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

Abstract

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 –CHN–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 (R1=CH2Ph, X=F), 17 (R1=CH2Ph, X=CF3), 18 (R1=COPh, X=F) and 20 (R1=COPh, X=CF3) were identified as effective and selective COX-2 inhibitors (COX-2 IC50’s=0.32–0.84μM 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 >100μM; COX-2 IC50=0.32μM) 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=0.13μM; COX-2 IC50=6.9μM, COX-2 SI=0.02). Molecular modeling studies employing compound 20 showed that the phenyl CF3 substituent attached to the CN spacer is positioned near the secondary pocket of the COX-2 active site, the CN nitrogen atom is hydrogen bonded (N⋯NH=2.85Å) to the H90 residue, and the indole N-1 benzoyl is positioned in a hydrophobic pocket of the COX-2 active site near W387.