Abstract

Naproxen is a well-known nonsteroidal anti-inflammatory drug belonging to aryl propanoic acid family; it nonselectively inhibits major cyclo-oxygenase (COX) isoforms causing GIT irritation as a side effect. A series of Naproxen analogs with modifiable carboxylic acid functionality (2–14) have been synthesized aiming to retain anti-inflammatory activity with reduced ulcerogenic effect. Docking studies of the new compounds into cyclo-oxygenase-2 complexes with its bound inhibitor SC-558 (1CX2) were performed in order to predict the binding affinities and orientations of these compounds at the active site. Best fit Naproxen analogs, 3, 5b, 9, 10f, 14 to COX-2 active site were screened for their anti-inflammatory activity by carrageenan-induced rat paw edema test method. The target compound, 3 showed higher inhibition rate (74.71%) than the reference standard, Naproxen (71.11%), compound 10f showed comparable inhibition rate (68.94%) to Naproxen, while the other targets 5b, 9, 14 elicited moderate anti-inflammatory activities (47.98–40.27%). All the test compounds were devoid of ulcerogenicity effect compared to Naproxen. Detailed synthesis, spectroscopic, and pharmacological data are disclosed. ICM values of compounds 3 and 10f are –87.69 and –105.57 kcal/mol respectively and the number of hydrogen bonding to COX-2 prove their affinity and showed good agreement with their remarkable pharmacological data.

摘要

萘普生是一种众所周知的非甾体抗炎药，属于芳基丙酸家族。它非选择性地抑制主要的环加氧酶（COX）亚型，从而引起GIT刺激。已经合成了一系列具有可改变的羧酸官能度的萘普生类似物（2-14），目的是保留抗炎活性并降低致溃疡作用。为了预测这些化合物在活性位点的结合亲和力和方向，将新化合物与其结合的抑制剂SC-558（1CX2）对接至环加氧酶2复合物中。最适合的萘普生类似物3、5b ，9、10f，14通过角叉菜胶诱导的大鼠爪水肿试验方法筛选了对COX-2活性部位的抗炎活性。目标化合物3与参考标准品萘普生（71.11％）相比，显示出更高的抑制率（74.71％），化合物10f与萘普生具有相似的抑制率（68.94％），而其他目标5b， 9、14引起了中等程度的抗炎症活动（47.98–40.27％）。与萘普生相比，所有测试化合物都没有致溃疡作用。公开了详细的合成，光谱学和药理学数据。化合物的ICM值3和10F是-分别与87.69 kcal / mol和–105.57 kcal / mol以及与COX-2结合的氢的数量证明了它们的亲和力，并与它们出色的药理数据显示出良好的一致性。