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. 2024 Nov 14;67(21):19755-19776.
doi: 10.1021/acs.jmedchem.4c02093. Epub 2024 Oct 19.

Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines

Amrendra Kumar  1 , Sivanna Chithanna  1 , Yuexin Li  2 , Xiaowei Zhang  2 , Rozalia A Dodean  1   2 , Diana Caridha  3 , Michael S Madejczyk  3 , Patricia J Lee  3 , Xiannu Jin  3 , Ravi Chetree  3 , Cameron Blount  3 , William E Dennis  3 , Jesse DeLuca  3 , Chau Vuong  3 , Kristina Pannone  3 , Hieu T Dinh  3 , Susan Leed  3 , Alison Roth  3 , Kevin A Reynolds  1 , Jane X Kelly  1   2 , Papireddy Kancharla  1
Affiliations

Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines

Amrendra Kumar et al. J Med Chem. .

Abstract

Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure-activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic Plasmodium parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic Plasmodium yoelii infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage Plasmodium berghei sporozoite-induced infection in mice.

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Conflict of interest statement

The authors declare no competing financial interest.

The material has been reviewed by the Walter Reed Army Institute of Research (WRAIR). There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be constructed as official or as reflecting the true views of the Department of the Army or the Department of Defense.

Figures

Figure 1.
Figure 1.
Structures of representative natural TAs (2–4), PGs (5 and 6), and modified-PGs (7–10) containing methoxy (OMe) group on ring-B, and their common biosynthetic precursor (1).
Figure 2.
Figure 2.
Bioluminescence and real-time In Vivo Imaging System (IVIS) of parasite load in mice with and without compound 70 treatment. TQ, tafenoquine used as a reference drug and PEG-400 used as a vehicle control. The brighter areas of the image (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 light on the body surface represents total lack of parasite load (malaria free) or a parasite load below the limit of detection.
Figure 3.
Figure 3.
In vitro mutagenicity screening of PG 70 at 10 μM concentration and positive controls (2NF, 2-nitrofluorene; 2-AA, 2-aminoanthracene; NaN3, sodium azide).
Scheme 1.
Scheme 1.
Synthesis of Key MBC Analogues (1, 15a–c, 18a–c and 20a–c), and Target TAs (2, 3 and 21–56) Containing Various Alkoxy, Benzyloxy and Aryloxy Moieties on Ring-B.
Scheme 2.
Scheme 2.
Synthesis of Target PGs (5, 6, and 64–81) Containing Various Alkoxy, Benzyloxy and Aryloxy Moieties on Ring-B.
See this image and copyright information in PMC

References

    1. WHO. World Malaria Report 2023.
    1. Arya A; Kojom Foko LP; Chaudhry S; Sharma A; Singh V Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: A systematic review of clinical studies from two malaria endemic regions - India and sub-Saharan Africa. Int. J. Parasitol. Drugs Drug Resist 2021, 15, 43–56. - PMC - PubMed
    1. Uwimana A; Legrand E; Stokes BH; Ndikumana JM; Warsame M; Umulisa N; Ngamije D; Munyaneza T; Mazarati JB; Munguti K; Campagne P; Criscuolo A; Ariey F; Murindahabi M; Ringwald P; Fidock DA; Mbituyumuremyi A; Menard D Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat. Med 2020, 26, 1602–1608. - PMC - PubMed
    1. Rosenthal PJ; Asua V; Conrad MD Emergence, transmission dynamics and mechanisms of artemisinin partial resistance in malaria parasites in Africa. Nat. Rev. Microbiol 2024, 22, 373–384. - PubMed
    1. Ishengoma DS; Gosling R; Martinez-Vega R; Beshir KB; Bailey JA; Chimumbwa J; Sutherland C; Conrad MD; Tadesse FG; Juliano JJ; Kamya MR; Mbacham WF; Ménard D; Rosenthal PJ; Raman J; Tatarsky A; Tessema SK; Fidock DA; Djimde AA Urgent action is needed to confront artemisinin partial resistance in African malaria parasites. Nat. Med 2024, 30, 1807–1808. - PubMed