Investigating Sulfoxide-to-Sulfone Conversion as a Prodrug Strategy for a Phosphatidylinositol 4-Kinase Inhibitor in a Humanized Mouse Model of Malaria

Author:

Gibhard Liezl1ORCID,Njoroge Mathew1,Paquet Tanya2,Brunschwig Christel1,Taylor Dale1,Lawrence Nina1,Abay Efrem1,Wittlin Sergio34,Wiesner Lubbe5,Street Leslie J.2,Chibale Kelly267,Basarab Gregory S.1

Affiliation:

1. Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa

2. Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, South Africa

3. Swiss Tropical and Public Health Institute, Basel, Switzerland

4. University of Basel, Basel, Switzerland

5. Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Observatory, South Africa

6. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa

7. South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town, Rondebosch, South Africa

Abstract

The in vivo antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rγ null (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing.

Funder

Technology Innovation Agency

Medicines for Malaria Venture

National Research Foundation

South African Medical Research Council

Department of Science and Technology, Republic of South Africa

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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