期刊
MOLECULES
卷 27, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/molecules27123801
关键词
pyridazinones; monoamine oxidase-B; kinetics; reversibility; PAMPA; docking
资金
- Taif University, Taif, Saudi Arabia [TURSP-2020/56]
- AlMaarefa University, Riyadh, Saudi Arabia [2021-6]
The study synthesized and evaluated 16 compounds, finding that TR2 and TR16 showed potent and highly selective inhibition against MAO-B, making them promising for managing multiple neurodegenerative diseases.
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.
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