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 () 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 μM, demonstrated the strongest inhibitory activity against MAO-B, followed by , , , and (IC = 0.15, 0.18, 0.20, and 0.22 μM, 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 . In the inhibition kinetics study, the compounds and were identified as competitive inhibitors, with values of 0.097 ± 0.0021 and 0.10 ± 0.038 μM, respectively. In a reversibility experiment using the dialysis methods, and showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that and 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.