Inhibition of immune complex-mediated neutrophil oxidative metabolism: a pharmacophore model for 3-phenylcoumarin derivatives using GRIND-based 3D-QSAR and 2D-QSAR procedures.
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.
Kabeya
Luciana M
LM
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo. Av. Café s/n, Bairro Monte Alegre, Ribeirão Preto, SP, CEP 14040-903, Brazil.
da Silva
Carlos H T P
CH
Kanashiro
Alexandre
A
Campos
Joaquín M
JM
Azzolini
Ana Elisa C S
AE
Polizello
Ana Cristina M
AC
Pupo
Mônica T
MT
Lucisano-Valim
Yara M
YM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000502:physiology*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst