tetano
Editor, Senior Moderator
Eur J Med Chem. 2019 Dec 3;187:111940. doi: 10.1016/j.ejmech.2019.111940. [Epub ahead of print] [h=1]Discovery of novel 1,2,3-triazole oseltamivir derivatives as potent influenza neuraminidase inhibitors targeting the 430-cavity.[/h]
Ju H[SUP]1[/SUP], Xiu S[SUP]1[/SUP], Ding X[SUP]1[/SUP], Shang M[SUP]2[/SUP], Jia R[SUP]1[/SUP], Huang B[SUP]2[/SUP], Zhan P[SUP]1[/SUP], Liu X[SUP]3[/SUP].
[h=3]Author information[/h] 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. 2 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1, Jiaoxiao Road, 250023, Jinan, Shandong, PR China. 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
[h=3]Abstract[/h] A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC[SUB]50[/SUB] values of 0.12 μM, 0.049 μM and 0.16 μM and EC[SUB]50[/SUB] values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] 430-cavity; Broad-spectrum anti-influenza activity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 31835169 DOI: 10.1016/j.ejmech.2019.111940
Ju H[SUP]1[/SUP], Xiu S[SUP]1[/SUP], Ding X[SUP]1[/SUP], Shang M[SUP]2[/SUP], Jia R[SUP]1[/SUP], Huang B[SUP]2[/SUP], Zhan P[SUP]1[/SUP], Liu X[SUP]3[/SUP].
[h=3]Author information[/h] 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. 2 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1, Jiaoxiao Road, 250023, Jinan, Shandong, PR China. 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
[h=3]Abstract[/h] A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC[SUB]50[/SUB] values of 0.12 μM, 0.049 μM and 0.16 μM and EC[SUB]50[/SUB] values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] 430-cavity; Broad-spectrum anti-influenza activity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 31835169 DOI: 10.1016/j.ejmech.2019.111940