Abstract

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.

Graphical abstract

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.

Keywords: Pyrazolines; Pyrazole; COX-2; LOX; Enantiomers; Cyclooxygenase-2 inhibitors; Lipoxygenase inhibitors; anti-inflammation; Molecular modelling

Article Outline

1. Introduction

2. Chemistry

3. Results and discussion

4. Conclusions

5. Experimental

5.1. COX-inhibition-EIA assay

5.2. LOX-inhibition assay

5.3. Chemistry

5.3.1. General information

5.3.2. General procedure for the synthesis of substituted (E)1,1,1-trifluoro-4-(1H-indol-3-yl)-but-3-en-2-one (3)

5.3.2.1. 1,1,1-Trifluoro-4-(5-fluoro-1H-indol-3-yl)-but-3-en-2-one (3a)

5.3.2.2. 1,1,1-Trifluoro-4-(5-chloro-1H-indol-3-yl)-but-3-en-2-one (3b)

5.3.2.3. 1,1,1-Trifluoro-4-(6-fluoro-1H-indol-3-yl)-but-3-en-2-one (3c)

5.3.2.4. 1,1,1-Trifluoro-4-(6-chloro-1H-indol-3-yl)-but-3-en-2-one (3d)

5.3.2.5. 1,1,1-Trifluoro-4-(7-chloro-1H-indol-3-yl)-but-3-en-2-one (3e)

5.3.2.6. 1,1,1-Trifluoro-4-(5-cyano-1H-indol-3-yl)-but-3-en-2-one (3f)

5.3.2.7. 1,1,1-Trifluoro-4-(5-bromo-1H-indol-3-yl)-but-3-en-2-one (3g)

5.3.2.8. 1,1,1-Trifluoro-4-(5-amino-1H-indol-3-yl)-but-3-en-2-one (3h)

5.3.2.9. 1,1,1-Trifluoro-4-(4-amino-1H-indol-3-yl)-but-3-en-2-one (3i)

5.3.2.10. 1,1,1-Trifluoro-4-(5-nitro-1H-indol-3-yl)-but-3-en-2-one (3j)

5.3.2.11. 1,1,1-Trifluoro-4-(5-carboxy-1H-indol-3-yl)-but-3-en-2-one (3k)

5.3.2.12. 1,1,1-Trifluoro-4-(7-nitro-1H-indol-3-yl)-but-3-en-2-one (3l)

5.3.2.13. 1,1,1-Trifluoro-4-(4-methoxy-1H-indol-3-yl)-but-3-en-2-one (3m)

5.3.3. General procedure for the synthesis of substituted 4-[5-(1H-Indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5)

5.3.3.1. 4-[5-(1H-Indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5a)

5.3.3.2. 4-[5-(5-Fluoro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5b)

5.3.3.3. 4-[5-(5-Chloro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5c)

5.3.3.4. 4-[5-(6-Fluoro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5d)

5.3.3.5. 4-[5-(6-Chloro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5e)

5.3.3.6. 4-[5-(7-Chloro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5f)

5.3.3.7. 4-[5-(5-Cyano-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5g)

5.3.3.8. 4-[5-(6-Bromo-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5h)

5.3.3.9. 4-[5-(5-Amino-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5i)

5.3.3.10. 4-[5-(4-Amino-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5j)

5.3.3.11. 4-[5-(6-Cyano-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5k)

5.3.3.12. 4-[5-(6-Nitro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5l)

5.3.3.13. 4-[5-(6-Chloro-2-methyl-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (5m)

5.3.3.14. 4-[5-(4-Methoxy-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5n)

5.3.3.15. 4-[5-(6-Amino-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5o)

5.3.3.16. 4-[5-(5-Nitro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5p)

5.3.3.17. 4-[5-(5-Carboxy-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5q)

5.3.3.18. 4-[5-(7-Nitro-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5r)

5.3.3.19. 4-[5-(7-Amino-1H-indol-3-yl)-3-trifluoromethyl-4,5-dihydropyrazol-1-yl]-benzenesulfonamide (5s)

5.4. Computational details

Acknowledgements

References