title: The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen-Activated Protein Kinase Inhibitors.
abstract: The identification, synthesis, biological activity, and binding mode prediction of a series of pyrazolobenzothiazines as novel p38α MAPK inhibitors are reported. Some of these compounds showed interesting activity in both p38α MAPK and TNF-α release assays. Derivative 6 emerged as the most interesting compound with IC50 (p38α) = 0.457 μm, IC50 (TNF-α) = 0.5 μm and a promising kinase selectivity profile. The obtained results strongly indicate the pyrazolobenzothiazine core as a new p38α inhibitor chemotype worthy of future chemical optimization efforts directed toward identifying a new generation of anti-inflammatory agents.
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.affiliation: Department of Pharmaceutical & Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls University Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany.
authors.forename: Silke M
authors.initials: SM
authors.lastname: Bauer
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06100, Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Rolando
authors.initials: R
authors.lastname: Cannalire
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: CIMUS Research Center, University of Santiago de Compostela, Avda de Barcelona s/n, Planta 3. Despacho 1, 15782, Santiago de Compostela, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Brea
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06100, Perugia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.affiliation: Department of Medicine, University of Perugia, Piazzale Gambuli, 06100, Perugia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pirro
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Massari
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.affiliation: CIMUS Research Center, University of Santiago de Compostela, Avda de Barcelona s/n, Planta 3. Despacho 1, 15782, Santiago de Compostela, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Loza
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06100, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Pharmaceutical & Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls University Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123, Perugia, Italy.
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001581:Benzothiadiazines; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases
keywords: anti-TNF agents; ligand efficiency; molecular docking; p38α MAPK inhibitors; pyrazolobenzothiazines