Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses

European Journal of Medicinal Chemistry
Peng-Hao HsuJim-Min Fang

Abstract

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 equ...Continue Reading

Citations

Oct 24, 2019·Journal of Biomedical Science·Jiun-Jie Shie, Jim-Min Fang
Oct 6, 2020·Expert Opinion on Therapeutic Patents·Tiziana Ginex, F Javier Luque
Oct 3, 2020·Bioorganic & Medicinal Chemistry·Leandro Rocha SilvaEdeildo Ferreira da Silva-Júnior
Jun 20, 2020·Drug Discovery Today·Sumit Kumar Poonam

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