Design, synthesis, pharmacological and in silico screening of disubstituted-piperazine derivatives as selective and reversible MAO-A inhibitors for treatment of depression

Abstract

Monoamine oxidase-A inhibitors (MAO-AIs) are potential drug candidates for the treatment of depression. In the present study, a series of substituted benzenesulfonyl piperazine (NP1-NP16) derivatives was synthesized and screened for their MAO-A and MAO-B inhibitory activity using the Amplex Red assay. Most of the synthesized compounds were found to show selective inhibition of MAO-A isoform. Compounds NP4 and compound NP12 showed the most potent MAO-A inhibitor activity with IC50 values of 0.25 ± 0.04 μM and 0.46 ± 0.02 μM, respectively, and both the compounds were found reversible inhibitors. Compound NP4 was found most selective as an MAO-A inhibitor with a selectivity of 52 folds over the MAO-B isoform. In the cytotoxicity evaluation, the compounds were found nontoxic to SH-SY5Y cells and also exhibited neuroprotective properties. In the DPPH studies, compounds NP4 and NP12 showed free radical scavenging activity via reducing absorbance by around 50% at a concentration of 1 mM. In the in vivo Forced swimming test (FST) studies, NP4 and NP12 exhibited potential antidepressant-like behavior similar to standard drug fluoxetine while in the Tail suspension test (TST), both the compounds showed antidepressant-like activity better than the standard. The molecular docking studies further supported the results obtained in the in vitro and in vivo studies. Thus, the substituted benzenesulfonyl functionalized piperazinyl derivatives were found to be promising ligands and can be developed as new antidepressant molecules.