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Synthesis and evaluation of 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides as COX-2 and serotonin reuptake inhibitors.

Research paper by Jie J Dou, Lei L Shi, Aixi A Hu, Minyu M Dong, Jiangping J Xu, Ailin A Liu, Yiping Y Jiang

Indexed on: 19 Nov '13Published on: 19 Nov '13Published in: Archiv der Pharmazie



Abstract

Based on the positive effects of COX-2 inhibitors on depressive symptoms and the desirable physicochemical and biological properties of the morpholine group, a series of novel 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides were designed, synthesized, and tested for their COX-2 inhibitory and serotonin reuptake inhibitory activities in vitro. The structure-activity relationships of the 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides as dual COX-2 and serotonin reuptake inhibitors were determined and discussed in detail. The biological assays indicated that five of the compounds possess good COX-2 selectivity (selectivity index COX-1/COX-2 42.8-158.1). The compound 2-[2-(4-benzyloxyphenyl)morpholino]ethyl 2-(4-iso-butylphenyl)-propanoate hydrochloride (1k) shows better COX-2 inhibitory activity (IC50  = 0.78 µM) than ibuprofen (IC50  = 7.6 µM), and it simultaneously possesses favorable serotonin reuptake inhibitory activity.