title: Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition.
abstract: Following the results we previously reported on a series of ethyl 2-phenylthiomethyl 5-hydroxyindole-3-carboxylate derivatives as 5-lipoxygenase (5-LOX) inhibitors, in order to obtain a more selective compound with respect to the previous generation of derivatives, we decided to modify the structure of the core ligand. The first level of structural modification involved the annelation of benzene to the indole, yielding corresponding benzo[g]indole derivatives, systematic optimization of methyl or chlorine groups in meta-, ortho- and ortho/para-position of 2-phenylthiomethyl moiety were applied. The reported results show that extension of the aromatic core led to a great enhancement of activity, especially in cell-free assay, and the accurate structure-based design provided compounds 6f, 6g and 6l that block 5-LOX activity in cell-free assays with IC50 ranging from 0.17 to 0.22 μM, and suppress 5-LOX product synthesis in polymorphonuclear leukocytes with IC50 ranging from 0.19 to 0.37 μM. Moreover we have identified 6f and 6l as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors and compound 6l significantly reduces inflammatory reactions in the carrageenan-induced mouse paw oedema. The reported in vivo analysis, together with the accessible synthetic procedure, stimulate for the generation of further potent antinflammatory benzoindoles-based agents.
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Krauth
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Selene
authors.initials: S
authors.lastname: Collarile
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Fiederike
authors.initials: F
authors.lastname: Dehm
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Ambruosi
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Belardo
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
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: Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 4980131 Napoli, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Esposito
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16 - 80138 Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: de Rosa
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Experimental Medicine, Second 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: D000328:Adult; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009504:Neutrophils / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: C000611511:2-phenylthiomethyl-benzoindole; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D002351:Carrageenan; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-lipoxygenase; Indoles; Leukotriene