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First computational evidence of a competitive stepwise and concerted mechanism for the reduction of antimalarial endoperoxides

Lacaze-Dufaure, Corinne and Najjar, Fadia and André-Barrès, Christiane First computational evidence of a competitive stepwise and concerted mechanism for the reduction of antimalarial endoperoxides. (2010) Journal of Physical Chemistry B, 114 (30). 9848-9853. ISSN 1520-6106

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Official URL: http://dx.doi.org/10.1021/jp100718p

Abstract

We study structural analogues of endoperoxides belonging to the family of G factors which present moderate to good antimalarial activity. Their biological activity is related to the reduction and cleavage of the O-O bond. Generally, the O-O bond reduction of model endoperoxides, as well as artemisinin, occurs by a concerted dissociative electron transfer (ET) mechanism. For the G3 and G3Me compounds, the experimental counterpart indicates an unexpected competition between a concerted and a stepwise mechanism, but no intermediate species can be isolated. We thus perform DFT studies on the reduction of G3 and G3Me compounds. We confirm the formation of an intermediate radical anion followed by cleavage of the O-O bond in a second step. We characterize the stable conformations for the radical anions G3 •- and G3Me•- resulting from the ET and the associated reaction pathway. We also calculate the reorganization energy upon ET in relation to the Marcus theory using the DFT method. These results provide valuable insight into understanding the biological activity of G-factor endoperoxides as potential therapeutic antimalarial agents.

Item Type:Article
Additional Information:Thanks to American Chemical Society editor. The definitive version is available at http://pubs.acs.org/doi/abs/10.1021/jp100718p
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
Université de Toulouse > Institut National Polytechnique de Toulouse - INPT (FRANCE)
Other partners > Lebanese University - LU (LEBANON)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UPS (FRANCE)
Laboratory name:
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Deposited By: Dominique POQUILLON
Deposited On:14 Apr 2014 07:47

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