Abstract
Zanamivir (ZA) is a potent anti-influenza drug, but it cannot be administrated orally because of the hydrophilic carboxylate and guanidinium groups. Guanidino-oseltamivir (GO) is another effective neuraminidase inhibitor with polar guanidinium group under physiological conditions. The ester prodrugs ZA-HNAP (5) and GO-HNAP (6) were prepared to incorporate a 1-hydroxy-2-naphthoic (HNAP) moiety to attain good lipophilicity in the intramolecular ion-pairing forms. ZA-HNAP resumed high anti-influenza activity (EC(50)=48 nM), in cell-based anti-influenza assays, by releasing zanamivir along with nontoxic HNAP. Under similar conditions, the hydrolysis of the GO-HNAP ester was too sluggish to show the desired anti-influenza activity.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Antiviral Agents / therapeutic use
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Carbon Dioxide / chemistry
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Cell Line
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Esters / chemistry
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Guanidine / chemistry*
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Guanidine / pharmacology
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Humans
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Hydrophobic and Hydrophilic Interactions
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Influenza A virus / drug effects
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Influenza, Human / drug therapy
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Influenza, Human / enzymology
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Influenza, Human / epidemiology
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Ions / chemistry
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Molecular Structure
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Naphthols / chemistry
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Neuraminidase / antagonists & inhibitors
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Neuraminidase / chemistry
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Oseltamivir / chemistry*
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Oseltamivir / pharmacology
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Prodrugs / chemistry
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Prodrugs / pharmacology*
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Zanamivir / chemistry
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Zanamivir / pharmacology*
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Zanamivir / therapeutic use
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Esters
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Ions
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Naphthols
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Prodrugs
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Carbon Dioxide
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carboxyl radical
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Oseltamivir
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Neuraminidase
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Guanidine
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Zanamivir
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1-hydroxy-2-naphthoic acid