N-1 and C-3 substituted indole Schiff bases as selective COX-2 inhibitors: Synthesis and biological evaluation

作者：Kaur Jatinder; Bhardwaj Atul; Huang Zhangjian; Knaus Edward E^*

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(6): 2154-2159.

DOI：10.1016/j.bmcl.2012.01.130

• Inflammation
• Cyclooxygenase-1 and-2
• In vitro COX-2 inhibition
• Indole
• Molecular modeling

A group of N-1 and C-3 disubstituted-indole Schiff bases bearing an indole N-1 (R' = H, CH2Ph, COPh) substituent in conjunction with a C-3-CH=N-C6H4-4-X (X = F, Me, CF3, Cl) substituent were synthesized and evaluated as inhibitors of cyclooxygenase (COX) isozymes (COX-1/COX-2). Within this group of Schiff bases, compounds 15 (R-1 = CH2Ph, X = F), 17 (R-1 = CH2Ph, X = CF3), 18 (R-1 = COPh, X = F) and 20 (R-1 = COPh, X = CF3) were identified as effective and selective COX-2 inhibitors (COX-2 IC50's = 0.32-0.84 mu M range; COX-2 selectivity index (SI) = 113 to > 312 range). 1-Benzoyl-3-[(4-trifluoromethylphenylimino) methyl]indole (20) emerged as the most potent (COX-1 IC50 > 100 mu M; COX-2 IC50 = 0.32 mu M) and selective (SI >312) COX-2 inhibitor. Furthermore, compound 20 is a selective COX-2 inhibitor in contrast to the reference drug indomethacin that is a potent and selective COX-1 inhibitor (COX-1 IC50 = 0.13 mu M; COX-2 IC50 = 6.9 mu M, COX-2 SI = 0.02). Molecular modeling studies employing compound 20 showed that the phenyl CF3 substituent attached to the C=N spacer is positioned near the secondary pocket of the COX-2 active site, the C=N nitrogen atom is hydrogen bonded (N center dot center dot center dot NH = 2.85 angstrom) to the H90 residue, and the indole N-1 benzoyl is positioned in a hydrophobic pocket of the COX-2 active site near W387.

• 出版日期2012-3-15