Elaborate Structural Modifications Yielding Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Potent Neuraminidase Inhibitors with Significantly Improved Broad-Spectrum Antiresistance Profiles.

Autor:	Zhang J; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Jia R; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Jia H; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Li P; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Jiang Y; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Bonomini A; Department of Molecular Medicine, University of Padua, Via Gabelli 63, Padua 35121, Italy., Bertagnin C; Department of Molecular Medicine, University of Padua, Via Gabelli 63, Padua 35121, Italy., Xu Q; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Tan Z; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Ma X; Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 202 North Gongye Road, Jinan, Shandong 250100, China., Loregian A; Department of Molecular Medicine, University of Padua, Via Gabelli 63, Padua 35121, Italy., Huang B; Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 202 North Gongye Road, Jinan, Shandong 250100, China., Liu X; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China., Zhan P; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, P. R. China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 26; Vol. 67 (24), pp. 22191-22217. Date of Electronic Publication: 2024 Dec 07.
DOI:	10.1021/acs.jmedchem.4c02222
Abstrakt:	Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure-activity relationship (SAR) studies led to the identification of compounds 27c and 33c as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC 50 = 0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively). Additionally, these compounds did not exhibit significant toxicity (CC 50 > 200 μM in CEF cells; CC 50 > 250 μM in MDCK cells). These findings highlight 27c and 33c as promising next-generation anti-influenza agents.
Databáze:	MEDLINE
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