Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios

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 barrierpermeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD + was dependent on the electronwithdrawing or electron-donating substituents on the aldehyde-or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electrondonating 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.Abbreviations: 59 Fe2-Tf, iron-59 labelled diferric transferrin; 8-OH-QNH, 8-hydroxy-2-quinolinecarboxaldehyde nicotinoyl hydrazone; Aβ, β-amyloid; AcNH1, 4 0 -fluoro-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AcNH2, 5 0 -bromo-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AD, Alzheimer's disease; APP, amyloid precursor protein; BBB, blood-brain barrier; DTPA, diethylenetriaminepentaacetic acid; InNH1, 7-hydroxy-1-indanone nicotinoyl hydrazone; InNH2, 7-hydroxy-6-methyl-1-indanone nicotinoyl hydrazone; InNH3, 4-bromo-7-hydroxy-1-indanone nicotinoyl hydrazone; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNH, 2-hydroxy-1-naphthaldehyde nicotinoyl hydrazone; PAMPA-BBB, parallel artificial membrane permeability assay of the blood-brain barrier; PCNH, 2-pyridinecarboxaldehyde nicotinoyl hydrazone; PNH, pyridoxal nicotinoyl hydrazone; PrNH1, 5 0 -bromo-2 0

Iron Metabolism in Aging and Age-Related Diseases

“…It significantly increased the median lifespan of C. elegans . Based on these benefits to the organisms, SNH6 has the potential to act as a multifunctional therapeutic agent for AD treatment [ 150 ].…”

Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies

“…As PD and also Alzheimer's disease appear to be complex and multi-factorial conditions, ligands have been designed to demonstrate polyfunctional activity to target pathological hallmarks of these diseases [ 529 , 530 ] . For instance, multi-functional chelators that are neuroprotectants by having both monoamine oxidase inhibitor activity with antioxidant iron chelator capacity [ 531 ].…”

Tridentate N-Acylhydrazones as Moderate Ligands for the Potential Management of Cognitive Decline Associated With Metal-Enhanced Neuroaggregopathies

“…In 2020, another work from the Richardson group reported novel multifunctional iron chelators belonging to the nicotinoyl hydrazones' family for the treatment of Alzheimer's disease ( 22 ). Among them, there is an isomer of our lead compound INHHQ: 8-OH-QNH.…”