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

Liezl Gibhard; Mathew Njoroge; Tanya Paquet; Christel Brunschwig; Dale Taylor; Nina Lawrence; Efrem Abay; Sergio Wittlin; Lubbe Wiesner; Leslie J Street; Kelly Chibale; Gregory S Basarab

doi:10.1128/AAC.00261-18

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

Antimicrob Agents Chemother. 2018 Nov 26;62(12):e00261-18. doi: 10.1128/AAC.00261-18. Print 2018 Dec.

Authors

Liezl Gibhard^#¹, Mathew Njoroge^#¹, Tanya Paquet², Christel Brunschwig¹, Dale Taylor¹, Nina Lawrence¹, Efrem Abay¹, Sergio Wittlin^{3

4}, Lubbe Wiesner⁵, Leslie J Street², Kelly Chibale^{2

6

7}, Gregory S Basarab⁸

Affiliations

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.
⁸ Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa greg.basarab@uct.ac.za.

^# Contributed equally.

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. Both compounds had similar efficacy (90% effective dose [ED₉₀], 0.1 mg kg^-1 of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.

Keywords: NSG mouse model; malaria; prodrug; sulfoxide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors
1-Phosphatidylinositol 4-Kinase / genetics
1-Phosphatidylinositol 4-Kinase / metabolism
Animals
Antimalarials / blood
Antimalarials / chemical synthesis
Antimalarials / pharmacokinetics
Antimalarials / pharmacology*
Biotransformation
Disease Models, Animal
Dose-Response Relationship, Drug
Erythrocytes / drug effects
Erythrocytes / metabolism
Erythrocytes / parasitology
Gene Expression
Humans
Malaria, Falciparum / drug therapy*
Malaria, Falciparum / metabolism
Malaria, Falciparum / parasitology
Malaria, Falciparum / pathology
Male
Mice
Mice, Inbred NOD
Mice, SCID
Parasitemia / drug therapy*
Parasitemia / pathology
Plasmodium falciparum / drug effects
Plasmodium falciparum / enzymology
Plasmodium falciparum / growth & development
Prodrugs / chemical synthesis
Prodrugs / pharmacokinetics
Prodrugs / pharmacology*
Pyrazines / blood
Pyrazines / chemical synthesis
Pyrazines / pharmacokinetics
Pyrazines / pharmacology*
Sulfones / blood
Sulfones / chemical synthesis
Sulfones / pharmacokinetics
Sulfones / pharmacology*
Sulfoxides / blood
Sulfoxides / chemical synthesis
Sulfoxides / pharmacokinetics
Sulfoxides / pharmacology*
Treatment Outcome

Substances

Antimalarials
Prodrugs
Pyrazines
Sulfones
Sulfoxides
1-Phosphatidylinositol 4-Kinase