TY - JOUR
T1 - Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase
AU - Zhao, Hongqian
AU - Jiang, Siyuan
AU - Ye, Zhifan
AU - Zhu, Hongxi
AU - Hu, Baichun
AU - Meng, Peipei
AU - Hu, Yanmei
AU - Zhang, Huicong
AU - Wang, Kuanglei
AU - Wang, Jun
AU - Tian, Yongshou
N1 - Funding Information:
This work was financially supported by National Natural Science Foundation of China ( 81903428 ).
Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2021/10/5
Y1 - 2021/10/5
N2 - 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.
AB - 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.
KW - 150 cavity
KW - Hydrazide
KW - Influenza A
KW - Neuraminidase inhibitors
KW - Oseltamivir analogues
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U2 - 10.1016/j.ejmech.2021.113567
DO - 10.1016/j.ejmech.2021.113567
M3 - Article
C2 - 34082224
AN - SCOPUS:85107036010
SN - 0223-5234
VL - 221
JO - European journal of medicinal chemistry
JF - European journal of medicinal chemistry
M1 - 113567
ER -