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Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses.
Eur J Med Chem. 2018 Jun 25; 154:314-323.EJ

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 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.

Authors+Show Affiliations

Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan; The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan; The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. Electronic address: jmfang@ntu.edu.tw.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29843102

Citation

Hsu, Peng-Hao, et al. "Acylguanidine Derivatives of Zanamivir and Oseltamivir: Potential Orally Available Prodrugs Against Influenza Viruses." European Journal of Medicinal Chemistry, vol. 154, 2018, pp. 314-323.
Hsu PH, Chiu DC, Wu KL, et al. Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses. Eur J Med Chem. 2018;154:314-323.
Hsu, P. H., Chiu, D. C., Wu, K. L., Lee, P. S., Jan, J. T., Cheng, Y. E., Tsai, K. C., Cheng, T. J., & Fang, J. M. (2018). Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses. European Journal of Medicinal Chemistry, 154, 314-323. https://doi.org/10.1016/j.ejmech.2018.05.030
Hsu PH, et al. Acylguanidine Derivatives of Zanamivir and Oseltamivir: Potential Orally Available Prodrugs Against Influenza Viruses. Eur J Med Chem. 2018 Jun 25;154:314-323. PubMed PMID: 29843102.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses. AU - Hsu,Peng-Hao, AU - Chiu,Din-Chi, AU - Wu,Kuan-Lin, AU - Lee,Pei-Shan, AU - Jan,Jia-Tsrong, AU - Cheng,Yih-Shyun E, AU - Tsai,Keng-Chang, AU - Cheng,Ting-Jen, AU - Fang,Jim-Min, Y1 - 2018/05/21/ PY - 2018/01/13/received PY - 2018/05/05/revised PY - 2018/05/20/accepted PY - 2018/5/31/pubmed PY - 2018/7/31/medline PY - 2018/5/30/entrez KW - Acylguanidine KW - Influenza KW - Neuraminidase inhibitor KW - Oseltamivir KW - Zanamivir SP - 314 EP - 323 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 154 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/29843102/Acylguanidine_derivatives_of_zanamivir_and_oseltamivir:_Potential_orally_available_prodrugs_against_influenza_viruses_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(18)30443-4 DB - PRIME DP - Unbound Medicine ER -