The
parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many
nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as
tinidazole are used to treat
trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness.
Fexinidazole, a 2-substituted
5-nitroimidazole rediscovered by the Drugs for
Neglected Diseases initiative (DNDi) after extensive compound mining of public and
pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of
fexinidazole and its two active metabolites, the
sulfoxide and
sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more
nitroreductase(s). It is known that these
enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions.
Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled
DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus,
fexinidazole does not pose a genotoxic hazard to patients and represents a promising
drug candidate for HAT.
Fexinidazole is expected to enter Phase II clinical trials in 2012.