biostudies-literatureSkinner-Adams TSMedicines for Malaria VentureU.S. Department of Health &amp; Human Services | NIH | Office of Extramural Research, National Institutes of HealthNIAID NIH HHSDepartment of Health | National Health and Medical Research Council166https://www.ebi.ac.uk/biostudies/studies/S-EPMC6499835biostudies-literatureUnknown2Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil's action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against <i>P. berghei</i> liver-stage parasitCommunications biologyCyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone.PMC6499835APP1098848n/aR01 AI103058R01 AI090141Burrows JNWilson TChopra PAndrews KTFidock DARyan JHvon Itzstein MSkinner-Adams TSJarvis KEClarke MHutt OERiches AGFisher GMWinzeler EAAntonova-Koch YMeister SfalseCyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone.Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil's action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against <i>P. berghei</i> liver-stage parasit2019-01-01T00:00:00Z20192025-04-19T22:56:16.414Z2019-06-06T23:11:08ZS-EPMC64998353106927510.1038/s42003-019-0397-3