Inhibition of immune complex-mediated neutrophil oxidative metabolism: a pharmacophore model for 3-phenylcoumarin derivatives using GRIND-based 3D-QSAR and 2D-QSAR procedures.

Abstract

In this study, twenty hydroxylated and acetoxylated 3-phenylcoumarin derivatives were evaluated as inhibitors of immune complex-stimulated neutrophil oxidative metabolism and possible modulators of the inflammatory tissue damage found in type III hypersensitivity reactions. By using lucigenin- and luminol-enhanced chemiluminescence assays (CL-luc and CL-lum, respectively), we found that the 6,7-dihydroxylated and 6,7-diacetoxylated 3-phenylcoumarin derivatives were the most effective inhibitors. Different structural features of the other compounds determined CL-luc and/or CL-lum inhibition. The 2D-QSAR analysis suggested the importance of hydrophobic contributions to explain these effects. In addition, a statistically significant 3D-QSAR model built applying GRIND descriptors allowed us to propose a virtual receptor site considering pharmacophoric regions and mutual distances. Furthermore, the 3-phenylcoumarins studied were not toxic to neutrophils under the assessed conditions.

• Authors: Luciana M Kabeya, Carlos H T P da Silva, Alexandre Kanashiro, Joaquín M Campos, Ana Elisa C S Azzolini, Ana Cristina M Polizello, Mônica T Pupo, Yara M Lucisano-Valim
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 43 Issue 5 Pg. 996-1007 (May 2008) ISSN: 0223-5234 [Print] France
• PMID: 17804122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antigen-Antibody Complex
• Coumarins
• Reactive Oxygen Species

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Antigen-Antibody Complex (physiology)
• Coumarins (chemistry, pharmacology)
• Female
• Hydrophobic and Hydrophilic Interactions
• In Vitro Techniques
• Luminescent Measurements
• Models, Molecular
• Neutrophils (drug effects, metabolism)
• Quantitative Structure-Activity Relationship
• Rabbits
• Reactive Oxygen Species (metabolism)
• Respiratory Burst