title: Umbelliferone aminoalkyl derivatives as inhibitors of oxidosqualene cyclases from Saccharomyces cerevisiae, Trypanosoma cruzi, and Pneumocystis carinii.
abstract: A series of umbelliferone aminoalkyl derivatives, previously studied as inhibitors of squalene-hopene cyclase, were tested as inhibitors of yeast (Saccharomyces cerevisiae) oxidosqualene cyclase (OSC) and OSC from Trypanosoma cruzi and Pneumocystis carinii expressed in yeast. Enzymes from these pathogens were included in this study to provide a preliminary screening for antiparasitic activity. Tests were carried out both on cell homogenates incubated with radiolabeled oxidosqualene and on spheroplasts incubated with radiolabeled acetate. Derivatives bearing a methylallylamino group were the most effective on all of the three enzymes. The P. carinii enzyme was the most susceptible to the action of the inhibitors, with IC50 values for almost all of them ranging from 0.1 to 1 microM. The T. cruzi enzyme was appreciably inhibited (IC50 4-5 microM) only by derivatives bearing a methylallylaminoalkyl flexible chain. Results identify a particularly promising new family of OSC inhibitors, for the development of novel antiparasitic agents.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Turin, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Oliaro-Bosso
authors.forename: Franca
authors.initials: F
authors.lastname: Viola
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Cravotto
authors.forename: Silvia
authors.initials: S
authors.lastname: Tagliapietra
authors.forename: Gianni
authors.initials: G
authors.lastname: Balliano
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors; D020128:Inhibitory Concentration 50; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D045363:Pneumocystis carinii / Q000201:enzymology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D014468:Umbelliferones; D019751:Intramolecular Transferases; C021924:lanosterol synthase