INHIBITION OF TRYPANOSOMA-CRUZI EPIMASTIGOTES IN-VITRO BY IRON-CHELATING AGENTS

The relative effectiveness of 20 iron chelating agents in suppressing the growth and multiplication of Trypanosoma cruzi epimastigotes has b een examined in vitro. 1,2-Dimethyl-3 -hydroxypyrid-4-one (LI) and sev eral of its newly synthesized N-substituted analogs containing hydroph obic substituents were significantly more effective than deferoxamine even though they possess only two donor sites for iron(III) while defe roxamine has sis. Analogs with hydrophilic substituents were uniformly less active than L1 itself. Variations in effectiveness as the polari ty of the compounds is vaned indicate that the ability to cross the ce llular membrane is of critical importance in the determination of the in vitro trypanocidal activity of iron(III) chelating agents. A group of four tris(2-aminoethyl)amine based tris-imines were also screened, all of which had poor activity (0-28 % inhibition). Among the other ir on(III) chelating agents which showed a relatively high level of activ ity at 50 and 100 mu g/ml were salicylhydroxamic acid (70 and 73 % inh ibition) and hydroxyurea (42 and 52 % inhibition). '-Di(2-hydroxybenzy l)ethylenediamine-N,N'-diacetic acid and acetohydroxamic acid exhibite d only slight activity at 50 and 100 mu g/ml. The best of these iron(I II) chelating agents were as effective against the epimastigote form a t both 50 and 100 mu g/ml (74-81 % inhibition) as benznidazole (81 % i nhibition), the drug currently used in the clinic.