Characterization of antimalarial activity of artemisinin-based hybrid drugs

In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in the hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide and in inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed some limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/577447v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@6ea6b6org.highwire.dtl.DTLVardef@831dedorg.highwire.dtl.DTLVardef@21ee5dorg.highwire.dtl.DTLVardef@1a842b7_HPS_FORMAT_FIGEXP M_FIG C_FIG Hepatic and cell-host-mediated metabolism are responsible for short plasma half-lives of antimalarial artemisinins (ARTs), illustrated here by dihydroartemisinin (DHA). ART-based hybrid drugs that overcome rapid degradation can facilitate activity against ART-resistant parasites, as illustrated by hybrid 1.