Antimalarials based on the dioxane scaffold of plakortin. A concise synthesis and SAR studies.

@article{Fattorusso2011AntimalarialsBO,
  title={Antimalarials based on the dioxane scaffold of plakortin. A concise synthesis and SAR studies.},
  author={Caterina Fattorusso and Marco Giovanni Persico and Nicoletta Basilico and Donatella Taramelli and Ernesto Fattorusso and Fernando Scala and Orazio Taglialatela‐Scafati},
  journal={Bioorganic \& medicinal chemistry},
  year={2011},
  volume={19 1},
  pages={
          312-20
        }
}
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References

SHOWING 1-10 OF 30 REFERENCES
Endoperoxide derivatives from marine organisms: 1,2-dioxanes of the plakortin family as novel antimalarial agents.
TLDR
Results obtained confirmed the crucial role of the cycloperoxide functionality, and revealed other structural features critical for antimalarial activity, namely the "Western" alkyl side chain, the dioxane ring conformation, and the absolute configuration of the stereogenic carbons on the 1,2-doxane ring, when affecting the bioactive ring conformed.
Antimalarial Polyketide Cycloperoxides from the Marine SpongePlakortis simplex
Three new (5–7) and two known (4 and 8) polyketide derivatives have been isolated from the Caribbean sponge Plakortis simplex. Their stereostructures have been determined by spectroscopic methods and
Insight into the mechanism of action of plakortins, simple 1,2-dioxane antimalarials.
TLDR
The results show that these molecules, after interaction of the endoperoxide bond with Fe(ii), likely coming from the heme molecule, give rise to the formation of an oxygen radical, followed by rearrangement to give a carbon radical centered on the "western" alkyl side-chain.
1,2,4-Trioxanes as potential antimalarial agents.
TLDR
A number of 1,2,4-trioxanes were prepared and tested for antimalarial activity in search of a simplified analogue of the naturally occurring antimalaria qinghaosu, which showed an IC50 of 1 ng/mL for both strains.
Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials.
The new endoperoxyketal polyketides manadoperoxides A-D (2-5) have been isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic
Why artemisinin and certain synthetic peroxides are potent antimalarials. Implications for the mode of action.
TLDR
Experiments with ferrous reagents indicate that active peroxides including 14 and its congeners kill the parasite by alkylation with a sterically non-encumbered C-centered radical, however, another possibility is the involvement of a Fe(IV)=O species as the toxic agent.
Activity against Plasmodium falciparum of cycloperoxide compounds obtained from the sponge Plakortis simplex.
TLDR
Evaluated in vitro the antimalarial activity of the major cycloperoxides extracted from the sponge Plakortis simplex, and the activity of plakortin and dihydroplakortsin was significantly higher against chloroquine-resistant than chloroquin-susceptible parasites, following a pattern similar to that of artemisinin, although they were 50-fold less active.
Osmium catalyzed dihydroxylation of 1,2-dioxines: a new entry for stereoselective sugar synthesis.
TLDR
Preliminary work on the catalytic asymmetric ring-opening of meso-peroxy diols using the Co(II) Jacobsens's catalyst indicates that asymmetric sugar synthesis from 1,2-dioxines is possible.
Concise preparation of the (3E,5Z)-alkadienyl system. New approach to the synthesis of principal insect sex pheromone constituents.
TLDR
A new rapid and low-cost preparation of the (3E,5Z)-3,5-alkadienyl system was developed, encountered in several insect pheromone constituents, and constituted synthetic targets of considerable interest for the semiochemical community.
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