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 (ACH1–ACH14) 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, ACH10 demonstrated the strongest inhibitory activity against MAO-B, followed by ACH14, ACH13, ACH8, and ACH3 (IC₅₀ = 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 ACH6. In the inhibition kinetics study, the compounds ACH10 and ACH14 were identified as competitive inhibitors, with K_i values of 0.097 ± 0.0021 and 0.10 ± 0.038 μM, respectively. In a reversibility experiment using the dialysis methods, ACH10 and ACH14 showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that ACH10 and ACH14 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.