To date,
Chagas disease has defied all attempts to develop an efficient and safe
chemotherapy. Drugs effective on T. cruzi as
trypanocidal agents may be classified as (a) drugs of extensive clinical use:
Nifurtimox and
Benznidazole; (b) drugs of restricted clinical use:
azoles (e.g.
Ketoconazole,
Econazole;
Miconazole);
Amphotericin B;
Allopurinol,
Allopurinol ribosides and
Primaquine; (d) drugs effective on T. cruzi and in experimental
Chagas disease (murine model): alkyllysophospholipids; 5-amino-
imidazole-4-carboxamides; bisbenzyl-
isoquinolines;
cruzipain (crucein) inhibitors; Gossipol;
phenothiazines; d) drugs effective in vitro without other reported effects,
acridines,
actinomycin D,
Crystal Violet (
gentian violet),
diterpenes (Mikania obtusata); N,N'-dimethyl-2-propen-1-
amine, epoxidienthiol
carbamates, Fe-
chelators, guanyl
hydrazones, o-
naphthoquinones (
beta-lapachone); quinoids (
miconidine;
tingenone);
Olivacine,
phenazine methosulfate, phenoxi-phenoxyl drugs,
Proadifen, pyridinium azolate betaines,
sesquiterpenes (Lychophora sp),
sesquiterpene lactones, tetrahydrocarbazoles, DL-alpha-trifluoromethylarginine, triphenylmetane
dyes. It is generally agreed that
Nifurtimox and
Benznidazole (a) are effective on acute
Chagas' disease, but may not be effective in the chronic phase; (b) their effect depends on the susceptibility of T. cruzi strains to the
drug; (c) they produce adverse effects in patients that may prevent prolonged treatments; they are genotoxic and produce biochemical damage in the mammalian tissues. Redox-cycling of
Nifurtimox and Benznidazolee generates "
reactive oxygen species" which explain the
biological effects. At variance with the mammalian host, T. cruzi is deficient in
antioxidant enzymes which are essential to prevent oxidative damage.
Azoles are effective inhibitors of T. cruzi growth in vitro and in vivo since they inhibit
sterol C14-delta 24(25) demethylase, an
enzyme catalysing
ergosterol production.
Azoles reduce
parasitemia and extend the survival of infected mice but do not produce parasitological cure and their clinical effectiveness is questionable.
Allopurinol allopurinol ribosides and related compounds inhibit T. cruzi hypoxantine-
guanine ribosyl
transferase, thus preventing the synthesis of adenylic and guanylic
acids and also
DNA. They reduce
parasitemia and negativize xenodiagnosis but these effects may not be permanent, which invalidates their clinical use.
Cysteine-protease inhibitors recognize T. cruzi
protease (
cruzipain, crucein) active site, thus allowing a covalent linkage with the inhibitor. These
peptide inhibitors are effective in acute and chronic murine models.
Phenothiazines inhibit
trypanothione reductase and a specially favoured fit is a small 2-substitued 2-chloro and 2-trifluoromethyl with a remote hydrophobic patch. The essential phenotiazine nucleus can adopt more than one inhibitory orientation in its binding site.
Phenothiazines are promising
trypanocidal agents for the treatment of
Chagas' disease. The methodology for developing new drugs for the treatment of
Chagas' disease is discussed.