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 oxi...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 64; no. 4; pp. 1989 - 2009
Main Authors:	Salgin-Goksen, Umut, Telli, Gokcen, Erikci, Acelya, Dedecengiz, Ezgi, Tel, Banu Cahide, Kaynak, F. Betul, Yelekci, Kemal, Ucar, Gulberk, Gokhan-Kelekci, Nesrin
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 25-02-2021
Subjects:	Animals Antidepressive Agents - chemical synthesis Antidepressive Agents - metabolism Antidepressive Agents - pharmacokinetics Antidepressive Agents - therapeutic use Depression - drug therapy Hep G2 Cells Humans Hydrazones - chemical synthesis Hydrazones - metabolism Hydrazones - pharmacokinetics Hydrazones - therapeutic use Mice Molecular Docking Simulation Molecular Structure Monoamine Oxidase - metabolism Monoamine Oxidase Inhibitors - chemical synthesis Monoamine Oxidase Inhibitors - metabolism Monoamine Oxidase Inhibitors - pharmacokinetics Monoamine Oxidase Inhibitors - therapeutic use Protein Binding Pyrazoles - chemical synthesis Pyrazoles - metabolism Pyrazoles - pharmacokinetics Pyrazoles - therapeutic use Structure-Activity Relationship
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.0c01504