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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

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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 Zn2+ 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 Zn2+ 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.

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Abbreviations

Aβ:

β-Amyloid peptide

HPCIH:

Pyridine-2-carboxaldehyde isonicotinoyl hydrazone

INHHQ:

8-Hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone

MPACs:

Metal-protein attenuating compounds

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Acknowledgements

Nicolás A. Rey wishes to thank FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Brazil) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) for the research fellowships awarded. Daphne S. Cukierman thanks CNPq and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) for the scholarships granted. The authors are indebted to the Central Analytical Facility of the Department of Chemistry (PUC-Rio). The polycrystal X-ray diffraction analyses were done with the help of Prof. Dr. Roberto Avillez, at the X-Ray Diffraction Laboratory of the Chemical and Materials Engineering Department of PUC-Rio. The authors also thank LAMEM-UFF (Laboratório Multiusuário de Espectrometria de Massas da Universidade Federal Fluminense) for the mass spectrometry analyses.

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Authors and Affiliations

  1. Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, 22451-900, Brazil

    Daphne S. Cukierman, Elio Accardo, Rosana Garrido Gomes, Anna De Falco & Nicolás A. Rey

  2. Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, S2002LRK, Rosario, Santa Fe, Argentina

    Marco C. Miotto & Claudio O. Fernández

  3. Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 23890-000, Brazil

    Maria Clara Ramalho Freitas

  4. Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, 24020-141, Brazil

    Mauricio Lanznaster

Authors
  1. Daphne S. Cukierman
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  2. Elio Accardo
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  9. Nicolás A. Rey
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Correspondence to Nicolás A. Rey.

Electronic supplementary material

Below is the link to the electronic supplementary material.

775_2018_1606_MOESM1_ESM.pdf

Crystallographic data for complex (2) has been deposited with the Cambridge Crystallographic Data Centre as Supplementary Publications CCDC No. 1849711, respectively. Copies of the data can be obtained free of charge on application to the CCDC (http://www.ccdc.cam.ac.uk/conts/retrieving.html). Thermogravimetric curve (Fig. S1) and UV–Vis stability (Fig. S13) of HPCIH, as well as infrared and Raman (Figs. S2 and S3), and uni- and bidimensional NMR (Figs. S4 to S12) spectra of both HPCIH and complex (1) can be found as supplementary materials (PDF 912 kb)

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Cukierman, D.S., Accardo, E., Gomes, R.G. et al. 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. J Biol Inorg Chem 23, 1227–1241 (2018). https://doi.org/10.1007/s00775-018-1606-0

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