posaconazole and Acute-Disease

We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14alpha-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC(50) in the 0.4-10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20-50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.

Topics: Acute Disease; Animals; Chagas Disease; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Imidazoles; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Sterol 14-Demethylase; Structure-Activity Relationship; Trypanosoma cruzi

There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca(2+) homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca(2+) homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.

Topics: Acute Disease; Amiodarone; Animals; Calcium; Chagas Disease; Chlorocebus aethiops; Crystallography, X-Ray; Drug Synergism; Ergosterol; Intramolecular Transferases; Mice; Models, Molecular; Molecular Structure; Triazoles; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells