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There are two isoforms of this enzyme: MAO\u2010A and MAO\u2010B. MAO efficacy is widely investigated in neurodegenerative (MAO\u2010B) and depressive (MAO\u2010A) 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                    <jats:italic>N<\/jats:italic>\n                    \u2010acylhydrazone derivatives (\n                    <jats:bold>5a\u2013f<\/jats:bold>\n                    ,\n                    <jats:bold>6a\u2013f<\/jats:bold>\n                    ) were designed using ligand\u2010based design methods. Based on biological activity studies, the MAO\u2010A inhibition of the compounds was calculated to be 0.073\u20132.54\u2009\u00b5M, and the MAO\u2010B inhibition was 0.064\u20133.147\u2009\u00b5M. Among all compounds, the derivatives bearing a naphthalene ring (\n                    <jats:bold>5d<\/jats:bold>\n                    \u2013\n                    <jats:bold>f<\/jats:bold>\n                    ,\n                    <jats:bold>6d<\/jats:bold>\n                    \u2013\n                    <jats:bold>f<\/jats:bold>\n                    ) exhibited MAO enzyme inhibition at levels comparable to those of the reference compounds. The compound with the highest activity,\n                    <jats:bold>6e<\/jats:bold>\n                    , had IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.073 \u00b1 0.002 and 0.064 \u00b1 0.002\u2009\u00b5M against MAO\u2010A and MAO\u2010B, respectively. Due to its superior potency against human MAO\u2010B, enzyme kinetic studies were further conducted on compound\n                    <jats:bold>6e<\/jats:bold>\n                    . Consequently, the pronounced inhibitory potency, reversible competitive kinetics, and favorable pharmacokinetic profile of compound\n                    <jats:bold>6e<\/jats:bold>\n                    designate it as a strong lead candidate for advanced preclinical evaluation.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70416","type":"journal-article","created":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T01:18:59Z","timestamp":1786843139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Fragments to Function: Novel Hydrazone Derivatives as Monoamine Oxidase Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5339-6940","authenticated-orcid":false,"given":"Hasan Erdin\u00e7","family":"Sellitepe","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy Karadeniz Technical University  Trabzon 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