Novel Multifunctional Iron Chelators of the Aroyl Nicotinoyl Hydrazone Class That Markedly Enhance Cellular NAD ⁺ /NADH Ratios

Zhixuan Wu ¹ , Duraippandi Palanimuthu ¹ , Nady Braidy ^{2 3} , Nor Hawani Salikin ⁴ , Suhelen Egan ⁴ , Michael L H Huang ¹ , Des R Richardson ^{1 5}

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Affiliations

• ¹ Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia.
• ² Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
• ³ Schools of Medicine, Huzhou University, Huzhou Central Hospital, Huzhou, China.
• ⁴ School of Biological, Earth and Environmental Sciences, Centre for Marine Science and Innovation, University of New South Wales, Sydney, Australia.
• ⁵ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.

• PMID: 31895471
• PMCID: PMC7161547 (available on 2021-05-01)
• DOI: 10.1111/bph.14963

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Novel Multifunctional Iron Chelators of the Aroyl Nicotinoyl Hydrazone Class That Markedly Enhance Cellular NAD ⁺ /NADH Ratios

Zhixuan Wu et al. Br J Pharmacol.2020 May.

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Br J Pharmacol

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. 2020 May;177(9):1967-1987.

doi: 10.1111/bph.14963. Epub 2020 Feb 12.

Authors

Zhixuan Wu ¹ , Duraippandi Palanimuthu ¹ , Nady Braidy ^{2 3} , Nor Hawani Salikin ⁴ , Suhelen Egan ⁴ , Michael L H Huang ¹ , Des R Richardson ^{1 5}

Affiliations

• ¹ Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia.
• ² Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
• ³ Schools of Medicine, Huzhou University, Huzhou Central Hospital, Huzhou, China.
• ⁴ School of Biological, Earth and Environmental Sciences, Centre for Marine Science and Innovation, University of New South Wales, Sydney, Australia.
• ⁵ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.

• PMID: 31895471
• PMCID: PMC7161547 (available on 2021-05-01)
• DOI: 10.1111/bph.14963

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Abstract

Background and purpose: Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD.

Experimental approach: 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⁺ precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD⁺ /NADH ratio.

Key results: The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD⁺ to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD⁺ /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ_1-40 levels; and favourable blood-brain barrier-permeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD⁺ was dependent on the electron-withdrawing or electron-donating substituents on the aldehyde- or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electron-donating groups were required for NAD⁺ donation and low cytotoxicity.

Conclusions and implications: The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD⁺ precursors for AD treatment.