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. 2025 Apr 24;68(8):8817-8840.
doi: 10.1021/acs.jmedchem.5c00419. Epub 2025 Apr 3.

Development of Next-Generation Antimalarial Acridones with Radical Cure Potential

Rozalia A Dodean  1   2 , Yuexin Li  2 , Xiaowei Zhang  2 , Diana Caridha  3 , Michael S Madejczyk  3 , Xiannu Jin  3 , William E Dennis  3 , Ravi Chetree  3 , Karl Kudyba  3 , Sharon McEnearney  3 , Patricia J Lee  3 , Cameron Blount  3 , Jesse DeLuca  3 , Chau Vuong  3 , Kristina Pannone  3 , Hieu T Dinh  3 , Kennedy Mdaki  3 , Susan Leed  3 , Monica L Martin  3 , Brandon S Pybus  3 , Sovitj Pou  2 , Rolf W Winter  2 , Katherine M Liebman  2 , Rachel Williams  2 , Amrendra Kumar  1 , Anongruk Chim-Ong  4 , Liwang Cui  4 , Stephen Orena  5 , Jackson Assimwe  5 , Innocent Tibagambirwa  5 , Oswald Byaruhanga  5 , Patrick Angutoko  5 , Jennifer Legac  6 , Oriana Kreutzfeld  6 , Philip J Rosenthal  6 , Roland A Cooper  7 , Aaron Nilsen  2   8 , Michael K Riscoe  2   9 , Alison Roth  3 , Papireddy Kancharla  1 , Jane X Kelly  1   2
Affiliations

Development of Next-Generation Antimalarial Acridones with Radical Cure Potential

Rozalia A Dodean et al. J Med Chem. .

Abstract

Building from our previous lead compound T111 (1) possessing activity against both Plasmodium falciparum asexual blood-stage (ABS) and Plasmodium berghei liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using Plasmodium cynomolgi, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound 28 (T229) provided full LS protection and a sustained blood-stage cure for murine P. berghei infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound 28 demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Transition from first-generation to third-generation ACs.
Figure 2.
Figure 2.
Summary of SAR analyses of novel dual-stage antimalarial ACs and THACs.
Figure 3.
Figure 3.
Bioluminescence and real-time IVIS of parasite load in mice with and without treatment with test compounds (7, 28 and 36). The brighter areas (red or bright yellow) show a higher parasite load compared to the areas with a dimmer green or blue color, where fewer photons were detected. Lack of bioluminescence on the body surface represents a parasite load below the limit of detection.
Figure 4.
Figure 4.
A) In vitro mutagenicity screening of 28 (T229) and 36 (T251) at10 μM concentration and positive controls (2NF, 2-nitrofluoren; 2-AA, 2-aminoanthracene; NaN3, sodium azide); B) In vitro activity of 28 (T229) against ART-resistant parasite strains; C) Ex vivo susceptibility of 7 (T226) and 28 (T229) against P. falciparum clinical Ugandan isolates. The horizontal line shows the geometric mean. Mean IC50 values for the control laboratory strains 3D7 (red) and Dd2 (green) are shown; and D) Isobolograms of in vitro interaction of 28 (T229) and TQ against ABS pan-sensitive P. falciparum strain D6 and MDR P. falciparum strain C2B. The mean FIC indices ±SEM were derived from three independent experiments.
Scheme 1.
Scheme 1.
Synthesis of A- and B-ring Functionalized ACs (1–27). The Basic Core of the Target ACs is Filled with Color to Distinguish from the Intermediates.
Scheme 2.
Scheme 2.
Synthesis of THACs (28–46). The Basic Core of the Target THACs is Filled with Color to Distinguish from the Intermediates.
See this image and copyright information in PMC

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