CHELATING AGENT INHIBITION OF TRYPANOSOMA-CRUZI EPIMASTIGOTES IN-VITRO

A number of chelating agents and some of their derivatives are as effe ctive as, or superior to, benznidazole, the compound currently in clin ical use, in the suppression of the reproduction of epimastigotes of T rypanosoma cruzi, the protozoa that causes Chagas' disease. All compou nds were examined at a culture concentration of 5 mu g/mL. The most ef fective compounds included ,N,N',N'-tetrakis(2-pyridylmethyl)ethylened iamine, sodium diethylamine-N-carbodithioate, piperidine-N-carbodithio ate and several of its analogs, a numb er of other carbodithioates wit h two nonpolar groups on the nitrogen, and tetraethylthiuram disulfide , a prodrug of sodium diethylamine-N-carbodithioate and widely used in the treatment of alcoholism. The introduction of additional ionic or nonionic polar groups on the chelating molecule generally results in a lass of tyrpanocidal activity. Common commercially available chelatin g agents which exhibited no activity included D-penicillamine, meso-2, 3-dimercaptosuccinic acid, and triethylenetetramine tetrahydrochloride . Dose-response data on the culture indicated that some of these compo unds exhibited inhibition of Trypanosoma cruzi epimastigotes at concen trations as low,as 0.625 mu g/mL. It is proposed that the mechanism of action of these compounds is based on their ability to interfere with the essential metal metabolism at intracellular sites of the epinasti gote involving iron, copper, or zinc. The results also indicate that a certain degree of hydrophobicity may be necessary for the groups atta ched to the literal metal-bonding structure if the compounds are to su ccessfully inhibit the epimastigotes of Trypanosoma cruzi. The develop ment of antiprotozoal drugs which are chelating agents specifically de signed to selectively disrupt the essential metal metabolism of Trypan osoma cruzi should furnish a new generation of drugs which can be used in the treatment of Chagas' disease.