Novel Inhibitors of <i>Plasmodium</i> Phosphatidylinositol 4-kinase IIIβ with Low Propensity for Resistance: Life Cycle Stage Activity and <i>In Vivo</i> Efficacy in a Humanized Mouse Malaria Infection Model
Anticancer ATP-competitive inhibitors are a promising source of new starting points for antimalarial drug discovery. Herein, we present a novel antimalarial chemotype based on the anticancer human ataxia-telangiectasia-mutated (ATM) kinase inhibitor AZD0156. This class inhibits phosphatidylinositol 4-kinase IIIβ (PI4K) in the human malaria parasite <i>Plasmodium</i>, demonstrating remarkable activities against all stages of the <i>Plasmodium falciparum</i> life cycle. The current series exhibited a lower propensity for resistance and toxicity compared to previous <i>Plasmodium</i> PI4K inhibitors. The lead compound <b>18</b> was efficacious in a humanized NOD-<i>scid IL-2Rγnull</i> mouse model of <i>P. falciparum</i> malaria, with an ED<sub>90</sub> value of 4.6 mg kg<sup>-1</sup>.
Authors
- John G. Woodland (ORCID: https://orcid.org/0000-0001-6273-5596)
- Nonlawat Boonyalai (ORCID: https://orcid.org/0000-0002-9058-0840)
- Mathew Njoroge (ORCID: https://orcid.org/0000-0003-1276-2224)
- Godwin Akpeko Dziwornu (ORCID: https://orcid.org/0000-0003-1668-8818)
- Sandeep R. Ghorpade (ORCID: https://orcid.org/0000-0002-9311-1572)
- Janette Reader (ORCID: https://orcid.org/0000-0001-9026-0583)
- Lauren B. Coulson (ORCID: https://orcid.org/0000-0003-4699-0428)
- Dina Coertzen (ORCID: https://orcid.org/0000-0002-8408-244X)
- Rachael Coyle (ORCID: https://orcid.org/0000-0001-5838-1086)
- Kelly Chibale (ORCID: https://orcid.org/0000-0002-1327-4727)
- Kathryn J. Wicht (ORCID: https://orcid.org/0000-0001-6145-9956)
- Nicolaas Salomane (ORCID: https://orcid.org/0000-0002-8803-2538)
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Mmakwena M. Mmonwa
- J. Thomas
- Lyn‐Marié Birkholtz (ORCID: https://orcid.org/0000-0001-5888-2905)
- Meta Leshabane (ORCID: https://orcid.org/0000-0001-6885-1483)
- Nicole Sevilleno
- Lee M (ORCID: https://orcid.org/0000-0002-4973-0915)
- Shanté da Rocha (ORCID: https://orcid.org/0000-0003-2623-0114)
- Emily Mayville
- Keabetswe Masike
- Liezl Krugmann
Institutions
- South African Medical Research Council (ZA)
- University of Cape Town (ZA)
- University of Dundee (GB)
- Stellenbosch University (ZA)
- Columbia University Irving Medical Center (US)
- Discovery Centre (CA)
- Wellcome Sanger Institute (GB)
- Wellcome Centre for Anti-Infectives Research (GB)
- CNR de la Résistance aux Antibiotiques (FR)
- Wellcome Centre for Infectious Diseases Research in Africa (ZA)
- Institute for Sustainable Development (ET)
- University of Pretoria (ZA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01417
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Government of the United Kingdom
- UK Research and Innovation
- Royal Society
- National Research Foundation
- South African Medical Research Council
- University of Capetown
- Medicines for Malaria Venture
- University of Cape Town
- African Academy of Sciences
- National Institutes of Health
- Medical Research Council
- National Institute of Allergy and Infectious Diseases
- NHLBI Division of Intramural Research