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Molecules 2018, 23(7), 1680;

Activation of Anthracene Endoperoxides in Leishmania and Impairment of Mitochondrial Functions

Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, A-1210 Vienna, Austria
Department of Organic Chemistry, Institute of Chemistry, University of Potsdam, D-14476 Golm/Potsdam, Germany
Department of Pharmacology, Institute of Postgraduate Medical Education & Research, Kolkata 700020, India
Parasitology Department, Institute of Tropical Medicine “Pedro Kouri”, Havana 10400, Cuba
Author to whom correspondence should be addressed.
Received: 14 June 2018 / Revised: 2 July 2018 / Accepted: 7 July 2018 / Published: 10 July 2018
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Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs’ reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon-centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action. View Full-Text
Keywords: Leishmania; endoperoxides; EPR spectroscopy; mitochondria; radicals Leishmania; endoperoxides; EPR spectroscopy; mitochondria; radicals

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Geroldinger, G.; Tonner, M.; Fudickar, W.; De Sarkar, S.; Dighal, A.; Monzote, L.; Staniek, K.; Linker, T.; Chatterjee, M.; Gille, L. Activation of Anthracene Endoperoxides in Leishmania and Impairment of Mitochondrial Functions. Molecules 2018, 23, 1680.

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