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 Benzni dazole; (b) drugs of restricted clinical use: azoles (e.g. Ketoconazole, Ec onazole; Miconazole); Amphotericin B; Allopurinol, Allopurinol ribosides an d Primaquine; (d) drugs effective on T. cruzi and in experimental Chagas di sease (murine model): alkyllysophospholipids; 5-amino-imidazole-4-carboxami des; bisbenzyl-isoquinolines; cruzipain (crucein) inhibitors; Gossipol; phe nothiazines; d) drugs effective in vitro without other reported effects, ac ridines, actinomycin D. Crystal Violet (gentian violet), diterpenes (Mikani a obtusata); N,N'-dimethyl-2-propen-1-amine, epoxidienthiol carbamates, Fe- chelators, guanyl hydrazones, o-naphthoquinones (beta-lapachone); quinoids (miconidine; tingenone); Olivacine, phenazine methosulfate, phenoxiphenoxyl drugs, Proadifen, pyridinium azolate betaines, sesquiterpenes (Lychophora sp), sesquiterpene lactones, tetrahydrocarbazoles, DL-alpha-trifiuoromethyl arginine, triphenylmetane dyes. It is generally agreed that Nifurtimox and Benznidazole (a) are effective on acute Chagas' disease, but may not be eff ective in the chronic phase: (b) their effect depends on the susceptibility of T. cruzi strains to the drug; (c) they produce adverse effects in patie nts that may prevent prolonged treatments; they are genotoxic and produce b iochemical damage in the mammalian tissues. Redox-cycling of Nifurtimox and Benznidazolee generates "reactive oxygen species" which explain the biolog ical effects. At variance with the mammalian host, T. cruzi is deficient in antioxidant enzymes which are essential to prevent oxidative damage. Azole s are effective inhibitors of T. cruzi growth in vitro and in vivo since th ey inhibit sterol C14-Delta(24(25)) demethylase, an enzyme catalysing ergos terol production. Azoles reduce parasitemia and extend the survival of infe cted mice but do not produce parasitological cure and their clinical effect iveness is questionable. Allopurinol allopurinol ribosides and related comp ounds inhibit T. cruzi hypoxantine-guanine ribosyl transferase, thus preven ting the synthesis of adenylic and guanylic acids and also DNA. They reduce parasitemia and negativize xenodiagnosis but these effects may not be perm anent, which invalidates their clinical use. Cysteine-protease inhibitors r ecognize T. cruzi protease (cruzipain, crucein) active site, thus allowing a covalent linkage with the inhibitor. These peptide inhibitors are effecti ve in acute and chronic murine models. Phenothiazines inhibit trypanothione reductase and a specially favoured fit is a small 2-substitued 2-chloro an d 2-trifluoromethyl with a remote hydrophobic patch. The essential phenotia zine 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 treatmen t of Chagas' disease is discussed.