| Author | Calit, Juliana | |
| Author | Prajapati, Surendra K. | |
| Author | Benavente, Ernest D. | |
| Author | Araújo, Jessica E. | |
| Author | Deng, Bingbing | |
| Author | Miura, Kazutoyo | |
| Author | Annunciato, Yasmin | |
| Author | Moura, Igor M. R. | |
| Author | Usui, Miho | |
| Author | Medeiros, Jansen Fernandes de | |
| Author | Andrade, Carolina H. | |
| Author | Silva-Mendonça, Sabrina | |
| Author | Simeonov, Anton | |
| Author | Eastman, Richard T. | |
| Author | Long, Carole A. | |
| Author | Araújo, Maisa da Silva | |
| Author | Williamson, Kim C. | |
| Author | Aguiar, Anna Caroline C. | |
| Author | Bargieri, Daniel Y. | |
| Access date | 2025-01-02T20:21:16Z | |
| Available date | 2025-01-02T20:21:16Z | |
| Document date | 2024 | |
| Citation | CALIT, Juliana et al. Pyrimidine Azepine Targets the Plasmodium bc1 Complex and Displays Multistage Antimalarial Activity. JACS Au, v. 4, n. 10, p. 3705-4043, Oct. 2023. | en_US |
| ISSN | 2691-3704 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/67845 | |
| Language | eng | en_US |
| Publisher | American Chemical Society | en_US |
| Rights | open access | en_US |
| Title | Pyrimidine Azepine Targets the Plasmodium bc1 Complex andDisplays Multistage Antimalarial Activity | en_US |
| Type | Article | en_US |
| DOI | 10.1021/jacsau.4c00674 | |
| 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. falciparum PyAz90-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. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Fiocruz Rondônia. Laboratório de Entomologia. Plataforma de Produção e Infecção de Vetores da Malária. Porto Velho, RO, Brasil / Fundação Universidade Federal de Rondônia. Programa de pós-graduação em Biologia Experimental. Porto Velho, RO, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Fiocruz Rondônia. Laboratório de Entomologia. Plataforma de Produção e Infecção de Vetores da Malária. Porto Velho, RO, Brasil / Fundação Universidade Federal de Rondônia. Programa de pós-graduação em Biologia Experimental. Porto Velho, RO, Brasil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Fiocruz Rondônia. Laboratório de Entomologia. Plataforma de Produção e Infecção de Vetores da Malária. Porto Velho, RO, Brasil. | en_US |
| Affilliation | University of São Paulo. Institute of Biomedical Sciences. Department of Parasitology. São Paulo, SP, Brasil. | en_US |
| Affilliation | Uniformed Services University of the Health Sciences. Department of Microbiology and Immunology. Bethesda, Maryland, United States. | en_US |
| Affilliation | Utrecht University. University Medical Center Utrecht. Laboratory of Experimental Cardiology. Utrecht, The Netherlands | en_US |
| Affilliation | National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, United States. | en_US |
| Affilliation | National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, United States. | en_US |
| Affilliation | Federal University of São Paulo. Department of Bioscience. São Paulo, Brasil. | en_US |
| Affilliation | University of São Paulo. Institute of Physics of São Carlos. São Carlos, SP, Brasil. | en_US |
| Affilliation | Uniformed Services University of the Health Sciences. Department of Microbiology and Immunology. Bethesda, United States. | en_US |
| Affilliation | Federal University of Goias. Faculty of Pharmacy. Laboratory for Molecular Modeling and Drug Design. Goiania, GO, Brasil / Universidade Federal de Goiás. Institute of Informatics. Center for Excellence in Artificial Intelligence. Goiania, GO, Brasil. | en_US |
| Affilliation | Federal University of Goias. Faculty of Pharmacy. Laboratory for Molecular Modeling and Drug Design. Goiania, GO, Brasil / Universidade Federal de Goiás. Institute of Informatics. Center for Excellence in Artificial Intelligence, Goiania, GO, Brasil. | en_US |
| Affilliation | National Institutes of Health. National Center for Advancing Translational Sciences Division of Preclinical Innovation. Rockville, United States | en_US |
| Affilliation | National Institutes of Health. National Center for Advancing Translational Sciences Division of Preclinical Innovation. Rockville, United States. | en_US |
| Affilliation | National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, United States. | en_US |
| Affilliation | Uniformed Services University of the Health Sciences. Department of Microbiology and Immunology. Bethesda, United States. | en_US |
| Affilliation | Federal University of São Paulo. Department of Bioscience. São Paulo, Brasil / Federal University of São Paulo. Department of Microbiology, Immunology, and Parasitology. São Paulo, SP, Brasil. | en_US |
| Affilliation | University of São Paulo. Institute of Biomedical Sciences. Department of Parasitology. São Paulo, SP, Brasil. | en_US |
| Subject | Malaria | en_US |
| Subject | Resistance | en_US |
| Subject | Pyrimidine azepine | en_US |
| Subject | Bc1 complex | en_US |
| Subject | Plasmodium | en_US |
| DeCS | Malaria | en_US |
| DeCS | Plasmodium | en_US |
