tetano
Editor, Senior Moderator
Eur J Med Chem. 2014 May 2;81C:106-118. doi: 10.1016/j.ejmech.2014.04.082. [Epub ahead of print]
Tamiphosphor monoesters as effective anti-influenza agents.
Chen CL1, Lin TC1, Wang SY2, Shie JJ2, Tsai KC3, Cheng YS2, Jan JT2, Lin CJ4, Fang JM5, Wong CH6.
Author information
Abstract
Oseltamivir is a potent neuraminidase inhibitor for influenza treatment. By replacing the carboxylate group in oseltamivir with phosphonate monoalkyl ester, a series of tamiphosphor derivatives were synthesized and shown to exhibit high inhibitory activities against influenza viruses. Our molecular modeling experiments revealed that influenza virus neuraminidase contains a 371-cavity near the S1-site to accommodate the alkyl substituents of tamiphosphor monoesters to render appreciable hydrophobic interactions for enhanced affinity. Furthermore, guanidino-tamiphosphor (TPG) monoesters are active to the oseltamivir-resistant mutant. TPG monohexyl ester 4e having a more lipophilic alkyl substituent showed better cell permeability and intestinal absorption than the corresponding monoethyl ester 4c, but both compounds showed similar bioavailability. Intranasal administration of TPG monoesters at low dose greatly improved the survival rate of mice infected with lethal dose of H1N1 influenza virus, whereas 4c provided better protection of the infected mice than oseltamivir and other phosphonate congeners by oral administration.
Copyright ? 2014 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
BQLKEXSYWRBWQK-AFMQGRBTSA-N, Influenza, Inhibitor, Molecular modeling, Neuraminidase, Pharmacokinetics, Virus
PMID:
24836064
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24836064
Tamiphosphor monoesters as effective anti-influenza agents.
Chen CL1, Lin TC1, Wang SY2, Shie JJ2, Tsai KC3, Cheng YS2, Jan JT2, Lin CJ4, Fang JM5, Wong CH6.
Author information
Abstract
Oseltamivir is a potent neuraminidase inhibitor for influenza treatment. By replacing the carboxylate group in oseltamivir with phosphonate monoalkyl ester, a series of tamiphosphor derivatives were synthesized and shown to exhibit high inhibitory activities against influenza viruses. Our molecular modeling experiments revealed that influenza virus neuraminidase contains a 371-cavity near the S1-site to accommodate the alkyl substituents of tamiphosphor monoesters to render appreciable hydrophobic interactions for enhanced affinity. Furthermore, guanidino-tamiphosphor (TPG) monoesters are active to the oseltamivir-resistant mutant. TPG monohexyl ester 4e having a more lipophilic alkyl substituent showed better cell permeability and intestinal absorption than the corresponding monoethyl ester 4c, but both compounds showed similar bioavailability. Intranasal administration of TPG monoesters at low dose greatly improved the survival rate of mice infected with lethal dose of H1N1 influenza virus, whereas 4c provided better protection of the infected mice than oseltamivir and other phosphonate congeners by oral administration.
Copyright ? 2014 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
BQLKEXSYWRBWQK-AFMQGRBTSA-N, Influenza, Inhibitor, Molecular modeling, Neuraminidase, Pharmacokinetics, Virus
PMID:
24836064
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24836064