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Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2707–2717 | Cite as

Discovery two potent and new inhibitors of 15-lipoxygenase: (E)-3-((3,4-dihydroxybenzylidene) amino)-7-hydroxy-2H-chromen-2-one and (E)-O-(4-(((7-hydroxy-2-oxo-2H-chromen-3-yl) imino)methine) phenyl)dimethylcarbamothioate

  • Carolina Nuñez
  • Nicole Morales
  • Olimpo García-Beltran
  • Carolina Mascayano
  • Angelica Fierro
Original Research
  • 193 Downloads

Abstract

The mechanisms of action and structural determinants of lipoxygenases inhibitors have been explored on several occasions, but many questions remain unanswered, especially about the differences of the inhibition mechanisms and their effect on the selectivity of lipoxygenases isoenzymes. Thus, REDOX mechanism has been proposed in this research to clarify the lipoxygenases inhibition by coumarins derivates on 15-sLOX. A series of fifteen coumarin derivatives were synthetized and evaluated as 15-lipoxygenase inhibitors. The results showed that some molecules had submicromolar activities and compete with the substrate as we observed by kinetic studies. The most relevant and interesting result was found for compound 6 who showed an inhibitory activity comparable to nordihydroguaiaretic acid a potent and REDOX inhibitor of lipoxygenases (0.17 and 0.29 μM, respectively). Finally, the docking and molecular dynamics studies showed that the better ligands were accommodated into the binding site being related with those obtained biological data. In addition, our findings contribute at the understanding of inhibitor structural requirements and elucidate the inhibition mechanism of cumarin derivatives on 15-sLOX. Thus, we point to new parameters for the future design of new ligands with potential therapeutic utility where are involved the lipoxygenases enzymes.

Keywords

15-Lipoxygenase Coumarin derivatives Kinetic assay Pseudoperoxidase SAR study 

Notes

Acknowledgements

Financial support from DICYT 021641MC; Fondecyt 1120379, Fondecyt 1161375 and the Millennium Scientific Initiative (Grant P05-001-F).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1968_MOESM1_ESM.pdf (1.5 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Carolina Nuñez
    • 1
  • Nicole Morales
    • 2
  • Olimpo García-Beltran
    • 3
    • 4
  • Carolina Mascayano
    • 1
  • Angelica Fierro
    • 2
  1. 1.Facultad de Química y Biología, Departamento de Ciencias del Ambiente, Laboratorio de Simulación Molecular y Diseño Racional de FármacosUniversidad de Santiago de ChileSantiagoChile
  2. 2.Department of Organic Chemistry, Faculty of ChemistryPontificia Universidad Católica de ChileSantiagoChile
  3. 3.Facultad de Ciencias Naturales y MatemáticasUniversidad de IbaguéIbaguéColombia
  4. 4.Department of Chemistry, Faculty of SciencesUniversity of ChileSantiagoChile

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