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Medicinal Chemistry Research

, Volume 28, Issue 12, pp 2128–2141 | Cite as

Synthesis and in silico and in vitro evaluation of trimethoxy-benzamides designed as anti-prion derivatives

  • Raissa A. Conceição
  • Lucas M. Ascari
  • Natália C. Ferreira
  • Carolina F. Goes
  • Carolina O. Matos
  • Anderson S. Pinheiro
  • Marina A. Alves
  • Alessandra M. T. Souza
  • Rodolfo C. Maia
  • Byron Caughey
  • Yraima CordeiroEmail author
  • Maria Letícia C. BarbosaEmail author
Original Research
  • 91 Downloads

Abstract

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are neurodegenerative disorders which affect mammals, including the human species, and arise after the conversion of the monomeric cellular prion protein (PrPC) into the aggregated scrapie form (PrPSc). There is no therapy to treat TSEs and the identification of compounds that bind PrPC, preventing its conversion into PrPSc, is a viable therapeutic strategy. We designed and synthesized six novel trimethoxy-benzamide compounds as anti-prion drug candidates. Molecular docking analyses predicted that all the derivatives bind to a hotspot region located in the PrP globular domain with very similar spatial orientation and interaction mode. Although none of the analogs inhibited in vitro-aggregation of recombinant PrP (rPrP) in a cell-free conversion assay, the RT-QuIC, compound 8a accelerated rPrP conversion into PrPSc-like species. STD-NMR and ITC analyses indicated that both 8a and 8b bind to rPrP90–231. These analogs were toxic to PrPSc-infected cell lines, hence we could not assess their anti-prion activity by using this cellular approach, although this toxicity was cell line-dependent. These results point out that the 4-amino-quinoline trimethoxy-benzamide scaffold described herein represents a novel chemical pattern useful as a starting point for future structural optimization in the design of PrP ligands with improved affinity and safety profiles.

Keywords

Prion protein Anti-prion drug Therapy Anti-scrapie compounds Molecular hybridization Prion strains 

Notes

Acknowledgements

The authors thank the Faculty of Pharmacy of the Federal University of Rio de Janeiro (FF-UFRJ, BR); the Laboratory for the Support of Technological Development of the Federal University of Rio de Janeiro (LADETEC-UFRJ, BR); the Laboratory of Evaluation and Synthesis of Bioactive Substances of the Federal University of Rio de Janeiro (LASSBio-UFRJ, BR); the Laboratory of Persistent Viral Diseases from Rocky Mountain Laboratories of the National Institutes of Health (USA); and the funding agencies INCT-INOFAR (BR), CAPES (BR), CNPq (BR) and FAPERJ (BR) for fellowship and financial support. The authors thank the LAMAR laboratory, from Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro (IPPN-UFRJ, BR) for NMR analysis. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2441_MOESM1_ESM.pdf (2.4 mb)
Supplementary Information.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Raissa A. Conceição
    • 1
  • Lucas M. Ascari
    • 1
  • Natália C. Ferreira
    • 1
    • 2
  • Carolina F. Goes
    • 1
  • Carolina O. Matos
    • 3
  • Anderson S. Pinheiro
    • 3
  • Marina A. Alves
    • 4
  • Alessandra M. T. Souza
    • 1
  • Rodolfo C. Maia
    • 5
  • Byron Caughey
    • 2
  • Yraima Cordeiro
    • 1
    Email author
  • Maria Letícia C. Barbosa
    • 1
    • 5
    Email author
  1. 1.Faculty of PharmacyFederal University of Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
  2. 2.Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthHamiltonUSA
  3. 3.Department of Biochemistry, Institute of ChemistryFederal University of Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
  4. 4.Laboratory for the Support of Technological Development (LADETEC), Institute of ChemistryFederal University of Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
  5. 5.Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical SciencesFederal University of Rio de Janeiro (UFRJ)Rio de JaneiroBrazil

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