The neglected tropical diseases Human African Trypanosomiasis and leishmaniasis are caused by infection with trypanosomatid parasites Trypanosoma brucei and Leishmania spp, respectively. The genomes of these organisms contain multiple putative G-quadruplex (G4) forming sequences which have recently been proposed to mediate processes relevant for parasite survival. Therefore, G4 could be considered as potential targets for a novel approach towards the development of antiparasitic drugs. Recently, we have demonstrated that G4 ligands such as carbohydrate naphthalene diimide conjugates (carb-NDIs) possess notable antiparasitic activity. Herein, we have synthesized a new family of carb-NDIs, characterized by significant structural variability, and evaluated their anti-parasitic activity, with special focus on T. brucei. The interaction with relevant G4 sequences was evaluated in vitro through independent biophysical methods (FRET melting assays under competing conditions with double stranded DNA, circular dichroism and fluorescence titrations). Finally, flow cytometry and confocal microscopy experiments demonstrated that the conjugates exhibit excellent uptake into T. brucei parasites, localizing in the nuclei and kinetoplasts. Promising antiparasitic activity and selectivity against control mammalian cells, together with their peculiar mechanism of action, render the carb-NDI conjugates as suitable candidates for the development of an innovative treatment of trypanosomiasis.

ARNA Laboratory Université; de Bordeaux Inserm U1212 CNRS UMR5320 Institut Européen de Chimie Biologie 2 Rue Robert Escarpit 33607 Pessac France; Institute of Biophysics AS CR 5 v i Kralovopolska 135 612 65 Brno Czech Republic

Department of Biochemistry and Molecular Pharmacology Instituto de Parasitología y Biomedicina López Neyra CSIC PTS Granada Avda Del Conocimiento 17 18016 Armilla Granada Spain

Department of Chemistry University of Pavia 5 le Taramelli 10 27100 Pavia Italy

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