New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors.

Abstract

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having '-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the results. Five compounds, (0.008 μM, Selectivity Index (SI): 9.70 × 10), (0.009 μM, SI: 4.55 × 10), (0.001 μM, SI: 8.00 × 10), (0.009 μM, SI: 1.37 × 10), and (0.010 μM, SI: 5.40 × 10), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds , and exhibited an MAO-A profile, which is highly consistent with the data.