Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD+/NADH ratios. (12th February 2020)

• Record Type: Journal Article
• Authors: Wu, Zhixuan; Palanimuthu, Duraippandi; Braidy, Nady; Salikin, Nor Hawani; Egan, Suhelen; Huang, Michael L.H.; Richardson, Des R.
• Is Part Of: British journal of pharmacology. Volume 177:Number 9(2020)
• Page Start: 1967
• Page End: 1987
• Publication Date: 2020-02-12
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.14963
• Languages: English
• ISSNs: 0007-1188

Abstract

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 Aβ1–40 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.