Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson’s disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound <b>S5</b> most potently inhibited MAO-B with an IC₅₀ value of 0.203 μM, followed by <b>S16</b> (IC₅₀ = 0.979 μM). In contrast, all compounds showed weak MAO-A inhibition. Among them, <b>S15</b> most potently inhibited MAO-A with an IC₅₀ value of 3.691 μM, followed by <b>S5</b> (IC₅₀ = 3.857 μM). Compound <b>S5</b> had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound <b>S5</b> (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH₃ > -F > -CN > -CH₃ > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except <b>S16</b> (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the K_i values of <b>S5</b> and <b>S16</b> for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 μM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood–brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-<b>S5</b> complex by pi–pi stacking with Tyr398 and Tyr326. These results suggest that <b>S5</b> and <b>S16</b> are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.