A pantetheinase-resistant pantothenamide with potent, on-target, and selective antiplasmodial activity

Antimicrob Agents Chemother. 2015;59(6):3666-8. doi: 10.1128/AAC.04970-14. Epub 2015 Apr 6.

Abstract

Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC50], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC50, 52 ± 6 nM), target specificity, and low toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / metabolism*
  • Antimalarials / metabolism*
  • Antimalarials / pharmacology*
  • Chloroquine / pharmacology
  • GPI-Linked Proteins / metabolism
  • Plasmodium falciparum / drug effects

Substances

  • Antimalarials
  • GPI-Linked Proteins
  • Chloroquine
  • Amidohydrolases
  • pantetheinase