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Hydroxyl mechanism of the antimalarial effect of artemisinin and its analogs

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Abstract

Kinetic schemes for the intramolecular oxidation of four artemisinin analogs, which are used as drugs against malaria, were developed. Each stage of the kinetic scheme is characterized by the enthalpy, activation energy, and rate constant calculated using the model of intersecting parabolas. The competition of mono- and bimolecular radical reactions was taken into account when developing the schemes. The hydroperoxide groups are formed as a result of the intramolecular oxidation of these compounds and generate free radicals in the reaction with FeII. Among these free radicals, hydroxyl radicals play the key role, since their yield (n OH) correlates with the antimalarial activity of the peroxide compound. The efficiency of the drug (index IC50) exponentially depends on n OH and is expressed by the formula IC50(Artemisinin)/IC50(Compound) = 1.54·10−6exp(3.9n OH). The elementary reactions resulting in the generation of hydroxyl radicals are considered. It is supposed that DNA of a malaria parasite is the main biological target for hydroxyl radicals.

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Authors and Affiliations

  1. Institute of the Problems of Chemical Physics, Russian Academy of Sciences, 1 prosp. Akad. Semenova, 142432, Chernogolovka, Moscow Region, Russian Federation

    E. T. Denisov & T. G. Denisova

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  1. E. T. Denisov
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  2. T. G. Denisova
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Correspondence to E. T. Denisov.

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Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1398–1412, July, 2011.

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Denisov, E.T., Denisova, T.G. Hydroxyl mechanism of the antimalarial effect of artemisinin and its analogs. Russ Chem Bull 60, 1421–1435 (2011). https://doi.org/10.1007/s11172-011-0213-9

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  • DOI: https://doi.org/10.1007/s11172-011-0213-9

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