Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors

• Published in: Bioorganic & medicinal chemistry 2008-04, Vol.16 (7), p.3907-3916
• Main Authors: Reddy, M.V. Ramana, Billa, Vinay K., Pallela, Venkat R., Mallireddigari, Muralidhar R., Boominathan, Rengasamy, Gabriel, Jerome L., Reddy, E. Premkumar
• Format: Article
• Language: English
• Subjects: anti-inflammation; Binding Sites; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - enzymology; Bones, joints and connective tissue. Antiinflammatory agents; COX-2; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2 inhibitors; Drug Design; Enantiomers; Fluorine Compounds - chemical synthesis; Fluorine Compounds - chemistry; Fluorine Compounds - pharmacology; Humans; Hydrogen Bonding; Indoles - chemistry; Lipoxygenase inhibitors; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; LOX; Magnetic Resonance Spectroscopy; Medical sciences; Methylation; Models, Molecular; Molecular modelling; Molecular Structure; Pharmacology. Drug treatments; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazolines; Stereoisomerism; Structure-Activity Relationship; Sulfur Compounds - chemical synthesis; Sulfur Compounds - chemistry; Sulfur Compounds - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.01.047

A new series of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were synthesized and evaluated as inhibitors of cyclooxygenase-2 and lipoxygenase-5,12,15 enzymes. A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity ( 5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.