Design, Synthesis, and Evaluation of Isoindoline Derivatives as New Antidepressant Agents

Background: Isoindoline derivatives exhibit a wide range of biological activities and have attracted considerable attention. However, few studies have been conducted on their antidepressant activity. Objective: Here, we designed and synthesized a series of isoindoline derivatives and studied their antidepressant activities. Methods: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mice brain by using ELISA. The biological activities of the compounds were verified by molecular docking studies. The pharmacokinetic properties of the target compounds were predicted by Discovery Studio (DS) 2020. Results: The results of the pharmacological experiments showed that most isoindoline derivatives exhibited significant antidepressant activity. Among these compounds, compound 4j showed the highest antidepressant activity. The results of the measurement of 5-HT levels in the brains of mice indicate that the antidepressant activity of isoindoline derivatives may be mediated by elevated 5-HT levels. Compound 4j was used in molecular docking experiments to simulate the possible interaction of these compounds with the 5-HT1A receptor. The results demonstrated that compound 4j had a significant interaction with amino acids around the active site of the 5-HT1A receptor in the homology model. Conclusion: Isoindoline derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.