Structure-based bioisosteric design, synthesis and biological evaluation of novel pyrimidines as antiplasmodial antifolate agents
Moaz M. Abdou, Paul M. O’Neill, Eric Amigues, Magdalini Matziari
Abstract
The efficacy of most marketed antimalarial drugs has been compromised by the development of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. This article describes the synthesis and the in vitro antimalarial profiling of antifolate P218 analogues, by exploring a bioisosteric replacement of the carboxylic group by a phosphinic moiety as well as structural isomerization of P218. The detailed synthetic route employed to access the title compounds is described. The listed compounds exhibited low antimalarial activity against drug-resistant strains of P. falciparum including chloroquine-resistant W2.
Topics & Concepts
AntifolateMoietyChemistryCombinatorial chemistryChloroquinePharmacologyStereochemistryPlasmodium falciparumDrugDrug discoveryComputational biologyBiochemistryMalariaMedicineBiologyOrganic chemistryToxicityAntimetaboliteImmunologySynthesis and Reactivity of Sulfur-Containing CompoundsHIV/AIDS drug development and treatmentSynthesis and biological activity