Find in Library

A series of novel 2,9-<i>bis</i>[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (<i>Plasmodium falciparum</i>, <i>Leishmania donovani</i> and <i>Trypanosoma brucei brucei</i>). Pharmacological results showed antiprotozoal activity with IC₅₀ values in the sub and μM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline <b>1l</b> was identified as the most potent antimalarial derivative with a ratio of cytotoxic to antiparasitic activities of 505.7 against the <i>P. falciparum</i> CQ-resistant strain W2. Against the promastigote forms of <i>L. donovani</i>, the phenanthrolines <b>1h</b>, <b>1j</b>, <b>1n</b> and <b>1o</b> were the most active with IC₅₀ from 2.52 to 4.50 μM. The phenanthroline derivative <b>1o</b> was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on <i>T. brucei brucei</i> strain. FRET melting and native mass spectrometry experiments evidenced that the nitrogen heterocyclic derivatives bind the telomeric G-quadruplexes of <i>P. falciparum</i> and <i>Trypanosoma</i>. Moreover, as the telomeres of the parasites <i>P. falciparum</i> and <i>Trypanosoma</i> could be considered to be possible targets of this kind of nitrogen heterocyclic derivatives, their potential ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.