Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity
Mukul Rawat, Gilda Padalino, Edem Adika, John Okombo, Tomas Yeo, Andrea Brancale, David A. Fidock, Karl F. Hoffmann, Marcus C. S. Lee
Abstract
The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum.
Introduction
Although significant progress has been made in malaria elimination, there were an estimated 263 million new cases and 597,000 deaths due to malaria infection in 2023 [1]. Artemisinin remains the gold standard antimalarial for uncomplicated malaria, with artemisinin-based combination therapies the recommended treatment since 2005. These combinations comprise fast-acting yet short-lived artemisinin derivatives that significantly reduce initial parasite biomass, partnered with longer-acting molecules with distinct modes of action to eliminate residual parasites.
Materials and method
Ethics statement
Parasites were cultured in fresh human erythrocytes obtained with ethical approval from anonymous healthy donors, with informed written consent as part of the recruitment process, from the National Health Services Blood and Transplant (NHSBT) or the Scottish National Blood Transfusion Service (SNBTS). The use of erythrocytes was with approval from NHS Cambridgeshire Research Ethics Committee (15/EE/0253) and the Wellcome Sanger Institute Human Materials and Data Management Committee, and the University of Dundee Schools of Medicine and Life Sciences Research Ethics Committee (21/39).
Results
Activity of quinoxaline compounds against Plasmodium falciparum
We investigated the anti-plasmodial activity of a lead anti-schistosomal molecule, compound 22 [13] (Fig 1A). This compound showed potent activity against both 3D7 (IC50 = 22 nM) and the multi-drug resistant strain Dd2 (IC50 = 32 nM). Modification of the nitro group on the C6 position of the central core to either a N-acetyl amide (compound 22c) or N-furan-2-carboxamide (compound 22f) greatly diminished activity against both P. falciparum strains (Fig 1A), similar to the effect on anti-schistosomal activity [13].
Discussion
Here, we report that a series of anti-schistosomal, quinoxaline-based compounds have potent activity against the asexual blood stage of P. falciparum. The compounds had sub-micromolar anti-plasmodial activity, reaching as low as single-digit nanomolar IC50 values against standard laboratory lines 3D7 and Dd2, parasite strains from Uganda, Tanzania and Ghana, as well as multi-drug resistant Cambodian isolates. To understand the mode of action of this compound series, we performed in vitro resistance selections with three compounds (22, 31, and 33).
Acknowledgments
We would like to thank R. Fairhurst for providing the Cambodian strains. We are grateful to members of the Lee lab and the reviewers for constructive feedback.
Citation: Rawat M, Padalino G, Adika E, Okombo J, Yeo T, Brancale A, et al. (2025) Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity. PLoS Pathog 21(2): e1012216. https://doi.org/10.1371/journal.ppat.1012216
Editor: Richard J. Martin, Iowa State University, UNITED STATES OF AMERICA
Received: April 23, 2024; Accepted: January 14, 2025; Published: February 3, 2025
Copyright: © 2025 Rawat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All associated sequence data are available at the European Nucleotide Archive under accession code PRJEB74174. https://www.ebi.ac.uk/ena/browser/view/PRJEB74174.
Funding: This work was supported by funding from Wellcome (206194/Z/17/Z; wellcome.org) to MCSL, from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (R01 AI124678, R01 AI185559 and R01 AI109023; www.nih.gov/grants-funding) and the Bill & Melinda Gates Foundation (INV-033538; www.gatesfoundation.org) to DAF, and from the Life Sciences Research Network Wales (www.lsrnw.ac.uk/home) to KFH and AB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
