Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.
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'.
Agić
Dejan
D
Department of Chemistry, Faculty of Agriculture, The Josip Juraj Strossmayer University, Trg Sv. Trojstva 3, P.O. Box 719, HR-31107 Osijek, Croatia.
Hranjec
Marijana
M
Jajcanin
Nina
N
Starcević
Kristina
K
Karminski-Zamola
Grace
G
Abramić
Marija
M
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
D000577:Amides; D001562:Benzimidazoles; D011480:Protease Inhibitors; C045483:valorphin; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III; D000218:Adamantane