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The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD<jats:sup>+<\/jats:sup> precursor to cells, to target metal dyshomeostasis, oxidative stress, \u03b2\u2010amyloid (A\u03b2) aggregation, and a decrease in the NAD<jats:sup>+<\/jats:sup>\/NADH ratio.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The most promising compound, 6\u2010methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)\u2010chelation efficacy, significant inhibition of copper\u2010mediated A\u03b2 aggregation, oxidative stress alleviation, effective donation of NAD<jats:sup>+<\/jats:sup> to NAD\u2010dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD<jats:sup>+<\/jats:sup>\/NADH ratios, as well as significantly increased median <jats:styled-content style=\"fixed-case\"><jats:italic>Caenorhabditis elegans<\/jats:italic><\/jats:styled-content> lifespan (to 1.46\u2010fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein\u2010\u03b2 (sAPP\u03b2) and A\u03b2<jats:sub>1\u201340<\/jats:sub> levels; and favourable blood\u2013brain barrier\u2010permeation properties. Structure\u2013activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD<jats:sup>+<\/jats:sup> was dependent on the electron\u2010withdrawing or electron\u2010donating substituents on the aldehyde\u2010 or ketone\u2010derived moiety. Aldehyde\u2010derived hydrazones containing the ONO donor set and electron\u2010donating groups were required for NAD<jats:sup>+<\/jats:sup> donation and low cytotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD<jats:sup>+<\/jats:sup> precursors for AD treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14963","type":"journal-article","created":{"date-parts":[[2020,1,2]],"date-time":"2020-01-02T14:59:40Z","timestamp":1577977180000},"page":"1967-1987","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD<sup>+<\/sup>\/NADH ratios"],"prefix":"10.1111","volume":"177","author":[{"given":"Zhixuan","family":"Wu","sequence":"first","affiliation":[{"name":"Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute The University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duraippandi","family":"Palanimuthu","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute The University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nady","family":"Braidy","sequence":"additional","affiliation":[{"name":"Centre for Healthy Brain Ageing, School of Psychiatry University of New South Wales  Sydney Australia"},{"name":"Schools of Medicine Huzhou University, Huzhou Central Hospital  Huzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nor Hawani","family":"Salikin","sequence":"additional","affiliation":[{"name":"School of Biological, Earth and Environmental Sciences, Centre for Marine Science and Innovation University of New South Wales  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhelen","family":"Egan","sequence":"additional","affiliation":[{"name":"School of Biological, Earth and Environmental Sciences, Centre for Marine Science and Innovation University of New South Wales  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.H.","family":"Huang","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute The University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Des R.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute The University of Sydney  Sydney New South Wales Australia"},{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya 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