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Background  Drug efficacy against  kelch 13  mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin.    Methods  Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration–time profile of these ozonides in humans and a novel, semi-automated readout was introduced.    Results  When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the  Plasmodium falciparum  clinical isolate Cam3.I R539T .    Conclusion  If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48 h, OZ439 and OZ609 will be highly potent against  kelch 13  mutant isolates, such as  P. falciparum  Cam3.I R539T .

Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay