Aroylhydrazones constitute a promising class of ‘metal-protein attenuating compounds’ for the treatment of Alzheimer’s disease: a proof-of-concept based on the study of the interactions between zinc(II) and pyridine-2-carboxaldehyde isonicotinoyl hydrazone

Abstract

With the increasing life expectancy of the world's population, neurodegenerative diseases, such as Alzheimer's disease (AD), will become a much more relevant public health issue. This fact, coupled with the lack of efficacy of the available treatments, has been driving research directed to the development of new drugs for this pathology. Metal-protein attenuating compounds (MPACs) constitute a promising class of agents with potential application on the treatment of neurodegenerative diseases, such as AD. Currently, most MPACs are based on 8-hydroxyquinoline. Recently, our research group has described the hybrid aroylhydrazone containing the 8-hydroxyquinoline group INHHQ as a promising MPAC. By studying the known structure-related ligand HPCIH, which does not contain the phenol moiety, as a simplified chemical model for INHHQ, we aimed to clarify the real impact of the aroylhydrazone group for the MPAC activity of a compound with potential anti-Alzheimer's activity. The present work describes a detailed solution and solid-state study of the coordination of HPCIH with Zn ions, as well as its in vitro binding-ability towards this metal in the presence of the Aβ(1-40) peptide. Similar to INHHQ, HPCIH is able to efficiently compete with Aβ(1-40) for Zn ions, performing as expected for an MPAC. The similarity between the behaviors of both ligands is remarkable. Taken together, the data presented herein point to aroylhydrazones, such as the compounds HPCIH and the previously published INHHQ, as encouraging MPACs for the treatment of AD.

Coordinating Ability of Anions, Solvents, Amino Acids, and Gases towards Alkaline and Alkaline‐Earth Elements, Transition Metals, and Lanthanides

“…[23] Particularly interesting is the use of solvents of varying coordinating abilities to obtain solvent-coordinated Er III complexes whereupon the size and shape of the cavities,a sw ell as the dimensionality of the structure is determined by the coordinated solvent. [24] The preferentialc oordination of DMSO to Zn II in competition with am ethanol-rich mediumh as also been observed, [20] and other cases in whicht he choice of as olvent was made based on its coordinating abilities have also been reported. [25][26][27][28] The reactiono fN i II with at ridentate ligand in DMFy ields a precipitate that, recrystallized in am ixture of DMSO/CH 2 Cl 2 / MeOH in a1 :1:1 ratio results in ab inuclear complex with no methanol or dichloromethane, but with coordinated DMSO, the solvent of the mixture with the highest coordinating ability index.…”

“…Particularly interesting is the use of solvents of varying coordinating abilities to obtain solvent‐coordinated Er III complexes whereupon the size and shape of the cavities, as well as the dimensionality of the structure is determined by the coordinated solvent . The preferential coordination of DMSO to Zn II in competition with a methanol‐rich medium has also been observed, and other cases in which the choice of a solvent was made based on its coordinating abilities have also been reported …”

“…[19] Analogous approaches have been applied by other researchers when studying substitution reactions. [20,21] Also ac ationic Ta complex with coordinated water hasb een seen to be stable when obtained as the triflate salt, butt od ecompose readily in solution in the presence of the less coordinating BF 4 À and [BMe(C 6 F 5 ) 3 ] À ions. [22]…”

“…In another case, the indices were used to explain the different roles played by two anions in the self‐assembly of AgX with a tridentate ligand: while for X=triflate the anion is coordinated, when hexafluorophosphate is used instead, it remains as a non‐coordinated counterion . Analogous approaches have been applied by other researchers when studying substitution reactions . Also a cationic Ta complex with coordinated water has been seen to be stable when obtained as the triflate salt, but to decompose readily in solution in the presence of the less coordinating BF 4 − and [BMe(C 6 F 5 ) 3 ] − ions …”

Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments

“…Besides that, it is able to cross the BBB, disrupt anomalous Cu-α-Syn interactions, and also inhibits oligomerization of this enzyme, which is an advantage in PD treatment [272]. In order to investigate the role of arylhydrazone moiety in MPAC activity, the compound HPCIH ( 46 ) (Figure 12) [274] was tested, and it also showed competition with Aβ for Zn 2+ ions. Peptidic ligands can also act as a MPAC compound.…”