tetano
Editor, Senior Moderator
Eur J Med Chem. 2019 May 30;178:64-80. doi: 10.1016/j.ejmech.2019.05.076. [Epub ahead of print]
[h=1]Design, synthesis and biological evaluation of "Multi-Site"-binding influenza virus neuraminidase inhibitors.[/h] Jia R[SUP]1[/SUP], Zhang J[SUP]1[/SUP], Ai W[SUP]1[/SUP], Ding X[SUP]1[/SUP], Desta S[SUP]1[/SUP], Sun L[SUP]1[/SUP], Sun Z[SUP]1[/SUP], Ma X[SUP]2[/SUP], Li Z[SUP]1[/SUP], Wang D[SUP]1[/SUP], Huang B[SUP]3[/SUP], Zhan P[SUP]4[/SUP], Liu X[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH[SUB]2[/SUB] of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC[SUB]50[/SUB] of 0.66 μM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] 150-Cavity; 430-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 31176096 DOI: 10.1016/j.ejmech.2019.05.076
[h=1]Design, synthesis and biological evaluation of "Multi-Site"-binding influenza virus neuraminidase inhibitors.[/h] Jia R[SUP]1[/SUP], Zhang J[SUP]1[/SUP], Ai W[SUP]1[/SUP], Ding X[SUP]1[/SUP], Desta S[SUP]1[/SUP], Sun L[SUP]1[/SUP], Sun Z[SUP]1[/SUP], Ma X[SUP]2[/SUP], Li Z[SUP]1[/SUP], Wang D[SUP]1[/SUP], Huang B[SUP]3[/SUP], Zhan P[SUP]4[/SUP], Liu X[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH[SUB]2[/SUB] of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC[SUB]50[/SUB] of 0.66 μM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] 150-Cavity; 430-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 31176096 DOI: 10.1016/j.ejmech.2019.05.076