title: Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi.
abstract: 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.
authors.affiliation: Laboratoire de chimie des substances naturelles, MNHN, ESA CNRS 8041, 63 rue Buffon, 75005, Paris, France. joyeau@mnhn.fr
authors.forename: R
authors.initials: R
authors.lastname: Joyeau
authors.forename: C
authors.initials: C
authors.lastname: Maoulida
authors.forename: C
authors.initials: C
authors.lastname: Guillet
authors.forename: F
authors.initials: F
authors.lastname: Frappier
authors.forename: A R
authors.initials: AR
authors.lastname: Teixeira
authors.forename: J
authors.initials: J
authors.lastname: Schrével
authors.forename: J
authors.initials: J
authors.lastname: Santana
authors.forename: P
authors.initials: P
authors.lastname: Grellier
mesh_terms: D000818:Animals; D002850:Chromatography, Gel; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D000085822:Prolyl Oligopeptidases; D015800:Protozoan Proteins; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D004151:Dipeptides; D015800:Protozoan Proteins; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D014344:Trypanocidal Agents; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; C000705288:Tc80 prolyl oligopeptidase, Trypanosoma cruzi