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

Autor: 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
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Molecules, Vol 27, Iss 12, p 3801 (2022)
Druh dokumentu: article
ISSN: 1420-3049
DOI: 10.3390/molecules27123801
Popis: 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.
Databáze: Directory of Open Access Journals
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