Table 1.

Tested alternative drugs to Chagas disease treatment

Alternative treatment	Class/Subclass	Observed results	Mechanism of action	Other comments	References
Ketaconazole Itraconazole	Inhibitors of ergostherol synthesis/C14 lanosterol demethylase (CYP51)	Presents suppressive but not curative effects against T. cruzi infections in humans or experimental animals and are unable stop the progression of the disease.	Inhibition of cytochrome P450-dependent lanosterol C14 demethylase, thus reducing ergosterol synthesis.	Itraconazole has been administered to indeterminate and cardiac Chagas disease patients based on the results in experimental investigations.	Urbina, 2002 Urbina & Docampo 2003 McCabe et al.,1986 Apt, 2010
Posaconazole	Inhibitors of ergostherol synthesis/C14 lanosterol demethylase (CYP51)	Induces parasitological cure in murine models of acute and chronic T. cruzi infection.	Inhibition of cytochrome P450 dependent lanosterol C14 demethylase, thus reducing ergosterol synthesis.	It was shown to eliminate intracellular amastigotes from infected cardiac cells.	Urbina et al. 1996 Urbina 2002 Urbina & Docampo 2003 Silva et al. 2006
Tak-187 UR-9825 Ravuconazole	Inhibitors of ergostherol synthesis/C14 Lanosterol demethylase (CYP51)	Exhibit trypanocidal activity both in vivo and in vitro. Present activity against T. cruzi strains partially resistant to conventional drugs and in which ketaconazole does not work.	Inhibition of sterol biosynthesis, which is essential for parasite viability and proliferation.	Recently, success was demonstrated with posaconazole in a patient with chronic Chagas disease and systemic lupus erythematosus. Ravuconazole is a prime candidate for clinical trials with Chagas disease patients	Urbina, 2003 Pinazo et al., 2010
E5700 ER-119884	Inhibitors of ergostherol synthesis/Squalene synthase	Are under development for their cholesterol and triglyceride lowering activity and have also shown in vitro activity against T. cruzi.	Inhibition of sterol biosynthesis, which is essential for parasite viability and proliferation.	E5700 was able to provide full protection against death and completely arrested development of parasitemia in a murine model of acute disease when orally administrated.	Urbina, 2009 Urbina et al., 2004
Amiodarone	Inhibitors of ergostherol synthesis/lanosterol synthase	Amiodarone has direct activity against T. cruzi, both in vitro and in vivo. It is an antiarrhythmic, frequently prescribed for the symptomatic treatment of Chagas' disease patients.	In addition to disrupting the parasites' Ca(2+) homeostasis, it also blocks ergosterol biosynthesis.	The combined use of amiodarone and posaconazole has synergistic effects that lead to an improvement in the parasitological burden in patients treated with both drugs.	Urbina, 2009 Benaim et al., 2009
K777	Inhibitor of cruzipain (a major cysteine protease of T. cruzi)	It has been shown to lower parasitemia levels and also improves cardiac damage in dogs.	Inhibition of vinyl sulfone (K777) cysteine protease.	The drug is now a candidate for clinical trial in partnership with DNDi.	Barr et al., 2005 McKerrow et al., 2009
Aryl-imidamine DB766 (AIA)	Aromatic diamidines (AD) and analogues	Effectively reduces the parasite load in the blood and cardiac tissue.	Targets the minor groove of DNA. Localizes in DNA-enriched compartments and induces considerable damage to the parasite mitochondria.	Advantage of being active at a low temperature (4°C), a condition that makes it suitable for the treatment of donated blood suspected of being infected with T. cruzi.	Batista et al., 2010
Allopurinol (HPP)	Analog of hypoxanthine	HPP inhibits the epimastigote forms in culture. In mice infected with T. cruzi and treated with allopurinol, an important reduction of the parasitemia is obtained, although some parasite strains are resistant to the drug.	Decreases uric acid and the conversion of hypoxanthine to xanthine.	In a multinational study, chronic chagasic patients treated with HPP presented no parasitological cure. In some patients, improvement of the electrocardiographic alterations was demonstrated.	Avila and Avila, 1981 Apt et al., 2005