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

• Published in: Bioorganic chemistry 2023-07, Vol.136, p.106544-106544, Article 106544
• Main Authors: Sahu, Bhaskar, Bhatia, Rohit, Kaur, Dilpreet, Choudhary, Diksha, Rawat, Ravi, Sharma, Shilpa, Kumar, Bhupinder
• Format: Article
• Language: English
• Subjects: Antidepressant activity; Antidepressive Agents - chemistry; Antioxidant; Benzylpiperazine; FST and TST; Humans; MAO inhibitors; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemistry; Neuroblastoma; Phenylpiperazine; Piperazine - pharmacology; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106544

[Display omitted] •A new series of oxadiazole clubbed piperazines (5a-j) was designed, synthesized and evaluated for MAO inhibitory potential.•In this series, compounds 5f and 5 g displayed most potent, selective and reversible inhibition of MAO-A enzyme.•These compounds also exhibited neuroprotective and free radical scavenging potential without toxicity against SH-SY5Y cells.•In FST and TST studies, 5f and 5 g exhibited potential antidepressant-like behaviour similar to standard drug fluoxetine. 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 µM µM and 0.81 ± 0.03 µM, 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.