Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity

Bioorg Med Chem. 2008 Sep 15;16(18):8745-59. doi: 10.1016/j.bmc.2008.07.041. Epub 2008 Jul 20.

Abstract

Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Benzene / chemistry
  • Benzene / pharmacology*
  • Hydrazines / chemical synthesis
  • Hydrazines / pharmacology*
  • Hydroxamic Acids
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / pharmacology*

Substances

  • Hydrazines
  • Hydroxamic Acids
  • Indoles
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Sulfonic Acids
  • ilomastat
  • Benzene