title: Synthesis, biological evaluation, and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors.
abstract: Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50)=0.061 microM and COX-2 IC(50)=0.325 microM; selectivity index (SI)=0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50)=0.011 microM and 0.398 microM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50)=1 microM, COX-2 IC(50)=0.011 microM; SI= approximately 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.
authors.affiliation: Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06330 Ankara, Turkey. gokcene@gazi.edu.tr
authors.forename: Gökçen
authors.initials: G
authors.lastname: Eren
authors.forename: Serdar
authors.initials: S
authors.lastname: Unlü
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Nuñez
authors.forename: Luis
authors.initials: L
authors.lastname: Labeaga
authors.forename: Francisco
authors.initials: F
authors.lastname: Ledo
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
authors.forename: Erden
authors.initials: E
authors.lastname: Banoğlu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: M Fethi
authors.initials: MF
authors.lastname: Sahin
mesh_terms: D001665:Binding Sites; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006571:Heterocyclic Compounds