TY  - JOUR
A1  - Geroldinger, Gerald
A1  - Tonner, Matthias
A1  - Fudickar, Werner
A1  - De Sarkar, Sritama
A1  - Dighal, Aishwarya
A1  - Monzote, Lianet
A1  - Staniek, Katrin
A1  - Linker, Torsten
A1  - Chatterjee, Mitali
A1  - Gille, Lars
T1  - Activation of anthracene endoperoxides in leishmania and impairment of mitochondrial functions
JF  - Molecules
N2  - 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.
KW  - Leishmania
KW  - endoperoxides
KW  - EPR spectroscopy
KW  - mitochondria
KW  - radicals
Y1  - 2018
U6  - https://doi.org/10.3390/molecules23071680
SN  - 1420-3049
VL  - 23
IS  - 7
PB  - MDPI
CY  - Basel
ER  -