With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC50 values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.
Bibliographical noteFunding Information:
We gratefully acknowledge financial support from National Basic Research Program of China (Grants 2009CB918502 and 2012CB518005 ), the National Natural Science Foundation of China (Grants 20721003 and 81025017 ), National S&T Major Projects (2012ZX09103-101-072), Silver Project (260644), the R&D Program of MKE/KEIT (10031969), Translational Research Center for Protein Function Control, NSF ( 2011-0001244 ) and a grant from the Korea Healthcare Technology R&D project, Ministry for Health, Welfare Family Affairs, Republic of Korea ( A085105 ).
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry