Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents

Abstract

A series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as antidepressants. Firstly, the serotonin reuptake inhibition of these compounds was tested in vitro, and most of them exhibited activity. Particularly, compounds 9d, 10a, and 10c demonstrated superior inhibitory effects and possibly avoided addiction via the μ-opioid receptor and CCK-B receptor. Secondly, the antidepressant effect of compound 10a was evaluated using chronic restraint stress (CRS)-induced mice. The results showed that compound 10a significantly improved CRS-induced depression-like behavior by increasing the neurotransmitters 5-HT in the cortex and THP2 expression in the hippocampus. Thirdly, compound 10a was further investigated and found to enhance CRS-induced hippocampal neuron damage recovery and elevate the expression of synaptic-associated proteins such as BDNF, TrkB, PSD95, and Spinophilin in CRS-induced mice. These findings suggested that novel isobenzofuran-1(3H)-one derivative showed efficacy in treating depression, with compound 10a emerging as a potential lead compound warranting further investigation.