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Misfolded prion protein (PrPSc) is known for its role in fatal neurodegenerative conditions, such as Creutzfeldt-Jakob disease. PrP fragments and their mutants represent important tools in the investigation of the neurotoxic mechanisms and in the evaluation of new compounds that can interfere with the processes involved in neuronal death. Metal-catalyzed oxidation of PrP has been implicated as a trigger for the conformational changes in protein structure, which, in turn, lead to misfolding. Targeting redox-active biometals copper and iron is relevant in the context of protection against the oxidation of biomolecules and the generation of oxidative stress, observed in several conditions and considered an event that might promote sporadic prion diseases as well as other neurodegenerative disorders. In this context, ortho-pyridine aroylhydrazones are of interest, as they can act as moderate tridentate ligands towards divalent metal ions such as copper(II). In the present work, we explore the potentiality of this chemical class as peptide protecting agents against the deleterious metal-catalyzed oxidation in the M112A mutant fragment of human PrP, which mimics relevant structural features that may play an important role in the neurotoxicity observed in prion pathologies. The compounds inhere studied, especially HPCFur, showed an improved stability in aqueous solution compared to our patented lead hydrazone INHHQ, displaying a very interesting protective effect toward the oxidation of methionine and histidine, processes that are related to both physiological and pathological aging.

Misfolded prion protein (PrP

Aroylhydrazones are versatile compounds with a series of applications, from biological to technological spheres. The simplicity of their preparation allows for a great chemical variability and synthetic manageability. However, the process can be not as straightforward as one would imagine. Some parameters such as specific reactants, the amount of acid employed as catalyst and reaction temperature can have a direct impact on the obtained product. In the present work, we describe two series of novel isoniazid-derived compounds prepared from a pair of different aldehyde precursors, as well as the solvolysis, under harsh synthetic conditions, of the initially formed aroylhydrazones, leading to unexpected dihydrazones. All compounds were unequivocally characterized in solution using 1D and 2D NMR experiments in DMSO‑d6 and, in the solid-state, by other classic techniques. System I is composed by 2-(1H-pyrazol-1-yl)benzaldehyde and its hydrazone derivatives, while system II comprises 2-(4-metoxyphenoxy)benzaldehyde and its related Schiff-base products. The first aldehyde was obtained for the first time via the copper-catalyzed Ullmann C–N coupling between 2-bromobenzaldehyde and pyrazole. Single crystals of its aroylhydrazone and dihydrazone derivatives were isolated and thoroughly characterized, including Hirshfeld surfaces and energy frameworks studies. Finally, we describe an NMR and theoretically-based proposed reaction pathway for the unexpected formation of the dihydrazones involving the solvolysis of the initially formed isonicotinoyl hydrazone followed by attack to a second free aldehyde molecule.