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  3. 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

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

  • Eur J Med Chem. 2014 Jun 23;81:492-8. doi: 10.1016/j.ejmech.2014.05.033.
Antonella Peduto 1,  Ferdinando Bruno 2,  Friedrike Dehm 3,  Verena Krauth 3,  Paolo de Caprariis 2,  Christina Weinigel 4,  Dagmar Barz 4,  Antonio Massa 5,  Mario De Rosa 6,  Oliver Werz 3,  Rosanna Filosa 7
Affiliations

Affiliations

  • 1 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Dermofarma Italia, Via Cortenocera, 82030 S. Salvatore Telesino, BN, Italy.
  • 2 Department of Pharmaceutical and Biomedical Sciences, Via Giovanni Paolo II, Fisciano, SA, Italy.
  • 3 Institute of Pharmacy, Friedrich-Schiller-University, Germany.
  • 4 Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany.
  • 5 Department of Chemistry, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
  • 6 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
  • 7 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. Electronic address: rosanna.filosa@unina2.it.
PMID: 24871899 DOI: 10.1016/j.ejmech.2014.05.033
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.

Keywords

5-Lipoxygenase; Indoles; Leukotriene.

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