SYNTHESIS AND IN-VITRO TRYPANOCIDAL ACTIVITY OF SOME NOVEL IRON-CHELATING AGENTS

This report describes the syntheses and in vitro trypanocidal activity of a number of iron(III) chelators against epimastigotes of Trypanoso ma cruzi. The compounds examined included a number of lipophilic N-alk yl derivatives of 2-ethyl- and 2-methyl-3-hydroxypyrid-4-ones, hydroxy benzyl)-(+/-)-trans-1,2-diaminocyclohexane, cyclotetrachromotropylene and four commercially available carboxy derivatives of pyridine, pyraz ine, and pyarazole. Benznidazole, the drug clinically used in the trea tment of Chagas' disease in humans, served as standard. All compounds were screened in vitro against Trypanosoma cruzi epimastigotes at 50 a nd 100 mu g/ml for 72 h of exposure. At 100 mu g/ml dosage, at least 4 compounds exhibited high epimastigote growth inhibition (65-69 %) com parable to benznidazole (72 %), whereas 9 compounds showed moderate to fair activity (53-64 %) in the in vitro assay. At the lower concentra tion (50 mu g/ml), the inhibitory activity of the best of these compou nds was reduced significantly (39-48 %) compared to the standard drug (59 %). The activity of all the carboxylic acids remained in the lower range (4-25 %). It is hypothesized that the enhanced activity of some of the compounds is due to their increased lipophilicity which enable s them to successfully pass through the cellular membrane of Trypanoso ma cruzi epimastigotes. The trypanocidal activities of the most effect ive compounds were significantly reduced when tested in the presence o f added ferric ion.