Elaborate Structural Modifications Yielding Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Potent Neuraminidase Inhibitors with Significantly Improved Broad-Spectrum Antiresistance Profiles
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 <b>27c</b> and <b>33c</b> 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<sub>50</sub> = 0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively). Additionally, these compounds did not exhibit significant toxicity (CC<sub>50</sub> > 200 μM in CEF cells; CC<sub>50</sub> > 250 μM in MDCK cells). These findings highlight <b>27c</b> and <b>33c</b> as promising next-generation anti-influenza agents.
Authors
- Arianna Loregian (ORCID: https://orcid.org/0000-0002-8900-861X)
- Huinan Jia (ORCID: https://orcid.org/0009-0005-3362-2150)
- Ruifang Jia (ORCID: https://orcid.org/0000-0001-6761-2085)
- Yuanmin Jiang
- Xinyong Liu (ORCID: https://orcid.org/0000-0002-7302-2214)
- Anna Bonomini (ORCID: https://orcid.org/0000-0001-9022-9551)
- Chiara Bertagnin (ORCID: https://orcid.org/0000-0003-2985-3392)
- Peng Zhan (ORCID: https://orcid.org/0000-0002-9675-6026)
- Zhou Tan (ORCID: https://orcid.org/0000-0003-0235-0306)
- Ping Li (ORCID: https://orcid.org/0000-0001-6328-036X)
- Xiuli Ma
- Bing Huang (ORCID: https://orcid.org/0000-0003-4424-1079)
- Q. Xu
- Jiwei Zhang
Institutions
- University of Padua (IT)
- Shandong University (CN)
- Shandong Academy of Agricultural Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02222
- Citations
- 4
- Primary Topic
- Travel-related health issues
- Type
- article
- Field-Weighted Citation Impact
- 2.17
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Natural Science Foundation of Shandong Province
- Ministero dell'Università e della Ricerca
- Key Technology Research and Development Program of Shandong
- Natural Science Fund for Distinguished Young Scholars of Shandong Province