Abstract：
Background: A dual COX/5-LOX strategy was adopted to develop new oxindole derivatives with superior anti-inflammatory activity. Methods: Three series of oxindoles - esters 4a-p, 6a-l and imines 7a-o - were synthesized and evaluated for their anti-inflammatory and analgesic activities. Molecular docking and predicted pharmacokinetic parameters were done for the most active compounds. A new LC-MS/MS method was developed and validated for the quantification of 4h in rat plasma. Results: Compounds 4h, 6d, 6f, 6j and 7m revealed % edema inhibition up to 100.00%; also, 4l and 7j showed 100.00% writhing protection. Compound 4h showed dual inhibitory activity with IC50 = 0.0533 and 0.4195 μM for COX-2 and 5-LOX, respectively. Molecular docking rationalized the obtained biological activity. The pharmacokinetic parameters of 4h from rat plasma were obtained.
[Box: see text].
[Box: see text].
摘要：
背景：采用双重COX/5-LOX策略来开发具有优异抗炎活性的新型羟吲哚衍生物。方法：三个系列的羟吲哚-酯4a-p，合成了6a-l和亚胺7a-o,并评价了它们的抗炎和镇痛活性。对最具活性的化合物进行分子对接和预测的药代动力学参数。建立了一种新的LC-MS/MS方法，并对大鼠血浆中4h的定量进行了验证。结果:化合物4h,6d,6f,6j和7m显示高达100.00%的水肿抑制；4l和7j显示100.00%的扭动保护。化合物4h对COX-2和5-LOX表现出双重抑制活性，IC50=0.0533和0.4195μM，分别。分子对接使获得的生物活性合理化。从年夜鼠血浆中获得4h的药代动力学参数。
