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Investigating sulfoxide to sulfone conversion as a prodrug strategy for a PI4K inhibitor in a humanized mouse model of malaria

Gibhard, Liezl and Njoroge, Mathew and Paquet, Tanya and Brunschwig, Christel and Taylor, Dale and Lawrence, Nina and Abay, Efrem and Wittlin, Sergio and Wiesner, Lubbe and Street, Leslie J. and Chibale, Kelly and Basarab, Gregory S.. (2018) Investigating sulfoxide to sulfone conversion as a prodrug strategy for a PI4K inhibitor in a humanized mouse model of malaria. Antimicrobial agents and chemotherapy, 62 (12). e00261-18.

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Official URL: https://edoc.unibas.ch/67910/

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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 [ED; 90; ], 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:15 Jan 2019 14:05
Deposited On:15 Jan 2019 14:05

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