RESUMEN

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 µm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 µm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action.

Asunto(s)

Nitroquinolinas/farmacología , Quinolonas/farmacología , Tripanocidas/farmacología , Catálisis , Células Hep G2 , Humanos , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Estructura Molecular , Nitroquinolinas/síntesis química , Nitroquinolinas/química , Nitroquinolinas/toxicidad , Paladio/química , Pruebas de Sensibilidad Parasitaria , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/toxicidad , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/toxicidad , Trypanosoma brucei brucei/efectos de los fármacos