A Series of Compounds Bearing a Dipyrido-Pyrimidine Scaffold Acting as Novel Human and Insect Pest Chitinase Inhibitors

J Med Chem. 2020 Feb 13;63(3):987-1001. doi: 10.1021/acs.jmedchem.9b01154. Epub 2020 Feb 3.


Chitinases not only play vital roles in the human innate immune system but are also 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 activities and selectivities 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 that chitotriosidase played a protective role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / pharmacology
  • Chitinases / antagonists & inhibitors*
  • Chitinases / metabolism
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inflammation / metabolism
  • Lepidoptera / enzymology
  • Macrophages / drug effects
  • Mice
  • Molecular Structure
  • Protein Binding
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Serratia marcescens
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Pyridines
  • Pyrimidines
  • Bleomycin
  • AMCase, mouse
  • CHIA protein, human
  • Chitinases