Abstract
Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective.
Highlights
Synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; known as arterolane) and OZ439, have been approved for marketing or are currently in clinical development
We previously examined the responses of laboratory and field strains of P. falciparum to artemisinins by using drug assays designed to mimic in vivo exposure [31, 34]
We examined the responses of parasites to OZ277 and OZ439 pulses of different durations
Summary
OZ277 (RBx11160; known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. Resistance initially manifested as delayed parasite clearance, but reports of clinical failure (recrudescence of infections) are increasing in areas with concomitant partner drug resistance [8, 9]. Another issue with the widespread application of the artemisinins is the difficulty of maintaining the supply. There is an urgent need for wholly synthetic endoperoxides that are as effective and as affordable as the currently used artemisinins These synthetic endoperoxides will show efficacy in shorter-course treatment regimens, and ideally, they will maintain activity against artemisinin-resistant strains [10]. Asymmetrical 1,2,4-trioxolanes, in which one side of the ozonide heterocycle is sterically hindered and the other is more accessible, exhibited excellent antimalarial activity along with good in vivo exposure, and they were developed for clinical use [17,18,19,20]
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