Synthesis, in vitro, and in silico studies of new derivatives of diphenylpiperazine scaffold: A key substructure for MAO inhibition

Fifteen new diphenylpiperazine hybrids were designed, synthesized and in vitro biologically evaluated against hMAOs Enzymes via fluorometric method. All of our new compounds displayed strong inhibitory activities against both two isoforms of hMAOs with IC₅₀ range of 0.091-16.32 µM. According to selectivity index values, all hybrids showed higher selectivity against hMAO-A over hMAO-B. Compound 8 exhibited the best hMAO-A inhibition activity (IC₅₀ value = 91 nM, SI = 19.55). With a selectivity index of 31.02 folds over MAO-B, compound 7 was revealed to be the most effective hMAO-A inhibitor. In silico prediction of physicochemical parameters and BBB permeability proved that all of the newly synthesized compounds have favorable pharmacokinetic profiles and acceptable ADME properties and can pass BBB. For clarification and explanation of the biological activity of compounds 7 and 8, molecular docking simulations were carried out. In LIGHT of this, 1,4-diphenylpiperazine analogues can be seen as an encouraging lead to develop safe and effective new drugs for treatment of many disorders such as anxiety and depression by inhibition of hMAO-A Enzyme.

Diphenylpiperazine; Docking; MAO-A inhibitors; Molecular hybridization.