title: Sulfonilamidothiopyrimidone and thiopyrimidone derivatives as selective COX-2 inhibitors: synthesis, biological evaluation, and docking studies.
abstract: Newly synthesized sulfonilamidothiopyrimidone derivatives and a subset of 14 sulfonilamidothiopyrimidones and thiopyrimidones selected by an MTT assays cell viability guided selection from an in house collection were evaluated to determine the inhibitory effect on the PGE(2) formation in human peripheral blood lymphocytes (PBLs) using commercial ELISA. The newly synthesized sulfonilamidothiopyrimidone derivatives showed interesting pharmacological activities. Preliminary in vitro assays showed that compounds 2-5 are endowed with very high activity. Compound 2 was the most active as hCOX-2 inhibitor. The observed effects were not due to an inhibition of cell proliferation as proved by the BrdU assay. Western blot of COX-2 confirmed the inhibition on the PGE(2) secretion. Further evidence on the inhibitory potential and selectivity as COX-2 inhibitors of the selected compounds came from the in vitro screening. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data. Compounds 2-5 were able to fit into the active site of COX-2 with highest scores and interaction energies. Furthermore, compound 2, which showed an inhibition of around 50% on PGE(2) production, was the best scored in all the docking calculations carried out.
authors.affiliation: EtnaLead s.r.l., c/o Etnabuilding, Scuola Superiore di Catania, via S. Nullo 5/i, I-95123 Catania, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Almudena
authors.initials: A
authors.lastname: Blanco
authors.forename: Andrea
authors.initials: A
authors.lastname: Santagati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Granata
authors.forename: Patrizia
authors.initials: P
authors.lastname: Di Pietro
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Muñoz-Fernández
mesh_terms: D015153:Blotting, Western; D001973:Bromodeoxyuridine; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013816:Thermodynamics; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007376:Interleukin-2; C580930:N-(2-((2,4-difluorophenyl)thio)-4-oxo-6-phenylthieno(2,3-d)pyrimidin-3(4H)-yl)methanesulfonamide; D011744:Pyrimidinones; D013449:Sulfonamides; D013830:Thiadiazoles; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001973:Bromodeoxyuridine; D015232:Dinoprostone