Design, Synthesis, and Antiprotozoal Evaluation of New Promising 2,9-[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline Derivatives, a Potential Alternative Scaffold to Drug Efflux.

A series of novel 2,9-[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (, and ). Pharmacological results showed antiprotozoal activity with IC 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 was identified as the most potent antimalarial derivative with a ratio of cytotoxic to antiparasitic activities of 505.7 against the CQ-resistant strain W2. Against the promastigote forms of , the phenanthrolines , , and were the most active with IC from 2.52 to 4.50 μM. The phenanthroline derivative was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on strain. FRET melting and native mass spectrometry experiments evidenced that the nitrogen heterocyclic derivatives bind the telomeric G-quadruplexes of and . Moreover, as the telomeres of the parasites and 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.