A series of compounds bearing a dipyrido-pyrimidine scaffold acting as novel human and insect pest chitinases inhibitors

Chitinases not only play vital roles in human innate immune system but also are essential for the development of pathogenic fungi and pests. Chitinase inhibitors are efficient tools to investigate the elusive role of human chitinases and to control pathogens and pests. Via hierarchical virtual screening, we have discovered a series of chitinase inhibitors with a novel scaffold that have high inhibitory activity and selectivity against human and insect chitinases. The most potent human chitotriosidase inhibitor, compound 40 exhibited a Ki of 49 nM and the most potent inhibitor of the insect pest chitinase OfChi-h, compound 53 exhibited a Ki of 9 nM. The binding of these two most potent inhibitors was confirmed by X-ray crystallography. In a murine model of bleomycin-induced pulmonary fibrosis, compound 40 was found to suppress the chitotriosidase activity by 60%, leading to a significant increase in inflammatory cells and suggesting chitotriosidase played a protective role.