Options
Tamiphosphor monoesters as effective anti-influenza agents
Journal
European Journal of Medicinal Chemistry
Journal Volume
81
Pages
106-118
Date Issued
2014
Author(s)
Chen, C.-L.
Lin, T.-C.
Wang, S.-Y.
Shie, J.-J.
Tsai, K.-C.
Cheng, Y.-S.E.
Jan, J.-T.
Wong, C.-H.
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. ? 2014 Elsevier Masson SAS. All rights reserved.
Subjects
Influenza; Inhibitor; Molecular modeling; Neuraminidase; Pharmacokinetics; Virus
SDGs
Other Subjects
alkyl group; antivirus agent; mono(3 phenylprop 1 yl) 4 acetamido 5 amino 3 (1 ethylpropoxy) 1 cyclohexene 1 phosphonate; mono(3 phenylpropyl) 4 acetamido 3 (1 ethylpropoxy) 5 guanidino 1 cyclohexene 1 phosphonate; monobutyl 4 acetamido 3 (1 ethylpropoxy) 5 guanidino 1 cyclohexene 1 phosphonate; monobutyl 4 acetamido 5 amino 3 (1 ethylpropoxy) 1 cyclohexene 1 phosphonate; monohexyl 4 acetamido 3 (1 ethylpropoxy) 5 guanidino 1 cyclohexene 1 phosphonate; mono[(1h 3 indol 3 yl)lpropyl] 4 acetamido 5 amino 3 (1 ethylpropoxy) 1 cyclohexene 1 phosphonate; oseltamivir; sialidase inhibitor; tamiphosphor monoester derivative; unclassified drug; virus sialidase; zanamivir; antivirus agent; enzyme inhibitor; ester; oseltamivir; phosphorous acid; sialidase; tamiphosphor; animal cell; animal experiment; antiviral activity; antiviral resistance; area under the curve; article; CACO 2 cell line; controlled study; drug absorption; drug bioavailability; drug clearance; drug half life; drug penetration; female; human; human cell; hydrogen bond; in vitro study; influenza A (H1N1); Influenza virus A H1N1; intestine absorption; lipophilicity; male; maximum plasma concentration; MDCK cell line; molecular dynamics; molecular model; mouse; nonhuman; plasma concentration-time curve; survival rate; time to maximum plasma concentration; analogs and derivatives; animal; antagonists and inhibitors; Bagg albino mouse; bioavailability; cell line; chemical structure; chemistry; chicken; conformation; dog; dose response; drug effects; Institute for Cancer Research mouse; metabolism; microbial sensitivity test; Orthomyxovirus; structure activity relation; Animals; Antiviral Agents; Biological Availability; Caco-2 Cells; Cell Line; Chickens; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Esters; Female; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Neuraminidase; Orthomyxoviridae; Oseltamivir; Phosphorous Acids; Structure-Activity Relationship
Type
journal article