Molecules (Jun 2022)

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

  • Mehmet Abdullah Alagöz,
  • Jong Min Oh,
  • Yaren Nur Zenni,
  • Zeynep Özdemir,
  • Mohamed A. Abdelgawad,
  • Ibrahim A. Naguib,
  • Mohammed M. Ghoneim,
  • Nicola Gambacorta,
  • Orazio Nicolotti,
  • Hoon Kim,
  • Bijo Mathew

DOI
https://doi.org/10.3390/molecules27123801
Journal volume & issue
Vol. 27, no. 12
p. 3801

Abstract

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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 μM, followed by TR2 (IC50 = 0.27 μM). 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 Ki values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, 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.

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