Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
Arch Pharm (Weinheim). 2012 Nov;345(11):878-83. doi: 10.1002/ardp.201200193. Epub 2012 Aug 21.
A novel series of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid derivatives was designed and synthesized by a new one-step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes in vitro. Among the synthesized compounds, the 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)acetic acid 4 emerged as the most potent COX-2 inhibitor (IC(50) value: 150 nM) with the highest selectivity index (COX-1/COX-2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX-2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.
设计并合成了一系列新型的 3,6,6-三甲基-4-氧代-4,5,6,7-四氢吲哚嗪-1-乙酸衍生物，通过新的一步法合成。通过各种光谱和元素分析确证了合成化合物的结构。评估了所制备的化合物抑制环加氧酶-2（COX-2）和环加氧酶-1（COX-1）酶的能力。在合成的化合物中，2-（3,6,6-三甲基-4-氧代-4,5,6,7-四氢吲哚嗪-1-基）乙酸 4 表现出最强的 COX-2 抑制活性（IC（50）值：150 nM），具有最高的选择性指数（COX-1/COX-2 抑制比：570.6）。化合物 4 在 COX-2 活性部位的对接研究确定了其与酶的潜在结合模式。基于初步结果，将化合物 4 视为进一步优化的先导化合物。
