Pyrimidine Azepine\nTargets the <i>Plasmodium\nbc</i><sub>1</sub> Complex and Displays Multistage Antimalarial\nActivity

Malaria control and\nelimination efforts would benefit\nfrom the\nidentification and validation of new malaria chemotherapeutics. Recently,\na transgenic Plasmodium berghei line\nwas used to perform a series of high-throughput in vitro screens for\nnew antimalarials acting against the parasite sexual stages. The screens\nidentified pyrimidine azepine chemotypes with potent activity. Here,\nwe validate the activity of <b>PyAz90</b>, the most potent pyrimidine\nazepine chemotype identified, against P. falciparum and P. vivax in the asexual and sexual\nstages. <b>PyAz90</b> blocked parasite transmission to the mosquito\nvector at nanomolar concentrations and inhibited in vitro asexual\nparasite multiplication with a fast-action profile. Through the generation\nof P. falciparum <b>PyAz90-</b>resistant parasites and in vitro assays of mitochondrial activity,\nwe identified cytochrome <i>b</i> as a molecular target\nof <b>PyAz90</b>. This work characterizes a promising chemotype\nthat can be explored for the future development of new antimalarials\ntargeting the <i>Plasmodium</i> cytochrome <i>bc</i><sub>1</sub> complex.