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 α-ketobenzothiazoles were shown to be potent reversible and competitive inhibitors of Tc 80 proteinase, with Ki values in the range 38–219 nM, and compared advantageously with some known mammalian prolyl oligopeptidase inhibitors.