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. 2025 Jun 6;16(7):1383-1390.
doi: 10.1021/acsmedchemlett.5c00251. eCollection 2025 Jul 10.

Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

Rozalia A Dodean  1   2 , Yuexin Li  2 , Xiaowei Zhang  2 , Amrendra Kumar  1 , Sovitj Pou  2 , Rolf W Winter  2 , Katherine M Liebman  2 , Lev N Zakharov  3 , Diana Caridha  4 , Michael S Madejczyk  4 , Chau Vuong  4 , Jesse DeLuca  4 , Geoffrey Chin  4 , Karl Kudyba  4 , Sharon McEnearney  4 , Xiannu Jin  4 , William E Dennis  4 , Ravi Chetree  4 , Cameron Blount  4 , Kristina Pannone  4 , Hieu T Dinh  4 , Kennedy Mdaki  4 , Susan Leed  4 , Patricia J Lee  4 , Alison Roth  4 , Papireddy Kancharla  1 , Jane X Kelly  1   2
Affiliations

Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

Rozalia A Dodean et al. ACS Med Chem Lett. .

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 T235, featuring a carbamate promoiety on the middle ring of the acridone core, demonstrated greater oral efficacy than its parent compound, T226. T235 provided a complete cure in Plasmodium yoelii-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, T235 offered full liver-stage protection and a sustained blood-stage cure in murine Plasmodium berghei infection when administered orally at 10 mg/kg/day, exhibiting superior prophylactic efficacy compared to T226. This study paves the way for the development of highly effective acridone-based prodrugs for both malaria prevention and treatment.

Keywords: acridones; antimalarial; antiplasmodial; blood-stage; dual-stage; liver-stage; malaria; prodrugs; prophylactic; radical cure.

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References

    1. World Health Organization . World Malaria Report; WHO: Geneva, Switzerland, 2023.
    1. Rosenthal P. J., Asua V., Conrad M. D.. Emergence, transmission dynamics and mechanisms of artemisinin partial resistance in malaria parasites in Africa. Nat. Rev. Microbiol. 2024;22:373–384. doi: 10.1038/s41579-024-01008-2. - DOI - PubMed
    1. Ishengoma D. S., Gosling R., Martinez-Vega R., Beshir K. B., Bailey J. A., Chimumbwa J., Sutherland C., Conrad M. D., Tadesse F. G., Juliano J. J., Kamya M. R., Mbacham W. F., Ménard D., Rosenthal P. J., Raman J., Tatarsky A., Tessema S. K., Fidock D. A., Djimde A. A.. Urgent action is needed to confront artemisinin partial resistance in African malaria parasites. Nat. Med. 2024;30:1807–1808. doi: 10.1038/d41591-024-00028-y. - DOI - PubMed
    1. Ishengoma D. S., Mandara C. I., Bakari C., Fola A. A., Madebe R. A., Seth M. D., Francis F., Buguzi C. C., Moshi R., Garimo I., Lazaro S., Lusasi A., Aaron S., Chacky F., Mohamed A., Njau R. J. A., Kitau J., Rasmussen C., Bailey J. A., Juliano J. J., Warsame M.. Evidence of artemisinin partial resistance in northwestern Tanzania: clinical and molecular markers of resistance. Lancet Infect. Dis. 2024;24:1225–1233. doi: 10.1016/S1473-3099(24)00362-1. - DOI - PMC - PubMed
    1. Siqueira-Neto J. L., Wicht K. J., Chibale K., Burrows J. N., Fidock D. A., Winzeler E. A.. Antimalarial drug discovery: progress and approaches. Nat. Rev. Drug Discov. 2023;22(10):807–826. doi: 10.1038/s41573-023-00772-9. - DOI - PMC - PubMed

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