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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Zhao H,Jiang S,Ye Z,Zhu H,Hu B,Meng P,Hu Y,Zhang H,Wang K,Wang J,Tian Ydoi
10.1016/j.ejmech.2021.113567keywords:
["150 cavity","Hydrazide","Influenza A","Neuraminidase inhibitors","Oseltamivir analogues"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113567eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00416-5journal_volume
221pub_type
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