The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold Articles uri icon

authors

  • SANDOVAL, ELENA
  • LAFUENTE-MONASTERIO, MARIA JOSE
  • ALMELA, MARIA J.
  • CASTAÑEDA, PABLO
  • JIMÉNEZ DÍAZ, MARÍA BELÉN
  • MARTINEZ-MARTINEZ, MARIA S.
  • VIDAL, JAUME
  • ANGULO BARTUREN, ÍÑIGO
  • BAMBOROUGH, PAUL
  • BURROWS, JEREMY
  • CAMMACK, NICHOLAS
  • CHAPARRO, MARIA J.
  • COTERON, JOSE M.
  • COZAR, CRISTINA DE
  • CRESPO, BENIGNO
  • DIAZ, BEATRIZ
  • DREWES, GERARD
  • FERNANDEZ, ESTHER
  • FERRER BAZAGA, SANTIAGO
  • FRAILE, MARIA TERESA
  • GAMO, FRANCISCO J.
  • GHIDELLI-DISSE, SONJA
  • GOMEZ, RUBEN
  • HASELDEN, JOHN
  • HUSS, SOPHIE
  • LEON, MARIA LUISA
  • MERCADO, JAIME DE
  • MACDONALD, SIMON J.F.
  • MARTIN HERNANDO, JOSE IGNACIO
  • PRATS, SARA
  • PUENTE, MARGARITA
  • RODRIGUEZ, ANNE
  • ROSA, JUAN C. DE LA
  • RUEDA, LOURDES
  • SELENSKI, CAROLYN
  • WILLIS, PAUL
  • WILSON, DAVID M.
  • WITTY, MICHAEL
  • CALDERON, FELIX

publication date

  • August 2017

start page

  • 6880

end page

  • 6896

issue

  • 16

volume

  • 60

International Standard Serial Number (ISSN)

  • 0022-2623

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

abstract

  • Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.

subjects

  • Biology and Biomedicine
  • Chemistry
  • Medicine

keywords

  • artemisinin resistance; starting points; reveals; malaria; identification; inhibitor; potent