Safer and more effective oral drugs are required to treat visceral 
leishmaniasis, a parasitic disease that kills 50,000 to 60,000 people each year 
in parts of Asia, Africa, and Latin America. Here, we report that fexinidazole, 
a drug currently in phase 1 clinical trials for treating African 
trypanosomiasis, shows promise for treating visceral leishmaniasis. This 
2-substituted 5-nitroimidazole drug is rapidly oxidized in vivo in mice, dogs, 
and humans to sulfoxide and sulfone metabolites. Both metabolites of 
fexinidazole were active against Leishmania donovani amastigotes grown in 
macrophages, whereas the parent compound was inactive. Pharmacokinetic studies 
with fexinidazole (200 mg/kg) showed that fexinidazole sulfone achieves blood 
concentrations in mice above the EC(99) (effective concentration inhibiting 
growth by 99%) value for at least 24 hours after a single oral dose. A 
once-daily regimen for 5 days at this dose resulted in a 98.4% suppression of 
infection in a mouse model of visceral leishmaniasis, equivalent to that seen 
with the drugs miltefosine and Pentostam, which are currently used clinically to 
treat this tropical disease. In African trypanosomes, the mode of action of 
nitro drugs involves reductive activation via a NADH (reduced form of 
nicotinamide adenine dinucleotide)-dependent bacterial-like nitroreductase. 
Overexpression of the leishmanial homolog of this nitroreductase in L. donovani 
increased sensitivity to fexinidazole by 19-fold, indicating that a similar 
mechanism is involved in both parasites. These findings illustrate the potential 
of fexinidazole as an oral drug therapy for treating visceral leishmaniasis.