Alagoz, Mehmet AbdullahOh, Jong MinZenni, Yaren NurOzdemir, ZeynepAbdelgawad, Mohamed A.Naguib, Ibrahim A.Ghoneim, Mohammed M.2024-08-042024-08-0420221420-3049https://doi.org/10.3390/molecules27123801https://hdl.handle.net/11616/100729Sixteen 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.eninfo:eu-repo/semantics/openAccesspyridazinonesmonoamine oxidase-BkineticsreversibilityPAMPAdockingArticle27123574492610.3390/molecules271238012-s2.0-85132408012Q1WOS:000818373600001Q2