Insight into the mechanism of action of plakortins, simple 1,2-dioxane antimalarials

Organic & Biomolecular Chemistry
Orazio Taglialatela-ScafatiCaterina Fattorusso

Abstract

A multidisciplinary approach, based on molecular dynamics/mechanics, ab initio calculations, dynamic docking studies, and chemical reactions, has been employed to gain insight into the mechanism of the antimalarial action of plakortin and dihydroplakortin, simple 1,2-dioxanes isolated from the sponge Plakortis simplex. Our 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. The carbon radicals generated on the side-chain, amenable for intermolecular reactions, should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The minimal structural requirements necessary for the activity of this class of antimalarial agents have been identified and discussed throughout the paper.

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Citations

Jul 19, 2011·Journal of Medicinal Chemistry·Sandra GemmaStefania Butini
Aug 4, 2012·Organic & Biomolecular Chemistry·Giuseppina ChianeseOrazio Taglialatela-Scafati
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May 28, 2016·The Journal of Organic Chemistry·Giuseppina ChianeseOrazio Taglialatela-Scafati
Aug 23, 2016·Molecular Informatics·Marco PersicoCaterina Fattorusso
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