Intramolecular ion-pair prodrugs of zanamivir and guanidino-oseltamivir.

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.

• Authors: Kung-Cheng Liu, Pei-Shan Lee, Shi-Yun Wang, Yih-Shyun E Cheng, Jim-Min Fang, Chi-Huey Wong
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 16 Pg. 4796-802 (Aug 15 2011) ISSN: 1464-3391 [Electronic] England
• PMID: 21778065 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Esters
• Ions
• Naphthols
• Prodrugs
• Carbon Dioxide
• carboxyl radical
• Oseltamivir
• Neuraminidase
• Guanidine
• Zanamivir
• 1-hydroxy-2-naphthoic acid

Topics

• Administration, Oral
• Antiviral Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Carbon Dioxide (chemistry)
• Cell Line
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Esters (chemistry)
• Guanidine (chemistry, pharmacology)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Influenza A virus (drug effects)
• Influenza, Human (drug therapy, enzymology, epidemiology)
• Ions (chemistry)
• Molecular Structure
• Naphthols (chemistry)
• Neuraminidase (antagonists & inhibitors, chemistry)
• Oseltamivir (chemistry, pharmacology)
• Prodrugs (chemistry, pharmacology)
• Zanamivir (chemistry, pharmacology, therapeutic use)