Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice

J Med Chem. 2011 Jun 9;54(11):3935-49. doi: 10.1021/jm200265b. Epub 2011 May 12.

Abstract

Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology
  • Dihydroorotate Dehydrogenase
  • Disease Models, Animal
  • Drug Design
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Plasmodium berghei / drug effects*
  • Plasmodium berghei / enzymology
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Protein Binding
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Solubility
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology

Substances

  • Antimalarials
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • Pyrimidines
  • Triazoles
  • Oxidoreductases Acting on CH-CH Group Donors