Pyrimidine Azepine Targets the Complex and Displays Multistage Antimalarial Activity.

Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic line was used to perform a series of high-throughput in vitro screens for new antimalarials acting against the parasite sexual stages. The screens identified pyrimidine azepine chemotypes with potent activity. Here, we validate the activity of , the most potent pyrimidine azepine chemotype identified, against and in the asexual and sexual stages. blocked parasite transmission to the mosquito vector at nanomolar concentrations and inhibited in vitro asexual parasite multiplication with a fast-action profile. Through the generation of resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome as a molecular target of . This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the cytochrome complex.