Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

In this study, we present a prodrug strategy that successfully led to the development of highly potent dual-stage antimalarial acridone analogs with radical cure potential. Notably, the prodrug <b>T235</b>, featuring a carbamate promoiety on the middle ring of the acridone core, demonstrated greater oral efficacy than its parent compound, <b>T226</b>. <b>T235</b> provided a complete cure in <i>Plasmodium yoelii</i>-infected mice up to 28 days at doses of 3 and 10 mg/kg administered over 4 days and was also curative with a single oral dose of 20 mg/kg. Furthermore, <b>T235</b> offered full liver-stage protection and a sustained blood-stage cure in murine <i>Plasmodium berghei</i> infection when administered orally at 10 mg/kg/day, exhibiting superior prophylactic efficacy compared to <b>T226</b>. This study paves the way for the development of highly effective acridone-based prodrugs for both malaria prevention and treatment.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-06-06
DOI
https://doi.org/10.1021/acsmedchemlett.5c00251
Citations
1
Primary Topic
Computational Drug Discovery Methods
Type
article
Field-Weighted Citation Impact
1.50

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article

Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

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1 citations
ACS Medicinal Chemistry Letters
Computational Drug Discovery Methods
1.50
article

Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

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article en
1 citations

Abstract

In this study, we present a prodrug strategy that successfully led to the development of highly potent dual-stage antimalarial acridone analogs with radical cure potential. Notably, the prodrug <b>T235</b>, featuring a carbamate promoiety on the middle ring of the acridone core, demonstrated greater oral efficacy than its parent compound, <b>T226</b>. <b>T235</b> provided a complete cure in <i>Plasmodium yoelii</i>-infected mice up to 28 days at doses of 3 and 10 mg/kg administered over 4 days and was also curative with a single oral dose of 20 mg/kg. Furthermore, <b>T235</b> offered full liver-stage protection and a sustained blood-stage cure in murine <i>Plasmodium berghei</i> infection when administered orally at 10 mg/kg/day, exhibiting superior prophylactic efficacy compared to <b>T226</b>. This study paves the way for the development of highly effective acridone-based prodrugs for both malaria prevention and treatment.

ACS Medicinal Chemistry LettersVol. 16(7)
Portland State University (US), University of Oregon (US), Portland VA Medical Center (US), Campo Arqueologico de Mertola (PT), Walter Reed Army Institute of Research (US)
U.S. Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, Congressionally Directed Medical Research Programs
Openalex Percentile: Top 16%
Computational Drug Discovery Methods
1.50
DOIOpen Access PDFOpenAlex
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