Aminothiol multidentate chelators as antimalarials.
The antimalarial effects of two compounds from an aminothiol family of multidentate chelators, ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol) (BAT) and N',N',N'-tris(2-methyl-2-mercaptopropyl)-1,4,7-triazacyclononane (TAT), were studied in Plasmodium falciparum cultured in erythrocytes. Both drugs inhibited parasite growth, as was judged from [3H]hypoxanthine incorporation into the nucleic acids of parasites, with 50% inhibitory concentrations (IC50 values: 7.6 +/- 1.2 microM for BAT and 3.3 +/- 0.3 microM for TAT) that exceeded the antimalarial action of desferrioxamine B by 5-10 times. The inhibitory effects of both agents on P. falciparum cultures were fully reversed by pre-complexation with iron, suggesting that this action was related mainly to the withholding of iron. Spectrofluorometric studies with the fluorescent iron-sensing probe calcein showed that both compounds withheld iron from calcein at pH 8.2. The trophozoite and schizont stages of parasite development were the stages most susceptible to inhibition. The IC50 values of BAT and TAT for mammalian cells, which were estimated by [3H]thymidine incorporation into the nucleic acids of cells, were 10-20 times higher than those required to inhibit plasmodial growth. This indicates that multidentate aminothiols may prove to have a clinical margin of safety that makes them appropriate candidates for future clinical development.