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

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 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.