Pyrimidine Azepine Targets the <i>Plasmodium bc</i><sub>1</sub> 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 <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.
Authors
- Igor M. R. Moura (ORCID: https://orcid.org/0000-0003-3279-6894)
- Surendra K. Prajapati (ORCID: https://orcid.org/0000-0003-1188-668X)
- Kim C. Williamson (ORCID: https://orcid.org/0000-0003-2749-4082)
- Richard T. Eastman (ORCID: https://orcid.org/0000-0003-3580-380X)
- Jansen Fernandes Medeiros (ORCID: https://orcid.org/0000-0003-4196-8985)
- Miho Usui (ORCID: https://orcid.org/0000-0003-2784-7642)
- Carole A. Long (ORCID: https://orcid.org/0000-0002-3835-5443)
- Daniel Y. Bargieri (ORCID: https://orcid.org/0000-0003-2564-3742)
- Jéssica E. Araújo (ORCID: https://orcid.org/0000-0001-6683-3003)
- Anna Caroline Campos Aguiar (ORCID: https://orcid.org/0000-0003-0139-8279)
- Ernest Diez Benavente (ORCID: https://orcid.org/0000-0002-4313-4290)
- Juliana Calit (ORCID: https://orcid.org/0000-0002-4835-249X)
- Anton Simeonov (ORCID: https://orcid.org/0000-0002-4523-9977)
- Yasmin Annunciato (ORCID: https://orcid.org/0000-0003-1855-5170)
- Carolina Horta Andrade (ORCID: https://orcid.org/0000-0003-0101-1492)
- Kazutoyo Miura (ORCID: https://orcid.org/0000-0003-4455-2432)
- Maísa da Silva Araújo (ORCID: https://orcid.org/0000-0003-3607-0433)
- Sabrina Silva-Mendonça
- Bingbing Deng
Institutions
- Universidade Federal de Rondônia (BR)
- National Institutes of Health (US)
- Instituto Biológico (BR)
- Uniformed Services University of the Health Sciences (US)
- Universidade Federal de São Carlos (BR)
- Universidade de São Paulo (BR)
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- National Institute of Allergy and Infectious Diseases (US)
- Drug Discovery Laboratory (Norway) (NO)
- National Center for Advancing Translational Sciences (US)
- Vector Oncology (United States) (US)
- Institute of Biomedical Science (GB)
- Artificial Intelligence in Medicine (Canada) (CA)
- Fundação Oswaldo Cruz (BR)
- Universidade Federal do Pará (BR)
- Universidade Federal de Goiás (BR)
- Veeco (United States) (US)
- Universidade Federal de São Paulo (BR)
Publication Details
- Journal
- JACS Au
- Published
- 2024-10-07
- DOI
- https://doi.org/10.1021/jacsau.4c00674
- Citations
- 9
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 4.89
Funders
- Bill and Melinda Gates Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Goiás
- Instituto Serrapilheira
- National Institutes of Health
- Uniformed Services University of the Health Sciences
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences
- NHLBI Division of Intramural Research