Novel pantothenate derivatives for anti-malarial chemotherapy

Malar J. 2015 Apr 18;14:169. doi: 10.1186/s12936-015-0673-8.

Abstract

Background: A number of synthetic pantothenate derivatives, such as pantothenamides, are known to inhibit the growth of the human malaria parasite Plasmodium falciparum, by interfering with the parasite Coenzyme A (CoA) biosynthetic pathway. The clinical use of pantothenamides is limited by their sensitivity to breakdown by ubiquitous human pantetheinases of the vanin family.

Methods: A number of pantothenate derivatives (pantothenones) with potent and specific inhibitory activity against mammalian vanins were tested in a proliferation assay of asexual P. falciparum blood stages alone, and in combination with pantothenamides.

Results: The vanin inhibitors were found to protect pantothenamides against breakdown by plasma vanins, thereby preserving the in vitro anti-malarial activity. Moreover, some of the vanin inhibitors showed in vitro anti-malarial activity in the low micromolar range. The most potent antimalarial in this series of compounds (RR8), was found to compete with pantothenate in a combination proliferation assay. No correlation, however, was found between anti-vanin and anti-malarial activity, nor was pantetheinase activity detected in P. falciparum extracts.

Conclusions: Growth inhibition is most likely due to competition with pantothenate, rather than pantetheinase inhibition. As vanin inhibitors of the pantothenone class are stable in biological fluids and are non-toxic to mammalian cells, they may represent novel pantothenate-based anti-malarials, either on their own or in combination with pantothenamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Antimalarials / therapeutic use*
  • Humans
  • Malaria, Falciparum / drug therapy
  • Pantothenic Acid / analogs & derivatives
  • Pantothenic Acid / pharmacology
  • Pantothenic Acid / therapeutic use*
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / growth & development

Substances

  • Antimalarials
  • Pantothenic Acid