Synthesis and antiprotozoal activity of some 2-(trifluoromethyl)-1H-benzimidazole bioisosteres

A series of 2-(trifluoromethyl)-1H-benzimidazole derivatives with various 5- and 6-position bioisosteric substituents (–Cl, –F, –CF3, –CN), namely 1–7, were prepared using a short synthetic route. Each analogue was tested in vitro against the protozoa Giardia intestinalis and Trichomonas vaginalis in comparison with albendazole and metronidazole. Several analogues had IC50 values < 1 μM against both species, which make them significantly more potent than either standard. Compound 4 [2,5(6)-bis(trifluoromethyl)-1H-benzimidazole], was 14 times more active than albendazole against T. vaginalis. This compound (4) also showed moderate antimalarial activity against W2 and D6 strains of Plasmodium falciparum (5.98 and 6.12 μM, respectively). Studying further structure activity relationships through the use of bioisosteric substitution in these benzimidazolic derivatives should provide new leads against protozoal and possibly malarial diseases.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide