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-ethyl butyl-3-thiol) (BAT) and (2-methyl-2-mercaptopropyl)1,4,7-triazacyclon onane (TAT), were studied in Plasmodium falciparum cultured in erythro cytes. Both drugs inhibited parasite growth, as was judged from [H-3]h ypoxanthine incorporation into the nucleic acids of parasites, with 50 % inhibitory concentrations (IC50 values: 7.6 +/- 1.2 mu M for BAT and 3.3 +/- 0.3 mu M for TAT) that exceeded the antimalarial action of de sferrioxamine B by 5-10 times. The inhibitory effects of both agents o n P. falciparum cultures were fully reversed by pre-complexation with iron, suggesting that this action was related mainly to the withholdin g of iron. Spectrofluorometric studies with the fluorescent iron-sensi ng probe calcein showed that both compounds withheld iron from calcein at pH 8.2. The trophozoite and schizont stages of parasite developmen t were the stages most susceptible to inhibition. The IC50 values of B AT and TAT for mammalian cells, which were estimated by [H-3]thymidine incorporation into the nucleic acids of cells, were 10-20 times highe r than those required to inhibit plasmodial growth. This indicates tha t multidentate aminothiols may prove to have a clinical margin of safe ty that makes them appropriate candidates for future clinical developm ent. (C) 1997 EIsevier Science Inc.