Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors

Alagöz M. A., Oh J. M., Zenni Y. N., Özdemir Z., Abdelgawad M. A., Naguib I. A., ...More

MOLECULES, vol.27, no.12, 2022 (SCI-Expanded, Scopus) identifier identifier

  • Publication Type: Article / Article
  • Volume: 27 Issue: 12
  • Publication Date: 2022
  • Doi Number: 10.3390/molecules27123801
  • Journal Name: MOLECULES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Metadex, Veterinary Science Database, Directory of Open Access Journals, Civil Engineering Abstracts
  • Keywords: pyridazinones, monoamine oxidase-B, kinetics, reversibility, PAMPA, docking, MONOAMINE-OXIDASE, MOLECULES, DOCKING, PROTEIN, POTENT, SERIES
  • Inonu University Affiliated: Yes

Abstract

Sixteen compounds (TR1-TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 mu M, followed by TR2 (IC50 = 0.27 mu M). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with K-i values of 0.230 +/- 0.004 and 0.149 +/- 0.016 mu M, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.