Synthesis and anti-inflammatory structure–activity relationships of thiazine–quinoline–quinones: Inhibitors of the neutrophil respiratory burst in a model of acute gouty arthritis

Synthesised thiazine–quinoline–quinones were assayed for inhibition of superoxide production in vitro. Analogues were tested in vivo for inhibition of neutrophil superoxide production and infiltration induced by monosodium urate crystals. Sixteen new thiazine–quinoline–quinones have been synthesised...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-11, Vol.16 (21), p.9432-9442
Main Authors: Chia, Elizabeth W., Pearce, A. Norrie, Berridge, Michael V., Larsen, Lesley, Perry, Nigel B., Sansom, Catherine E., Godfrey, Colette A., Hanton, Lyall R., Lu, Guo-Liang (Leon), Walton, Michaela, Denny, William A., Webb, Victoria L., Copp, Brent R., Harper, Jacquie L.
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Arthritis
Arthritis, Gouty - drug therapy
Arthritis, Gouty - metabolism
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cell Proliferation - drug effects
Disease Models, Animal
HL-60 Cells
Humans
Inflammation
Inflammation - drug therapy
Inflammation - metabolism
Male
Medical sciences
Mice
Mice, Inbred C57BL
Neutrophils
Neutrophils - drug effects
Pharmacology. Drug treatments
Quinolines - chemistry
Quinones - chemistry
Respiratory Burst - drug effects
Structure-Activity Relationship
Superoxide
Superoxides - metabolism
Thiazines - chemistry
Thiazine–quinoline–quinones
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Summary:Synthesised thiazine–quinoline–quinones were assayed for inhibition of superoxide production in vitro. Analogues were tested in vivo for inhibition of neutrophil superoxide production and infiltration induced by monosodium urate crystals. Sixteen new thiazine–quinoline–quinones have been synthesised, plus one bicyclic analogue. These compounds inhibited neutrophil superoxide production in vitro with IC 50s as low 60 nM. Compounds with high in vitro anti-inflammatory activity were also tested in a mouse model of acute inflammation. The most active compounds inhibited both neutrophil infiltration and superoxide production at doses 2.5 μmol/kg, highlighting their potential for development as novel NSAIDs.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.09.052