tetano
Editor, Senior Moderator
Bioorg Med Chem Lett. 2018 Sep 12. pii: S0960-894X(18)30745-5. doi: 10.1016/j.bmcl.2018.09.014. [Epub ahead of print]
[h=1]Design, synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors.[/h] Wang B[SUP]1[/SUP], Wang K[SUP]2[/SUP], Meng P[SUP]1[/SUP], Hu Y[SUP]1[/SUP], Yang F[SUP]1[/SUP], Liu K[SUP]1[/SUP], Lei Z[SUP]1[/SUP], Chen B[SUP]1[/SUP], Tian Y[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC[SUB]50[/SUB] = 1.30 ? 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (LogD = -0.12) is more lipophilic than oseltamivir carboxylate (LogD = -1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.
[h=4]KEYWORDS:[/h] Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 30266543 DOI: 10.1016/j.bmcl.2018.09.014
[h=1]Design, synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors.[/h] Wang B[SUP]1[/SUP], Wang K[SUP]2[/SUP], Meng P[SUP]1[/SUP], Hu Y[SUP]1[/SUP], Yang F[SUP]1[/SUP], Liu K[SUP]1[/SUP], Lei Z[SUP]1[/SUP], Chen B[SUP]1[/SUP], Tian Y[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC[SUB]50[/SUB] = 1.30 ? 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (LogD = -0.12) is more lipophilic than oseltamivir carboxylate (LogD = -1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.
[h=4]KEYWORDS:[/h] Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 30266543 DOI: 10.1016/j.bmcl.2018.09.014