Synthesis of Mono- and Bisperoxide-Bridged Artemisinin Dimers to Elucidate the Contribution of Dimerization to Antimalarial Activity

Lichorowic, Cynthia L.; Zhao, Yingzhao; Maher, Steven P.; Padín-Irizarry, Vivian; Mendiola, Victoria; Castro, Sagan T de; Worden, Jacob A; Casandra, Debora; Kyle, Dennis E.; Manetsch, Roman

doi:10.1021/acsinfecdis.1c00066

Cited by 5 publications

(9 citation statements)

References 33 publications

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“…Apart from this mechanism, another plausible explanation for the preserved or even superior potency of hybrid-based drugs in comparison to single quinoline drugs is the enhanced lipophilicity for the hybrid 163A in comparison to parental drugs, possibly enhancing drug permeability and accumulation. In line with this, a recent work has indicated that enhanced lipophilicity is an important aspect for explaining superior antimalarial activity of homobivalent drugs based on artemisinin dimers in comparison to monomers [49].…”

Section: Discussionmentioning

confidence: 64%

Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle

et al. 2021

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A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme.

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Section: Discussionmentioning

confidence: 64%

Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle

et al. 2021

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“…This species and stage is also the largest contributor to malaria morbidity and mortality, making it the top priority for antimalarial targeting . In continuation of our work toward identifying antimalarial synthetic small molecules − and natural products, − we determined the potency of anguidine, verrucarin A, and verrucarol against the asexual blood stages of P. falciparum , with selectivity calculated against cytotoxicity to the human hepatoblastoma cell line HepG2 (Table ). For this, we used a standard ABS assay in which ring stage parasites are treated and quantified after 72 h using high content imaging .…”

Section: Resultsmentioning

confidence: 99%

“…In continuation of our work toward identifying antimalarial synthetic small molecules − and natural products, − we determined the potency of anguidine, verrucarin A, and verrucarol against the asexual blood stages of P. falciparum , with selectivity calculated against cytotoxicity to the human hepatoblastoma cell line HepG2 (Table ). For this, we used a standard ABS assay in which ring stage parasites are treated and quantified after 72 h using high content imaging . Following three independent experiments, we found anguidine and verrucarin A were very potent against the ABS, with EC 50 ’s of 6.16 and 0.45 nM, respectively, while verrucarol was nearly inactive at the highest concentration tested.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Antimalarial Activity of Trichothecenes against Liver and Blood Stages of Plasmodium Species

Parvatkar,

Maher,

Zhao

et al. 2024

J. Nat. Prod.

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Trichothecenes (TCNs) are a large group of tricyclic sesquiterpenoid mycotoxins that have intriguing structural features and remarkable biological activities. Herein, we focused on three TCNs (anguidine, verrucarin A, and verrucarol) and their ability to target both the blood and liver stages of Plasmodium species, the parasite responsible for malaria. Anguidine and verrucarin A were found to be highly effective against the blood and liver stages of malaria, while verrucarol had no effect at the highest concentration tested. However, these compounds were also found to be cytotoxic and, thus, not selective, making them unsuitable for drug development. Nonetheless, they could be useful as chemical probes for protein synthesis inhibitors due to their direct impact on parasite synthesis processes.

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“…The structural necessity of the endoperoxide bond for artemisinin to display antimalarial activity has been directly assessed by multiple studies from different research groups [76,77]. Further evidence for this was recently disclosed by systematically showing that the chemical replacement of endoperoxide with an ether bond is deleterious for the antimalarial activity of artemisinin derivatives [78]. With the ability to alkylate molecules compromised, how can hematin-drug adducts kill Plasmodium parasites?…”

Section: Heme Alkylation Versus Protein Alkylation: the Debatementioning

confidence: 99%

The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs

2022

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Plasmodium has evolved to regulate the levels and oxidative states of iron protoporphyrin IX (Fe-PPIX). Antimalarial endoperoxides such as 1,2,4-trioxane artemisinin and 1,2,4-trioxolane arterolane undergo a bioreductive activation step mediated by heme (FeII-PPIX) but not by hematin (FeIII-PPIX), leading to the generation of a radical species. This can alkylate proteins vital for parasite survival and alkylate heme into hematin–drug adducts. Heme alkylation is abundant and accompanied by interconversion from the ferrous to the ferric state, which may induce an imbalance in the iron redox homeostasis. In addition to this, hematin–artemisinin adducts antagonize the spontaneous biomineralization of hematin into hemozoin crystals, differing strikingly from artemisinins, which do not directly suppress hematin biomineralization. These hematin–drug adducts, despite being devoid of the peroxide bond required for radical-induced alkylation, are powerful antiplasmodial agents. This review addresses our current understanding of Fe-PPIX as a bioreductive activator and molecular target. A compelling pharmacological model is that by alkylating heme, endoperoxide drugs can cause an imbalance in the iron homeostasis and that the hematin–drug adducts formed have strong cytocidal effects by possibly reproducing some of the toxifying effects of free Fe-PPIX. The antiplasmodial phenotype and the mode of action of hematin–drug adducts open new possibilities for reconciliating the mechanism of endoperoxide drugs and for malaria intervention.

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Synthesis of Mono- and Bisperoxide-Bridged Artemisinin Dimers to Elucidate the Contribution of Dimerization to Antimalarial Activity

Cited by 5 publications

References 33 publications

Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle

Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle

In Vitro Antimalarial Activity of Trichothecenes against Liver and Blood Stages of Plasmodium Species

The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs

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