Design, synthesis, and antiprotozoal evaluation of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives.

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 (<italic>Plasmodium falciparum</italic>,<italic> Leishmania donovani</italic>, and <italic>Trypanosoma brucei brucei</italic>). Biological results showed antiparasitic activity with IC50 values in the μ m 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 <bold>1h</bold> 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 <italic>P. falciparum</italic>, respectively. As the telomeres of the parasite <italic>P. falciparum</italic> 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 <bold>1f</bold> and <bold>1m</bold> were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence. [ABSTRACT FROM AUTHOR]