Synthesis and human monoamine oxidase inhibitory activity of novel C2-, C3-and C4-substituted phthalonitriles


Ali H. E. A. , Ozalp L., DANIŞ Ö., Odabas Z.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol.74, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 74
  • Publication Date: 2022
  • Doi Number: 10.1016/j.bmcl.2022.128917
  • Journal Name: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
  • Journal Indexes: 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
  • Keywords: Phthalonitriles, Monoamine oxidase inhibitors, Docking studies, MAO, Reversible inhibition, Structure -activity relationship, POTENT INHIBITORS, MAO INHIBITORS, OXIDATION, MUTANT
  • Marmara University Affiliated: Yes

Abstract

Development of new selective reversible monoamine oxidase (MAO) B inhibitors is still essential for the treatment of Alzheimer's and Parkinson's disease. Phthalonitrile compounds have been shown to display MAO inhibitory activity with MAO-B selectivity. In this study, we synthesized and evaluated the inhibitory activities of a new series of phthalonitrile compounds. Compound 3, 4 and 5 presented selective MAO-B inhibition, compound 5 being the most selective (75.16-fold). Additionally, molecular docking simulations were carried out. Investigation of binding modes of each compound with both isoforms were carried out to elaborate structure-activity relationships. Druglikeness was calculated for each compound, revealing that the lipophilicity of compound 5 (logP = 3.37) is optimal to cross membranes.