Optimization of benzoquinone and hydroquinone derivatives as potent inhibitors of human 5-lipoxygenase.
Aiming to assess the biological activities of synthetic 1,4-benzoquinones, we previously synthesized different libraries of benzoquinones with lipophilic and bulky alkyl- or aryl-substituents that inhibited 5-lipoxygenase (5-LO). The high potency of 4,5-dimethoxy-3-alkyl-1,2-benzoquinones on 5-LO led to the idea to further modify the structures and thus to improve the inhibitory potential in vitro and in vivo as well as to investigate SARs. Systematic structural optimization through accurate structure-based design resulted in compound 30 (3-tridecyl-4,5-dimethoxybenzene-1,2-diol), an ubiquinol derivative that exhibited the strongest anti-inflammatory effect, with a 10-fold improved 5-LO inhibitory activity (IC50= 28 nM) in activated neutrophils. Moreover, 30 significantly reduced inflammatory reactions in the carrageenan-induced mouse paw oedema and in zymosan-induced peritonitis in mice. Compound 30 (1 mg/kg, i.p.) potently suppressed the levels of cysteinyl-LTs 30 min after zymosan, outperforming zileuton at a dose of 10 mg/kg. The binding patterns of the quinone- and hydroquinone-based 5-LO inhibitors were analyzed by molecular docking. Together, we elucidated the optimal alkyl chain pattern of quinones and corresponding hydroquinones and reveal a series of highly potent 5-LO inhibitors with effectiveness in vivo that might be useful as anti-inflammatory drugs.
Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Dermofarma, Via Cortenocera, 82030 S. Salvatore Telesino, BN, Italy.
Antonella
A
Peduto
Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
Maria
M
Scuotto
Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
Verena
V
Krauth
Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples, Italy.
Fiorentina
F
Roviezzo
Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples, Italy.
Antonietta
A
Rossi
Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Center for Molecular Biosciences Innsbruck, Innrain 80/82, AT-6020 Innsbruck, Austria.
Veronika
V
Temml
Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples, Italy.
Veronica
V
Esposito
Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Center for Molecular Biosciences Innsbruck, Innrain 80/82, AT-6020 Innsbruck, Austria.
Hermann
H
Stuppner
Institute of Pharmaceutical Chemistry, University of Innsbruck, Center for Molecular Biosciences Innsbruck, Innrain 80/82, AT-6020 Innsbruck, Austria.
Daniela
D
Schuster
Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
Bruno
B
D'Agostino
Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
Chiara
C
Schiraldi
Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
Mario
M
de Rosa
Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
Oliver
O
Werz
Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Dermofarma, Via Cortenocera, 82030 S. Salvatore Telesino, BN, Italy. Electronic address: rosanna.filosa@unina2.it.
Rosanna
R
Filosa
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D006801:Humans; D006873:Hydroquinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010538:Peritonitis / Q000188:drug therapy; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D006873:Hydroquinones; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; C031927:hydroquinone
5-Lipoxygenase; Quinones