Juliana Calit, Surendra K Prajapati, Ernest D Benavente, Jessica E Araújo, Bingbing Deng, Kazutoyo Miura, Yasmin Annunciato, Igor M R Moura, Miho Usui, Jansen F Medeiros, Carolina H Andrade, Sabrina Silva-Mendonça, Anton Simeonov, Richard T Eastman, Carole A Long, Maisa da Silva Araujo, Kim C Williamson, Anna Caroline C Aguiar, Daniel Y Bargieri
{"title":"Pyrimidine Azepine Targets the <i>Plasmodium bc</i> <sub>1</sub> Complex and Displays Multistage Antimalarial Activity.","authors":"Juliana Calit, Surendra K Prajapati, Ernest D Benavente, Jessica E Araújo, Bingbing Deng, Kazutoyo Miura, Yasmin Annunciato, Igor M R Moura, Miho Usui, Jansen F Medeiros, Carolina H Andrade, Sabrina Silva-Mendonça, Anton Simeonov, Richard T Eastman, Carole A Long, Maisa da Silva Araujo, Kim C Williamson, Anna Caroline C Aguiar, Daniel Y Bargieri","doi":"10.1021/jacsau.4c00674","DOIUrl":null,"url":null,"abstract":"<p><p>Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic <i>Plasmodium berghei</i> 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 <b>PyAz90</b>, the most potent pyrimidine azepine chemotype identified, against <i>P. falciparum</i> and <i>P. vivax</i> in the asexual and sexual stages. <b>PyAz90</b> 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 <i>P. falciparum</i> <b>PyAz90-</b>resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome <i>b</i> as a molecular target of <b>PyAz90</b>. This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the <i>Plasmodium</i> cytochrome <i>bc</i> <sub>1</sub> complex.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 10","pages":"3942-3952"},"PeriodicalIF":8.5000,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522906/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JACS Au","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1021/jacsau.4c00674","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/28 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic Plasmodium berghei 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 PyAz90, the most potent pyrimidine azepine chemotype identified, against P. falciparum and P. vivax in the asexual and sexual stages. PyAz90 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 P. falciparumPyAz90-resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome b as a molecular target of PyAz90. This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the Plasmodium cytochrome bc1 complex.