title: Thiazole derivatives as inhibitors of cyclooxygenases in vitro and in vivo.
abstract: Cyclooxygenases (COXs) are important membrane-bound heme containing enzymes important in platelet activation and inflammation. COX-1 is constitutively expressed in most cells whereas COX-2 is an inducible isoform highly expressed in inflammatory conditions. Studies have been carried out to evaluate thiazole derivatives as anti-inflammatory molecules. In this study, we investigated the in vitro and in vivo effects of two novel thiazole derivatives compound 1 (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl] acetamide) and compound 2 (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol) on prostaglandin E2 (PGE2) production and COX activity in inflammatory settings. Our results reveal a potent inhibition of both compound 1 (IC50 9.01±0.01µM) and 2 (IC50 11.65±6.20µM) (Mean±S.E.M.) on COX-2-dependent PGE2 production. We also determined whether COX-1 activity was inhibited. Using cells stably over-expressing COX-1 and human blood platelets, we showed that compound 1 is a specific inhibitor of COX-1 with IC50 (5.56×10(-8)±2.26×10(-8)µM), whereas compound 2 did not affect COX-1. Both compounds exhibit anti-inflammatory effect in the dorsal air pouch model of inflammation as shows by inhibition of PGE2 secretion. Modeling analysis of docking in the catalytic site of COX-1 or COX-2 further confirmed the difference in the effect of these two compounds. In conclusion, this study contributes to the design of new anti-inflammatory agents and to the understanding of cyclooxygenase inhibition by thiazole.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, PO Box 11-236, Lebanon; INSERM U955, Equipe 12, Faculty of Medicine, University Paris-Est, Creteil, France.
authors.forename: Ghewa A
authors.initials: GA
authors.lastname: El-Achkar
authors.affiliation: Genomic and Health Laboratory ER 031/PRASE-EDST, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
authors.forename: Mariam
authors.initials: M
authors.lastname: Jouni
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, PO Box 11-236, Lebanon.
authors.forename: May F
authors.initials: MF
authors.lastname: Mrad
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, PO Box 11-236, Lebanon.
authors.forename: Taghreed
authors.initials: T
authors.lastname: Hirz
authors.affiliation: Bioinformatics and Computational Genomics Laboratory, Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Nehme
authors.initials: N
authors.lastname: El Hachem
authors.affiliation: Département de Chimie et de Biochimie, Laboratoire de Chimie Médicinale et des Produits Naturels & PRASE, EDST Lebanese University, Hadath, Lebanon.
authors.forename: Ali
authors.initials: A
authors.lastname: Khalaf
authors.affiliation: Département de Chimie et de Biochimie, Laboratoire de Chimie Médicinale et des Produits Naturels & PRASE, EDST Lebanese University, Hadath, Lebanon.
authors.forename: Soukaina
authors.initials: S
authors.lastname: Hammoud
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000 Bruxelles, Belgium.
authors.forename: Hussein
authors.initials: H
authors.lastname: Fayyad-Kazan
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, PO Box 11-236, Lebanon.
authors.forename: Assaad A
authors.initials: AA
authors.lastname: Eid
authors.affiliation: Laboratory of Immunology/EDST-PRASE, Lebanese University, Faculty of Sciences, Hadath, Beirut, Lebanon.
authors.forename: Bassam
authors.initials: B
authors.lastname: Badran
authors.affiliation: Genomic and Health Laboratory ER 031/PRASE-EDST, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
authors.forename: Raghida Abou
authors.initials: RA
authors.lastname: Merhi
authors.affiliation: Département de Chimie et de Biochimie, Laboratoire de Chimie Médicinale et des Produits Naturels & PRASE, EDST Lebanese University, Hadath, Lebanon.
authors.forename: Ali
authors.initials: A
authors.lastname: Hachem
authors.affiliation: Genomic and Health Laboratory ER 031/PRASE-EDST, Faculty of Sciences, Lebanese University, Beirut, Lebanon. Electronic address: eva.hamade@ul.edu.lb.
authors.forename: Eva
authors.initials: E
authors.lastname: Hamade
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, PO Box 11-236, Lebanon; Centre de recherche sur l'inflammation, INSERM UMR 1149-Université Paris Diderot, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, F-75018 Paris, France. Electronic address: aida.habib@inserm.fr.
authors.forename: Aïda
authors.initials: A
authors.lastname: Habib
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010974:Platelet Aggregation / Q000187:drug effects; D011487:Protein Conformation; D000067996:RAW 264.7 Cells; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D013844:Thiazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: Air pouch model of inflammation; Cyclooxygenase; NSAIDs; Platelet aggregation; Prostaglandin; Thiazole derivatives