A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to-antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.

INSERM U1094 Tropical Neuroepidemiology Limoges France

INSERM U1212 UMR CNRS 5320 ARNA Laboratory UFR des Sciences Pharmaceutiques Université de Bordeaux Bordeaux France

Institute of Biophysics of the CAS v v i Brno Czech Republic

Institute of Neuroepidemiology and Tropical Neurology Université de Limoges Limoges France

Laboratoire de Glycochimie des Antimicrobiens et des Agroressouces UMR CNRS 7378 UFR de Pharmacie Université de Picardie Jules Verne Amiens France

Laboratory of Parasitology UMR MD3 Faculty of Pharmacy Aix Marseille University Marseille France

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