Abstract
A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively.
Keywords:
Anti-inflammatory activity; Butanehydrazides; Dual PDE4/7 inhibitors; Inflammation; Purine-2,6-dione; TNF-α inhibitors.
Copyright © 2018 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Butanes / analysis
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Butanes / chemical synthesis
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Butanes / chemistry
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Butanes / pharmacology*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Cyclic Nucleotide Phosphodiesterases, Type 7 / antagonists & inhibitors*
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Cyclic Nucleotide Phosphodiesterases, Type 7 / metabolism
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Dose-Response Relationship, Drug
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Drug Design*
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Endotoxemia / drug therapy
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Humans
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Hydrazines / chemical synthesis
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Hydrazines / chemistry
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Hydrazines / pharmacology*
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Male
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Molecular Structure
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacology*
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Purinones / chemical synthesis
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Purinones / chemistry
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Purinones / pharmacology*
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Rats
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Rats, Wistar
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Butanes
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Hydrazines
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Lipopolysaccharides
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Phosphodiesterase Inhibitors
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Purinones
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butane
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Cyclic Nucleotide Phosphodiesterases, Type 7