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

Arch Pharm (Weinheim). 2014 Feb;347(2):89-95. doi: 10.1002/ardp.201300279. Epub 2013 Nov 18.

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.

Keywords: 2-(2-Arylmorpholino)ethyl ester hydrochloride; COX-2 inhibitors; Ibuprofen; Serotonin reuptake inhibitors; Synthesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / chemical synthesis*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Esters / chemical synthesis*
  • Esters / pharmacology*
  • Humans
  • Ibuprofen / analogs & derivatives
  • Ibuprofen / chemical synthesis*
  • Ibuprofen / pharmacology*
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / enzymology
  • Mice
  • Molecular Structure
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / metabolism
  • Rats
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis*
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin Plasma Membrane Transport Proteins / drug effects
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Cyclooxygenase 2 Inhibitors
  • Esters
  • RNA-Binding Proteins
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Sert1 protein, rat
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Ibuprofen