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

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 = 0.32–0.84 μM 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 μM; COX-2 IC50 = 0.32 μM) 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 μM; COX-2 IC50 = 6.9 μM, 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 = 2.85 Å) to the H90 residue, and the indole N-1 benzoyl is positioned in a hydrophobic pocket of the COX-2 active site near W387.

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