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

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.

Anti-Oxidant and Tyrosinase Inhibitory In Vitro Activity of Amino Acids and Small Peptides: New Hints for the Multifaceted Treatment of Neurologic and Metabolic Disfunctions

“…Excellent reports have highlighted the role of this amino acid, in terms of steric and polar effects, in decreasing peptide radical formation and stabilization in vivo [38]. On the other hand, semicarbazones, as well as thiosemicarbazones and hydrazones, are known to possess a wide array of biological activities, essentially due to their ability to form strongly H-bond stabilized chelates with heavy metals [39].…”

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

“…Partial success in ameliorating the symptoms of AD, glaucoma, and AMD with iron chelators re-enforces the central role of iron-mediated ROS in AD pathogenesis [ 124 , 125 ]. For example, iron chelators have been used to ameliorate the symptoms of AD with partial success [ 126 ].…”

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

“…The most promising compound was Px-CAH, a tridentate N -acylhydrazone derived from the cholic acid hydrazide ( 18 ). On the other hand, Richarson, Kalinowski and co-workers presented novel semicarbazone and hydrazone families of adamantane-containing chelators aiming to target multiple Alzheimer's hallmarks ( 19 ). Among these, pyridine-2-carboxaldehyde ( N -adamantan-1-yl)benzoyl-4-amidohydrazone, namely 10, was identified as a lead compound.…”