title: Structure-Based Design of Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitors using a Virtual Fragment Growing Optimization Scheme.
abstract: A small library of 2,3-dihydroxybenzamide- and N-(2,3-dihydroxyphenyl)-4-sulfonamide-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors was identified following a step-by-step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES-1. During the virtual optimization process, the 2,3-dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure-guided replacement of the 2,3-dihydroxybenzamide by the N-(2,3-dihydroxyphenyl)sulfonamide moiety led to the identification of N-(2,3-dihydroxyphenyl)-4-biphenylsulfonamide (6), the most potent small molecule of the series (IC50 =0.53 ± 0.04 μM). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES-1-inhibitory activity, with potential application as anti-inflammatory and anticancer agents.
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.affiliation: Department of Pharmacy, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70126, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.affiliation: Department of Pharmacy, Università degli Studi di Napoli "Federico II", Via Montesano 49, 80131, Napoli, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Ostacolo
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743, Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.affiliation: Department of Pharmacy, Università degli Studi di Napoli "Federico II", Via Montesano 49, 80131, Napoli, Italy.
authors.forename: Isabel Maria
authors.initials: IM
authors.lastname: Gomez-Monterrey
authors.affiliation: Department of Pharmacy, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70126, Bari, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Tauro
authors.affiliation: Department of Pharmacy, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70126, Bari, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.affiliation: Department of Pharmacy, Università degli Studi di Napoli "Federico II", Via Montesano 49, 80131, Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743, Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy. bifulco@unisa.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Department of Pharmacy, Università di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy. pcampiglia@unisa.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; D016861:Cyclooxygenase Inhibitors; C000618631:N-(2,3-dihydroxyphenyl)-4-biphenylsulfonamide; D013449:Sulfonamides; D051545:Cyclooxygenase 1
keywords: inflammation; medicinal chemistry; molecular modelling; prostaglandins; structure-activity relationships