Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase

J Med Chem. 2008 Feb 14;51(3):439-48. doi: 10.1021/jm7010673. Epub 2008 Jan 12.

Abstract

Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities.

Publication types

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

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Models, Molecular
  • Orotidine-5'-Phosphate Decarboxylase / antagonists & inhibitors*
  • Plasmodium / drug effects*
  • Plasmodium / enzymology
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology
  • Plasmodium vivax / drug effects
  • Structure-Activity Relationship
  • Uridine / analogs & derivatives*
  • Uridine / chemical synthesis*
  • Uridine / pharmacology
  • Uridine Monophosphate / analogs & derivatives
  • Uridine Monophosphate / chemical synthesis
  • Uridine Monophosphate / pharmacology

Substances

  • Antimalarials
  • Uridine Monophosphate
  • Orotidine-5'-Phosphate Decarboxylase
  • Uridine