Discovery and Optimization of a Novel Macrocyclic Amidinourea Series Active as Acidic Mammalian Chitinase Inhibitors

Abstract

Our research group has been involved for a long time in the development of macrocyclic amidinoureas (MCAs) as antifungal agents. The mechanistic investigation drove us to perform an in silico target fishing study, which allowed the identification of chitinases as one of their putative targets, with 1a showing a submicromolar inhibition of Trichoderma viride chitinase. In this work, we investigated the possibility to further inhibit the corresponding human enzymes, acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1), involved in several chronic inflammatory lung diseases. Thus, we first validated the inhibitory activity of 1a against AMCase and CHIT1 and then designed and synthesized new derivatives aimed at improving the potency and selectivity against AMCase. Among them, compound 3f emerged for its activity profile along with its promising in vitro ADME properties. We also gained a good understanding of the key interactions with the target enzyme through in silico studies.

Design, Synthesis, and Biological Investigations of Novel Carbamoylguanidinyl Nitrobenzoxadiazoles against Chitinolytic Enzymes

“…Sugawara et al linked the 14-membered lactone of erythromycin to the N -methylcarbamoylguanidinyl to obtain a chitinase inhibitor EN30 with better activity than that of argifin (IC 50 value of 64 nM against Sm ChiB) . Dreassi et al identified the chitinase inhibitor AMC with submicromolar inhibitory activity ( K i value of 1.9 μM against AMCase) on mammalian acidic chitinase (AMCase) . All of these results demonstrated that the N -methylcarbamoylguanidinyl was a crucial active fragment of chitinase inhibitors.…”