title: Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.
abstract: Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is a zinc-hydrolase with an indicated role in the mammalian pain modulatory system. In order to find a potent antagonist of this enzyme, we synthesized and screened the effect of a small set of benzimidazole derivatives on its activity. To improve the inhibitory potential, a cyclobutane ring was introduced as rigid conformation support to the diamidino substituted dibenzimidazoles. Two such compounds (1' and 4') from the group of cyclobutane derivatives containing amidino-substituted benzimidazole moieties, obtained by photochemical cyclization in water and by respecting rules of the "green chemistry" approach, were found to be strong DPP III inhibitors, with IC(50) value below 5 microM. Compound 1' displayed time-dependent inhibition towards human DPP III, characterized by the second-order rate constant of 6924+/-549 M(-1)min(-1) (K(i)=0.20 microM). The peptide substrate valorphin protected the enzyme from inactivation by 1'.
authors.affiliation: Department of Chemistry, Faculty of Agriculture, The Josip Juraj Strossmayer University, Trg Sv. Trojstva 3, P.O. Box 719, HR-31107 Osijek, Croatia.
authors.forename: Dejan
authors.initials: D
authors.lastname: Agić
authors.forename: Marijana
authors.initials: M
authors.lastname: Hranjec
authors.forename: Nina
authors.initials: N
authors.lastname: Jajcanin
authors.forename: Kristina
authors.initials: K
authors.lastname: Starcević
authors.forename: Grace
authors.initials: G
authors.lastname: Karminski-Zamola
authors.forename: Marija
authors.initials: M
authors.lastname: Abramić
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000465:Algorithms; D000577:Amides / Q000737:chemistry; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001562:Benzimidazoles; D011480:Protease Inhibitors; C045483:valorphin; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III; D000218:Adamantane