title: Isoxazole-Based-Scaffold Inhibitors Targeting Cyclooxygenases (COXs).
abstract: A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N-(9-{2-[(4-{2-[3-(5-chlorofuran-2-yl)-4-phenylisoxazol-5-yl]acetamido}butyl)carbamoyl]phenyl-6-(ethylamino)-2,7-dimethyl-3H-xanthen-3-ylidene}ethanaminium chloride] was found to be a selective COX-1 inhibitor, whereas 17 (2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]ethanone) was found to be a sub-micromolar selective COX-2 inhibitor. However, both were shown to interact with P-glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125, Bari, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125, Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vitale
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125, Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Panella
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125, Bari, Italy.
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125, Bari, Italy.
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università di Napoli "Federico II", Via D. Montesano 49, 80131, Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", Via E. Orabona 4, 70125, Bari, Italy. antonio.scilimati@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Scilimati
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D010539:Permeability; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: P-glycoprotein; cyclooxygenase; decomposition analysis; isoxazoles; molecular docking