Rosa Fernanda A, Gonçalves Davana S, Pianoski Karlos E, da Silva Michael J V, Ames Franciele Q, Aguiar Rafael P, Volpato Hélito, Lazarin-Bidóia Danielle, Nakamura Celso V, Bersani-Amado Ciomar A
Departamento de Química, Universidade Estadual de Maringá (UEM) 87030-900 Maringá PR Brazil
Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá (UEM) 87030-900 Maringá PR Brazil.
RSC Med Chem. 2024 Feb 8;15(3):1038-1045. doi: 10.1039/d3md00604b. eCollection 2024 Mar 20.
In this paper, we present the design and synthesis of a novel series of pyrido[2,3-]pyridazine-2,8-dione derivatives the annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for anti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its COX-1/COX-2 inhibitory activity. Compound 7c showed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern I transformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.
在本文中，我们介绍了一系列新型吡啶并[2,3 -]哒嗪 - 2,8 - 二酮衍生物的设计与合成，该衍生物通过2 - 吡啶酮模式的环合反应得到。使用耳部水肿模型对合成的衍生物进行抗炎活性评估。表现出对耳部水肿有更强抑制作用（82%）的化合物7c，进一步测试了其对COX - 1/COX - 2的抑制活性。化合物7c对COX - 1和COX - 2同工酶表现出相似的抑制活性。利用分子对接研究阐明了确保对COX - 1和COX - 2双重抑制的结构特征。总体而言，2 - 吡啶酮模式I的环合反应将这种高度选择性的COX - 2抑制剂转化为双重COX抑制剂（7c），它可作为确定对COX - 2选择性的模型。
