FROM FRAGMENTS TO FUNCTION: NOVEL HYDRAZONE DERIVATIVES AS MAO INHIBITORS

EFMC Young Scientist Semposium, Basel, İsviçre, 10 - 11 Eylül 2026, ss.101, (Özet Bildiri)

Monoamine oxidase 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, twelve 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 IC50 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.