Synthesis and evaluation of 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides as COX-2 and serotonin reuptake inhibitors.
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.
College of Chemistry and Chemical Engineering, Hunan University, Changsha, China.
Jie
J
Dou
Lei
L
Shi
Aixi
A
Hu
Minyu
M
Dong
Jiangping
J
Xu
Ailin
A
Liu
Yiping
Y
Jiang
D000818:Animals; D018938:Caco-2 Cells; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D007052:Ibuprofen; D016601:RNA-Binding Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human; C482440:Sert1 protein, rat; C077623:Ptgs2 protein, mouse; C496540:PTGS2 protein, human
2-(2-Arylmorpholino)ethyl ester hydrochloride; COX-2 inhibitors; Ibuprofen; Serotonin reuptake inhibitors; Synthesis