Volume 67, Issue 5 p. 186-196
RESEARCH ARTICLE

Synthesis of Deuterated Endochin-Like Quinolones

Sovitj Pou

Corresponding Author

Sovitj Pou

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

Correspondence:

Sovitj Pou ([email protected])

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Rolf W. Winter

Rolf W. Winter

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

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Katherine M. Liebman

Katherine M. Liebman

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

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Rosie A. Dodean

Rosie A. Dodean

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

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Aaron Nilsen

Aaron Nilsen

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, Oregon, USA

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Andrea DeBarber

Andrea DeBarber

Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, Oregon, USA

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J. Stone Doggett

J. Stone Doggett

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

Division of Infectious Diseases, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA

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Michael K. Riscoe

Michael K. Riscoe

Medical Research Service, VA Healthcare System, Portland, Oregon, USA

Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, USA

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First published: 25 April 2024

Funding: This project was supported with funds from the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Program Award number i01 BX003312 (M.K.R.). M.K.R. is a recipient of a VA Research Career Scientist Award (14S-RCS001). Research reported in this publication was also supported by the US National Institutes of Health under award numbers R01AI100569 and R01AI141412 (M.K.R.) and by the US Department of Defense Peer Reviewed Medical Research Program (PR181134) (M.K.R.). This work was also funded by VA Merit Review Award BX004522 to JSD from the US Department of Veterans Affairs Biomedical Laboratory Research and Development. The National Science Foundation provided instrument funding for the BioAnalytical Mass Spectrometry Facility at Portland State University (NSF, MRI 1828573), which was used to generate HRMS analytical measurements.

ABSTRACT

Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid.

Conflict of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.