,2,4]三唑并[1,5-]喹唑啉-5-基)苯甲酸()已被确定为具有最多表达抗炎作用的化合物活性并对炎症过程标志物水平产生显着影响。对СОХ-1和СОХ-2进行了分子对接研究，以证实所获得的化合物抗炎活性的可能机制。 已发现4-(2-(乙氧基羰基)-5,6-二氢-[1,2,4]三唑并[1,5-]喹唑啉-5-基)苯甲酸()分子在活性位点的固定酶的结构与参考配体非常相似。 SAR 分析的结果估计了羧基对于抗炎活性存在的基本价值。已经发现，所研究的一类化合物有望进一步进行结构修饰，以创造新型抗炎剂。
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