Pyrimidine Azepine Targets the Plasmodium bc₁ Complex and Displays Multistage Antimalarial Activity

Author(s):Show less -

Calit, Juliana ; Prajapati, Surendra K. ; Benavente, Ernest D. ; Araujo, Jessica E. ; Deng, Bingbing ; Miura, Kazutoyo ; Annunciato, Yasmin ; Moura, Igor M. R. ; Usui, Miho ; Medeiros, Jansen F. ; Andrade, Carolina H. ; Silva-Mendonca, Sabrina ; Simeonov, Anton ; Eastman, Richard T. ; Long, Carole A. ; Araujo, Maisa da Silva ; Williamson, Kim C. ; Aguiar, Anna Caroline C. ; Bargieri, Daniel Y.

• Document type: Journal article
• Source: JACS AU; v. 4, n. 10, p. 11-pg., 2024-10-07.

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 bc 1 complex. (AU)

• FAPESP's process: 18/24878-9 - Search for Plasmodium transmission-blocking compounds using new experimental models
• Grantee: Juliana Calit Paim
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/06769-0 - Discovery of vaccine targets and compounds against Malaria transmission
• Grantee: Daniel Youssef Bargieri
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 19/19708-0 - Identification of new antimalarial compounds: a multidisciplinary strategy aimed to search for potent chemical classes against new molecular targets and different stages of life of Plasmodium spp
• Grantee: Anna Caroline Campos Aguiar
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 23/02543-3 - Evaluation of the activity of new 4-quinolones compounds against hepatic and sexual forms of Plasmodium spp.
• Grantee: Yasmin Annunciato
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree