Synthesis and biological evaluation of 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives as potential SSRIs

A series of novel 1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives were synthesized and evaluated for their serotonin (5-HT) reuptake inhibitory activity. The results in vitro indicated that most of the evaluated compounds displayed potent 5-HT reuptake inhibition. The most promising compound A20 was stable in human liver microsomes and possessed good pharmacokinetic properties. Antidepressant study in vivo of the compound A20 showed that A20 could potently antagonize the p-chloroamphetamine (PCA)-induced depletion of serotonin in hypothalamus and reduce immobility times in the rat forced swimming test (FST). [Display omitted] •1-(4-(piperazin-1-yl)phenyl)pyridin-2(1H)-one derivatives were synthesized as 5-HT reuptake inhibitors.•Compounds displayed inhibitory activities with IC50 values ranging from 0.23–12 nM.•A20 was stable in rat liver microsomes and displayed desirable pharmacokinetic properties in rat.•A20 potently antagonized the p-chloroamphetamine (PCA)-induced depletion of serotonin in hypothalamus and reduced immobility times in the rat forced swimming test (FST).