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 IC50 value below 5 μM. Compound 1′ displayed time-dependent inhibition towards human DPP III, characterized by the second-order rate constant of 6924 ± 549 M−1 min−1 (Ki = 0.20 μM). The peptide substrate valorphin protected the enzyme from inactivation by 1′.