Novel chelators based on adamantane-derived semicarbazones and hydrazones that target multiple hallmarks of Alzheimer's disease

Dalton Transactions : an International Journal of Inorganic Chemistry
Duraippandi PalanimuthuDanuta S Kalinowski

Abstract

Alzheimer's disease (AD) is characterized by multiple pathological hallmarks, including β-amyloid aggregation, oxidative stress, and metal dys-homeostasis. In the absence of treatments addressing its multi-factorial pathology, we designed novel multi-functional adamantane-based semicarbazones and hydrazones (1-12) targeting AD hallmarks. Of these, 2-pyridinecarboxaldehyde (N-adamantan-1-yl)benzoyl-4-amidohydrazone (10) was identified as the lead compound, which demonstrated: (1) pronounced iron chelation efficacy; (2) attenuation of CuII-mediated β-amyloid aggregation; (3) low cytotoxicity; (4) inhibition of oxidative stress; and (5) favorable characteristics for effective blood-brain barrier permeation. Structure-activity relationships revealed that pyridine-derived hydrazones represent a promising pharmacophore for future design strategies due to their ability to bind critical FeII pools. Collectively, the unique multi-functional activity of these agents provides a novel therapeutic strategy for AD treatment.

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Citations

Jun 6, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Nataliya G SpitsynaEduard B Yagubskii
Oct 16, 2019·Mini Reviews in Medicinal Chemistry·Juliana de Oliveira Carneiro BrumJosé Daniel Figueroa Villar
Oct 8, 2020·International Journal of Molecular Sciences·Ajay AshokRithvik Ayyagari
Oct 29, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Andrew Gleason, Ashley I Bush
Aug 27, 2021·Journal of Drug Targeting·Yang XieLinhong Ning
Nov 11, 2021·Inorganic Chemistry·Nataliya G SpitsynaAlexander N Vasiliev

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Methods Mentioned

BETA
amidation
NMR
X-ray
flow cytometry

Software Mentioned

ChemBioDraw
Oxford Diffraction CrysAlisPro
SHELXL
GraphPad Prism
Excel

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