Design, synthesis and biological evaluation of oxadiazole clubbed piperazine derivatives as potential antidepressant agents

Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural features along with their pharmacological profile. In this study, we have designed and synthesized a series of 10 compounds of piperazine clubbed oxadiazole derivatives (5a-j) and screened for their MAO inhibitory activity. Compound 5f and 5 g were found to be the most potent MAO-A inhibitors of the series with IC50 values of 0.96 +/- 0.04 mu M mu M and 0.81 +/- 0.03 mu M, respectively with a selectivity index of 18-folds and 9-folds over MAO-B isoform. The compounds were found to be reversible inhibitors of MAO-A with no cytotoxicity against SH-SY5Y neuronal cells. The compounds also displayed good antioxidant activity. Further, in vivo TST studies revealed that both the compounds 5f and 5 g possessed good anti-depressant-like activity and reduced the immobility time significantly although were found inactive in FST studies. The molecular docking studies revealed that both compounds fit well at the active site of MAO-A enzyme as similar to clorgyline and form a stable complex. The results were confirmed via molecular dynamic studies which demonstrate the stable complex formation between MAO-A and 5f & 5 g. The appropriate drug-like characteristics with favourable ADMET profile, these molecules presented this piperazine clubbed oxadiazole structural framework as a key pharmacophore for the development of new antidepressant molecules along with strong candidature for further clinical investigations.

Automated summary

Piperazine derivatives have been synthesized and tested for their MAO inhibitory activity. Compound 5f and 5g showed the strongest potential as MAO-A inhibitors with IC50 values of 0.96 and 0.81 mu M, respectively. These compounds exhibited reversible inhibition of MAO-A without cytotoxicity and displayed good antioxidant activity. In vivo studies demonstrated their antidepressant-like activity. Molecular docking and dynamic studies confirmed the stable complex formation between these compounds and the MAO-A enzyme. These findings suggest that the piperazine clubbed oxadiazole structural framework is a promising target for developing new antidepressant molecules.