Identification of novel quinazolin-4(3H)-ones as inhibitors of thermolysin, the prototype of the M4 family of proteinases

Bioorg Med Chem. 2010 Jun 15;18(12):4317-27. doi: 10.1016/j.bmc.2010.04.083. Epub 2010 Apr 29.

Abstract

A combinatorial series of novel quinazolin-4(3H)-ones were synthesised and their structures were established based on spectroscopic data (IR, NMR, EI-MS, and FAB-MS). The compounds were tested for inhibition of the zinc metalloproteinase thermolysin (TLN) utilizing a chemical array-based approach. Some of the compounds were found to inhibit TLN, with IC(50) values ranging from 0.0115 microM (compound 3) to 122,637 microM (compound 29). Compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3H)-one] (IC(50)=0.0115 microM) and compound 35 [3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4 (1H)-one] (IC(50)=0.2477 microM) were found to be the most potent inhibitors.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Molecular Conformation
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry*
  • Quinazolinones / pharmacology
  • Structure-Activity Relationship
  • Thermolysin / antagonists & inhibitors*
  • Thermolysin / metabolism

Substances

  • 3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one
  • 3-phenyl-2-(trifluoromethyl)quinazolin-4(3H)-one
  • Protease Inhibitors
  • Quinazolines
  • Quinazolinones
  • Thermolysin