Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity Articles uri icon

authors

  • Kokkonda, Sreekanth
  • Deng, Xiaoyi
  • White, Karen L.
  • Coteron, Jose M.
  • Marco, Maria
  • De Las Heras, Laura
  • White, John
  • El Mazouni, Farah
  • Tomchick, Diana R.
  • Manjalanagara, Krishne
  • Rudra, Kakali Rani
  • Chen, Gong
  • Morizzi, Julia
  • Ryan, Eileen
  • Kaminsky, Werner
  • Leroy, Didier
  • Martinez Martinez, Maria Santos
  • Jimenez Diaz, Maria Belen
  • FERRER BAZAGA, SANTIAGO
  • Angulo Barturen, Iñigo
  • Waterson, David
  • Burrows, Jeremy N.
  • Matthews, Dave
  • Charman, Susan A.
  • Phillips, Margaret A.
  • Rathod, Pradipsinh K.

publication date

  • June 2016

issue

  • 11

volume

  • 59

International Standard Serial Number (ISSN)

  • 0022-2623

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

abstract

  • Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.