Falcipain Inhibitors: Optimization Studies of the 2-Pyrimidinecarbonitrile Lead Series

Coteron, Jose M.; Catterick, David; Castro, Julia; Chaparro, María J.; Díaz, Beatriz; Fernández, Esther; Ferrer, Santiago; Gamo, Francisco Javier; Gordo, Mariola; Gut, Jiří; Heras, Laura de las; Legac, Jennifer; Marco, María; Miguel, Juan; Muñoz, V.; Porras, Esther; Rosa, Juan Carlos de la; Ruíz, José Rafael; Sandoval, Elena; Ventosa, Pilar; Rosenthal, Philip J.; Fiandor, José M.

doi:10.1021/jm100556b

Cited by 103 publications

(83 citation statements)

References 40 publications

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“…Falcipain inhibitors show promise as antimalarial agents (40), however, our results suggest that inhibitors of hemoglobin hydrolysis are not suitable for use in combination with artemisinins. By contrast, unique modes of chemotherapy that facilitate hemoglobin uptake, hemoglobin hydrolysis, or intracellular oxidative stress may enhance the action of artemisinins and circumvent evolving tolerance mechanisms.…”

Section: Discussionmentioning

confidence: 66%

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Klonis

Crespo-Ortiz²,

Bottová³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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322

314

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Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin-induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance.erythrocyte | endoperoxide

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Section: Discussionmentioning

confidence: 66%

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Klonis

Crespo-Ortiz²,

Bottová³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

322

314

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“…The activity of compounds against cultured P. falciparum was evaluated as previously reported [48]. Briefly, synchronized ringstage W2 strain parasites were cultured with multiple concentrations of test compounds (added from 1000 Â stocks in DMSO) in RPMI 1640 medium with 10% human serum or 0.5% Albumax serum substitute.…”

Section: Antiplasmodial Activity Assaysmentioning

confidence: 99%

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

Pérez¹,

Teixeira²,

Figueiras³

et al. 2012

European Journal of Medicinal Chemistry

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“…In vitro blood schizonticidal activity assays were performed as reported elsewhere (8). Briefly, synchronized ring-stage P. falciparum strain W2 parasites were cultured with multiple concentrations of test compounds (added from 1,000ϫ stocks in dimethyl sulfoxide [DMSO]) in RPMI 1640 medium with 10% human serum.…”

Section: Parasites Cells and Micementioning

confidence: 99%

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Capela

Cabal

Rosenthal

et al. 2011

Antimicrob Agents Chemother

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It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC 50 ], ϳ10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.

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Falcipain Inhibitors: Optimization Studies of the 2-Pyrimidinecarbonitrile Lead Series

Cited by 103 publications

References 40 publications

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

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