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

Thirty
compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl)
acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds
having N′-(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 in vitro results. Five compounds, 6 (0.008
μM, Selectivity Index (SI): 9.70 × 10–4), 7 (0.009 μM, SI: 4.55 × 10–5), 14 (0.001 μM, SI: 8.00 × 10–4), 21 (0.009 μM, SI: 1.37 × 10–5), and 42 (0.010 μM, SI: 5.40 × 10–6), 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 14, 21, and 42 exhibited an ex vivo MAO-A
profile, which is highly consistent with the in vitro data.