title: Discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors.
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.
authors.affiliation: 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.
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Meng
authors.affiliation: 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.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Gang
authors.initials: G
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006146:Guanidines / Q000737:chemistry*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D053139:Oseltamivir; D009439:Neuraminidase; C535162:oseltamivir carboxylate
keywords: Acylguanidine oseltamivir carboxylate; H1N1; H3N2; Influenza viruses; Neuraminidase inhibitors; Oseltamivir-resistant strain (H259Y)