From Fragments to Function: Novel Hydrazone Derivatives as Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) catalyzes the breakdown of neurotransmitters, including serotonin, dopamine, and norepinephrine. There are two isoforms of this enzyme: MAO‐A and MAO‐B. MAO efficacy is widely investigated in neurodegenerative (MAO‐B) and depressive (MAO‐A) disorders. Upon examining the structures of known inhibitors, it becomes evident that many share an aliphatic amine structure. Furthermore, the literature suggests that compounds with naphthalene skeletons, phenolic structures, and hydrazone moieties exhibit MAO inhibitory activity. In this study, 12 N ‐acylhydrazone derivatives ( 5a–f , 6a–f ) were designed using ligand‐based design methods. Based on biological activity studies, the MAO‐A inhibition of the compounds was calculated to be 0.073–2.54 µM, and the MAO‐B inhibition was 0.064–3.147 µM. Among all compounds, the derivatives bearing a naphthalene ring ( 5d – f , 6d – f ) exhibited MAO enzyme inhibition at levels comparable to those of the reference compounds. The compound with the highest activity, 6e , had IC ₅₀ values of 0.073 ± 0.002 and 0.064 ± 0.002 µM against MAO‐A and MAO‐B, respectively. Due to its superior potency against human MAO‐B, enzyme kinetic studies were further conducted on compound 6e . Consequently, the pronounced inhibitory potency, reversible competitive kinetics, and favorable pharmacokinetic profile of compound 6e designate it as a strong lead candidate for advanced preclinical evaluation.