Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.

扎那米韦（ZA）和胍基奥司他韦羧酸（GOC）是非常有效的流感神经氨酸酶（NA）抑制剂。胍部分在NA结合中起重要作用。然而，其极性阳离子性质也阻碍了口服给药ZA和GOC的使用。在这项研究中，我们调查了ZA和GOC酰基胍衍生物作为口服可用前药的用途。酰基胍衍生物是通过与正辛酸或（S）萘普生。亲脂性酰基取代基经过验证可提高细胞通透性，并且还可以提高酰基胍化合物的生物利用度。相比之下，带有直链辛酰基链的酰基胍显示出比具有庞大支链萘普生部分的相应衍生物更好的NA抑制活性和更高的水解速率。我们的分子对接实验表明，辛酰基直链可以延伸至NA的150腔和430腔，从而获得额外的疏水性相互作用。接受ZA辛酰基胍衍生物的小鼠比ZA治疗的小鼠在流感感染中存活的更好，而GOC辛酰基胍衍生物可以口服给药以治疗等效于oseltamivir的小鼠。