Discovery of aromatic 2-(3-(methylcarbamoyl) guanidino)-N-aylacetamides as highly potent chitinase inhibitors

Abstract

Chitinases are important glycoside hydrolases that are closely related to bacterial pathogenesis, fungal cell wall remodelling, and insect moulting. Consequently, chitinases have become attractive targets for therapeutic drugs and pesticides. In this study, we designed and synthesised a series of novel chitinase inhibitors based on the N-methylcarbamoylguanidinyl group of the natural product argifin. The most active compound 8h showed strong inhibitory activity against the group I chitinases HsChit1, SmChiB, and OfChi-h, with IC50 values of 0.19 µM, 4.2 nM, and 25 nM, respectively. Binding mode studies revealed that the compound 8h formed π-π stacking/hydrophobic interactions at +1 or +2 subsite of chitinases. In addition, a key hydrogen bond net was formed between the pharmacophore N-methylcarbamoylguanidinyl and key residues at the −1 subsite. Together, the findings of this study provide novel insights into the development of potent small-molecule chitinase inhibitors using a combination of planar structures and N-methylcarbamoylguanidinyl.