title: Exploration of the dihydropyrimidine scaffold for the development of new potential anti-inflammatory agents blocking prostaglandin E₂ synthase-1 enzyme (mPGES-1).
abstract: Agents targeting microsomal prostaglandin E2 synthase-1 (mPGES-1) would inhibit only PGE2 production induced by inflammatory stimuli and thus could represent a valuable alternative to non-steroidal anti-inflammatory drugs (NSAIDs) as they should be free from the severe side effects of the classic anti-inflammatory drugs. Although several mPGES-1 inhibitors have been so far identified, none of them is currently in clinical trials, therefore the discovery of new molecular platforms, able to interfere with this interesting target, is urgently required. Here, we report the results of a focused collection of dyhidropyrimidin-2(1H)-one based molecules projected by Virtual Screening computational techniques. The key interactions with the receptor counterpart were introduced as a qualitative filter for the selection of the most promising compounds. The biological data obtained are consistent with the computer-aided suggestions and disclosed two interesting molecules showing in vitro mPGES-1 inhibitory activity in the low μM range.
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Strocchia
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy. Electronic address: brunoin@unisa.it.
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pergola
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084 Fisciano, Italy. Electronic address: bifulco@unisa.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D000071876:Prostaglandin-E Synthases; D017433:Protein Structure, Secondary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: Biginelli reaction; Inflammation; Molecular docking; mPGES-1 inhibitors