title: 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, CH(2)Ph, COPh) substituent in conjunction with a C-3 -C=HN-C(6)H(4)-4-X (X=F, Me, CF(3), 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)=CH(2)Ph, X=F), 17 (R(1)=CH(2)Ph, X=CF(3)), 18 (R(1)=COPh, X=F) and 20 (R(1)=COPh, X=CF(3)) were identified as effective and selective COX-2 inhibitors (COX-2 IC(50)'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 IC(50) >100 μM; COX-2 IC(50)=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 IC(50)=0.13 μM; COX-2 IC(50)=6.9 μM, COX-2 SI=0.02). Molecular modeling studies employing compound 20 showed that the phenyl CF(3) 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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012545:Schiff Bases / Q000138:chemical synthesis* / Q000494:pharmacology; D012756:Sheep; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D011994:Recombinant Proteins; D012545:Schiff Bases; D012996:Solutions; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D007213:Indomethacin