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

oleh: 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

Format: Article
Diterbitkan: MDPI AG 2022-06-01

Deskripsi

Sixteen compounds (<b>TR1–TR16</b>) 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 <b>TR16</b> was the most potent inhibitor against MAO-B with an IC<sub>50</sub> value of 0.17 μM, followed by <b>TR2</b> (IC<sub>50</sub> = 0.27 μM). <b>TR2</b> and <b>TR16</b> 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 <i>para</i>-chloro substituent in <b>TR2</b> and <b>TR16</b> increased the inhibitory activity of MAO-B. <b>TR2</b> and <b>TR16</b> were reversible MAO-B inhibitors that were competitive, with K<sub>i</sub> values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds <b>TR2</b> and <b>TR16</b> 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.