Novel chelators based on adamantane-derived semicarbazones and hydrazones that target multiple hallmarks of Alzheimer's disease.
Palanimuthu D1, Wu Z1, Jansson PJ1, Braidy N2, Bernhardt PV3, Richardson DR4, Kalinowski DS1.
Dalton Trans. 2018 May 11. doi: 10.1039/c8dt01099d. [Epub ahead of print] 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.

PMID: 29749416 DOI: 10.1039/c8dt01099d

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