Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones

A total of 14 acyl hydrazine derivatives (<bold>ACH1-ACH14</bold>) were developed and examined for their ability to block monoamine oxidase (MAO). Thirteen analogues showed stronger inhibition potency against MAO-B than MAO-A. With a half-maximum inhibitory concentration of 0.14 mu M, <bold>ACH10</bold> demonstrated the strongest inhibitory activity against MAO-B, followed by <bold>ACH14</bold>, <bold>ACH13</bold>, <bold>ACH8</bold>, and <bold>ACH3</bold> (IC50 = 0.15, 0.18, 0.20, and 0.22 mu M, respectively). Structure-activity relationships suggested that the inhibition effect on MAO-B resulted from the combination of halogen substituents of the A- and/or B-rings. This series concluded that when -F was substituted to the B-ring, MAO-B inhibitory activities were high, except for <bold>ACH6</bold>. In the inhibition kinetics study, the compounds <bold>ACH10</bold> and <bold>ACH14</bold> were identified as competitive inhibitors, with K-i values of 0.097 +/- 0.0021 and 0.10 +/- 0.038 mu M, respectively. In a reversibility experiment using the dialysis methods, <bold>ACH10</bold> and <bold>ACH14</bold> showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that <bold>ACH10</bold> and <bold>ACH14</bold> were efficient, reversible competitive MAO-B inhibitors. In addition, the lead molecules showed good blood-brain barrier permeation with the PAMPA method. The molecular docking and molecular dynamics simulation study confirmed that the hit compound ACH10 can form a stable protein-ligand complex by forming a hydrogen bond with the NH atom in the hydrazide group of the compound.