title: 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.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Kung-Cheng
authors.initials: KC
authors.lastname: Liu
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Lee
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Wang
authors.forename: Yih-Shyun E
authors.initials: YS
authors.lastname: Cheng
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000284:Administration, Oral; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002245:Carbon Dioxide / Q000737:chemistry; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004952:Esters / Q000737:chemistry; D019791:Guanidine / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009980:Influenza A virus / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy / Q000201:enzymology / Q000453:epidemiology; D007477:Ions / Q000737:chemistry; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry; D053139:Oseltamivir / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D053243:Zanamivir / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004952:Esters; D007477:Ions; D009284:Naphthols; D011355:Prodrugs; D002245:Carbon Dioxide; C041069:carboxyl radical; D053139:Oseltamivir; D009439:Neuraminidase; D019791:Guanidine; D053243:Zanamivir; C050175:1-hydroxy-2-naphthoic acid