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

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Salgin-Goksen U., Telli G., Erikci A., Dedecengiz E., Tel B. C., Kaynak F. B., ...Daha Fazla

Journal of medicinal chemistry, cilt.64, sa.4, ss.1989-2009, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 64 Sayı: 4
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1021/acs.jmedchem.0c01504
  • Dergi Adı: Journal of medicinal chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1989-2009
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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 mu M, Selectivity Index (SI): 9.70 x 10(-4)), 7 (0.009 mu M, SI: 4.55 x 10(-5)), 14 (0.001 mu M, SI: 8.00 x 10(-4)), 21 (0.009 mu M, SI: 1.37 x 10(-5)), and 42 (0.010 mu M, SI: 5.40 x 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.