2. Academic Validation
  3. Discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors

Discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors

  • Bioorg Med Chem. 2017 May 15;25(10):2772-2781. doi: 10.1016/j.bmc.2017.03.052.
Zhaoliang Li 1,  Yanchun Meng 2,  Shengtao Xu 2,  Wang Shen 3,  Zhaoqing Meng 3,  Zhenzhong Wang 3,  Gang Ding 3,  Wenzhe Huang 3,  Wei Xiao 4,  Jinyi Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; Jiangsu Kanion Pharmaceutical Co. Ltd., 58 South Haichang Road, Lianyungang 222001, PR China; State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, PR China.
  • 2 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
  • 3 Jiangsu Kanion Pharmaceutical Co. Ltd., 58 South Haichang Road, Lianyungang 222001, PR China; State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, PR China.
  • 4 Jiangsu Kanion Pharmaceutical Co. Ltd., 58 South Haichang Road, Lianyungang 222001, PR China; State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang 222001, PR China. Electronic address: kanionlunwen@163.com.
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.
PMID: 28385598 DOI: 10.1016/j.bmc.2017.03.052
Abstract

In search of novel anti-influenza agents with higher potency, a series of acylguanidine oseltamivir carboxylate analogues were synthesized and evaluated against influenza viruses (H1N1 and H3N2) in vitro. The representative compounds with strong inhibitory activities (IC50 <40nM) against neuraminidase (NA) were further tested against the NA from oseltamivir-resistant strain (H259Y). Among them, compounds 9 and 17 were potent NA inhibitors that exhibited a 5 and 11-fold increase in activity comparing with oseltamivir carboxylate (2, OC) against the H259Y mutant, respectively. Furthermore, the effect against Influenza Virus H259Y mutant (H1N1) replication and cytotoxicity assays indicated that compounds 9 and 17 exhibited a 20 and 6-fold increase than the parent compound 2, and had no obvious cytotoxicity in vitro. Moreover, the molecular docking studies revealed that the docking modes of compounds 9 and 17 were different from that of oseltamivir, and the new hydrogen bonds and hydrophobic interaction were formed in this case. This work provided unique insights in the discovery of potent inhibitors against NAs from wild-type and oseltamivir-resistant strains.

Keywords

Acylguanidine oseltamivir carboxylate; H1N1; H3N2; Influenza viruses; Neuraminidase inhibitors; Oseltamivir-resistant strain (H259Y).

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