Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi.

Pyrrolidinyl- and thiazolidinyl- dipeptide derivatives, featuring either a vinyl sulfone-, a 2-ketobenzothiazole-, a nitrile-, or a benzimidazole group at the C-terminus, were designed and synthesized as potential inhibitors of the prolyl-specific Tc80 proteinase from Trypanosoma cruzi, the agent of Chagas' disease. These compounds were evaluated in vitro towards the target enzyme which was classified as a serine protease belonging to the prolyl oligopeptidase family (EC 3.4.21.26). A peptidyl nitrile and two peptidyl alpha-ketobenzothiazoles were shown to be potent reversible and competitive inhibitors of Tc 80 proteinase, with K(i) values in the range 38-219 nM, and compared advantageously with some known mammalian prolyl oligopeptidase inhibitors.