Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein farnesyltransferase.

A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC(50) of 2 microM and blocked the growth of the bloodstream parasite in vitro with an ED(50) of 10 microM. The same compound inhibited rat protein farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration.