[The chemotherapy of Chagas disease]

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.