Tamiphosphor monoesters as effective anti-influenza agents.
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.
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC.
Chun-Lin
CL
Chen
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC.
Tzu-Chen
TC
Lin
The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
Shi-Yun
SY
Wang
The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
Jiun-Jie
JJ
Shie
National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC.
Keng-Chang
KC
Tsai
The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
Yih-Shyun E
YS
Cheng
The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
Jia-Tsrong
JT
Jan
School of Pharmacy, National Taiwan University, Taipei 100, Taiwan, ROC. Electronic address: clementumich@ntu.edu.tw.
Chun-Jung
CJ
Lin
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC; The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC. Electronic address: jmfang@ntu.edu.tw.
Jim-Min
JM
Fang
The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC. Electronic address: chwong@gate.sinica.edu.tw.
Chi-Huey
CH
Wong
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D002460:Cell Line; D002645:Chickens; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009975:Orthomyxoviridae / Q000187:drug effects*; D053139:Oseltamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010757:Phosphorous Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004952:Esters; D010757:Phosphorous Acids; C530824:tamiphosphor; D053139:Oseltamivir; D009439:Neuraminidase
BQLKEXSYWRBWQK-AFMQGRBTSA-N; Influenza; Inhibitor; Molecular modeling; Neuraminidase; Pharmacokinetics; Virus