As part of our efforts to develop new compounds aimed at the
therapy of
parasitic infections, we synthesized and assayed analogues of a lead compound
megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of
megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the
thiadiazole by an
oxadiazole, replacement of the
nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic
nitrogen atom for evaluation of an improved import by the
glucose or the
purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that
megazol was more active than the derivatives.
Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage
central nervous system infections in combination with
suramin. Full recovery was observed in five monkeys in the study with no relapse of
parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and
Chagas disease in South America,
megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.