Synthesis and structure-activity relationship of novel cinnamamide derivatives as antidepressant agents

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure-activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b-c and 6a-b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10 mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold. (C) 2014 Elsevier Ltd. All rights reserved.