title: Further studies on ethyl 5-hydroxy-indole-3-carboxylate scaffold: design, synthesis and evaluation of 2-phenylthiomethyl-indole derivatives as efficient inhibitors of human 5-lipoxygenase.
abstract: 5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and biological evaluation of novel series of ethyl 5-hydroxyindole-3-carboxylate derivatives that efficiently inhibit human 5-LO. SAR analysis revealed that the potency of compounds is closely related to the positioning of the substituents at the phenylthiomethyl ring. The introduction of methyl or chlorine groups in ortho- and ortho/para-position of thiophenol represent the most favorable modifications. Among all tested compounds, ethyl 5-hydroxy-2-(mesitylthiomethyl)-1-methyl-1H-indole-3-carboxylate (19) is the most potent derivative which blocks 5-LO activity in cell-free assays with IC50 = 0.7 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 0.23 μM.
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Dermofarma Italia, Via Cortenocera, 82030 S. Salvatore Telesino, BN, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Via Giovanni Paolo II, Fisciano, SA, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Bruno
authors.affiliation: Institute of Pharmacy, Friedrich-Schiller-University, Germany.
authors.forename: Friedrike
authors.initials: F
authors.lastname: Dehm
authors.affiliation: Institute of Pharmacy, Friedrich-Schiller-University, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Krauth
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Via Giovanni Paolo II, Fisciano, SA, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: de Caprariis
authors.affiliation: Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Weinigel
authors.affiliation: Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.affiliation: Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Massa
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: Institute of Pharmacy, Friedrich-Schiller-University, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. Electronic address: rosanna.filosa@unina2.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C000595941:2-phenylthiomethyl-indole; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-Lipoxygenase; Indoles; Leukotriene