The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica.

A new 5-nitroimidazole compound, 1-methyl-2-(4-methylthiophenoxymethyl)-5-nitroimidazole: fexinidazole, HOE 239, was found to be highly active against experimental infections with Trypanosoma cruzi, Tritrichomonas foetus, Trichomonas vaginalis and Entamoeba histolytica. It was slightly superior to benznidazole and nifurtimox in suppressing parasitaemia in mice infected with T. cruzi. It also eradicated the parasites from infected mice after a prolonged treatment period. The order of activity of some standard 5-nitroimidazoles obtained on the basis of several mouse or hamster infections with trichomonads and E. histolytica, respectively, was: fexinidazole greater than tinidazole and ornidazole greater than metronidazole greater than nitrimidazine (nimorazole), except that ornidazole had an amoebicidal effect close to that of fexinidazole. The principal metabolites, the sulphoxide and the sulphone were as active as the parent compound against T. cruzi, trichomonads and E. histolytica infections in mice and hamsters, respectively. The general tolerability of fexinidazole in rodents, rabbits and dogs is good and there is a wide range between the effective and maximum tolerated dose. Some side effects, such as anaemia and reduction of body weight occurred in rats and dogs at high dose levels following prolonged administration (90-day test). Structure-activity relationships of various 5-nitroimidazoles substituted in the 2-position, pharmacokinetic properties and metabolism of the experimental compound, as well as its foetal and perinatal tolerance, are discussed.