X-ray Structure and Molecular Docking Guided Discovery of Novel Chitinase Inhibitors with a Scaffold of Dipyridopyrimidine-3-carboxamide

Chitinases are the glycosyl hydrolase for catalyzing the degradation of chitin and play an indispensable role in bacterial pathogenesis, fungal cell wall remodeling, and insect molting. Thus, chitinases are attractive targets for therapeutic drugs and pesticides. Here, we present a strategy of developing a novel chemotype of chitinase inhibitors by the construction of planar heterocycles that can stack with conserved aromatic residues. The rational design, guided by crystallographic analysis and docking results, leads to a series of dipyridopyrimidine-3-carboxamide derivatives as chitinase inhibitors. Among them, compound 6t showed the most potent activity against bacterial chitinase SmChiB and insect chitinase OfChi-h, with a Ki value of 0.14 and 0.0056 μM, respectively. The strong stacking interaction of compound 6p with Trp99 and Trp220 found in the SmChiB–6p co-crystal structure verifies the feasibility of our design. Our results provide novel insights into developing potent chitinase inhibitors for pathogen and pest control.