tetano
Editor, Senior Moderator
Eur J Med Chem
. 2021 May 23;221:113567.
doi: 10.1016/j.ejmech.2021.113567. Online ahead of print.
Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase
Hongqian Zhao[SUP] 1 [/SUP], Siyuan Jiang[SUP] 1 [/SUP], Zhifan Ye[SUP] 1 [/SUP], Hongxi Zhu[SUP] 1 [/SUP], Baichun Hu[SUP] 2 [/SUP], Peipei Meng[SUP] 1 [/SUP], Yanmei Hu[SUP] 3 [/SUP], Huicong Zhang[SUP] 4 [/SUP], Kuanglei Wang[SUP] 5 [/SUP], Jun Wang[SUP] 6 [/SUP], Yongshou Tian[SUP] 7 [/SUP]
Affiliations
Abstract
Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound 12 disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound 17a showed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1-H274Y, H1N1-H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stability in vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.
Keywords: 150 cavity; Hydrazide; Influenza A; Neuraminidase inhibitors; Oseltamivir analogues.
. 2021 May 23;221:113567.
doi: 10.1016/j.ejmech.2021.113567. Online ahead of print.
Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase
Hongqian Zhao[SUP] 1 [/SUP], Siyuan Jiang[SUP] 1 [/SUP], Zhifan Ye[SUP] 1 [/SUP], Hongxi Zhu[SUP] 1 [/SUP], Baichun Hu[SUP] 2 [/SUP], Peipei Meng[SUP] 1 [/SUP], Yanmei Hu[SUP] 3 [/SUP], Huicong Zhang[SUP] 4 [/SUP], Kuanglei Wang[SUP] 5 [/SUP], Jun Wang[SUP] 6 [/SUP], Yongshou Tian[SUP] 7 [/SUP]
Affiliations
- PMID: 34082224
- DOI: 10.1016/j.ejmech.2021.113567
Abstract
Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound 12 disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound 17a showed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1-H274Y, H1N1-H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stability in vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.
Keywords: 150 cavity; Hydrazide; Influenza A; Neuraminidase inhibitors; Oseltamivir analogues.