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The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

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ABSTRACT

4a: In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

No MeSH data available.


Artemisinin (1), plakortin (2), dihydroplakortin (3), and general structure of 3-methoxy-1,2-dioxane synthetic analogues (4).3,4-cis indicates that 4a displays the OCH3 at C3 and the COOCH3 at C4 in a cis orientation.
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f1: Artemisinin (1), plakortin (2), dihydroplakortin (3), and general structure of 3-methoxy-1,2-dioxane synthetic analogues (4).3,4-cis indicates that 4a displays the OCH3 at C3 and the COOCH3 at C4 in a cis orientation.

Mentions: Malaria, an infectious disease caused by protozoans belonging to the genus Plasmodium, continues to affect a large part of the world population, with a special incidence in the sub-Saharan Africa. Indeed, approximately 88% of malaria cases and 90% of malaria deaths occurred in the WHO African Region, with children aged under 5 years and pregnant women most severely affected1. Despite the introduction of artemisinin(1)-based combination therapies (ACTs) and the mass use of insecticide treated mosquito net (ITN), the pace of decrease in estimated malaria mortality rates slowed down1. Indeed, millions of people at risk of malaria still do not have access to interventions such as an ITN, indoor residual spraying (IRS), diagnostic testing, and ACTs. In addition, the emergence of artemisinin-resistant Plasmodium falciparum (Pf) strains is raising severe concerns1 and the rate at which resistance is growing outpaces the development of new effective and low-cost antimalarials2. In the course of a search for new antimalarial lead compounds, we reported that plakortin (2) and dihydroplakortin (3) (Fig. 1), simple endoperoxide-containing polyketides isolated from the Caribbean sponge Plakortis simplex345, show significant in vitro activity against chloroquine (CQ)-resistant strains of Pf (i.e., IC50 0.4 μM), promising in vivo activity (P. berghei infected mice), and no observed toxicity346.


The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism
Artemisinin (1), plakortin (2), dihydroplakortin (3), and general structure of 3-methoxy-1,2-dioxane synthetic analogues (4).3,4-cis indicates that 4a displays the OCH3 at C3 and the COOCH3 at C4 in a cis orientation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5382535&req=5

f1: Artemisinin (1), plakortin (2), dihydroplakortin (3), and general structure of 3-methoxy-1,2-dioxane synthetic analogues (4).3,4-cis indicates that 4a displays the OCH3 at C3 and the COOCH3 at C4 in a cis orientation.
Mentions: Malaria, an infectious disease caused by protozoans belonging to the genus Plasmodium, continues to affect a large part of the world population, with a special incidence in the sub-Saharan Africa. Indeed, approximately 88% of malaria cases and 90% of malaria deaths occurred in the WHO African Region, with children aged under 5 years and pregnant women most severely affected1. Despite the introduction of artemisinin(1)-based combination therapies (ACTs) and the mass use of insecticide treated mosquito net (ITN), the pace of decrease in estimated malaria mortality rates slowed down1. Indeed, millions of people at risk of malaria still do not have access to interventions such as an ITN, indoor residual spraying (IRS), diagnostic testing, and ACTs. In addition, the emergence of artemisinin-resistant Plasmodium falciparum (Pf) strains is raising severe concerns1 and the rate at which resistance is growing outpaces the development of new effective and low-cost antimalarials2. In the course of a search for new antimalarial lead compounds, we reported that plakortin (2) and dihydroplakortin (3) (Fig. 1), simple endoperoxide-containing polyketides isolated from the Caribbean sponge Plakortis simplex345, show significant in vitro activity against chloroquine (CQ)-resistant strains of Pf (i.e., IC50 0.4 μM), promising in vivo activity (P. berghei infected mice), and no observed toxicity346.

View Article: PubMed Central - PubMed

ABSTRACT

4a: In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

No MeSH data available.