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Eur J Med Chem. 2019 May 30;178:64-80. doi: 10.1016/j.ejmech.2019.05.076. [Epub ahead of print]
Design, synthesis and biological evaluation of "Multi-Site"-binding influenza virus neuraminidase inhibitors.
Jia R1, Zhang J1, Ai W1, Ding X1, Desta S1, Sun L1, Sun Z1, Ma X2, Li Z1, Wang D1, Huang B3, Zhan P4, Liu X5.
Author information
Abstract
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-NH2 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 EC50 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.
KEYWORDS:
150-Cavity; 430-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 31176096 DOI: 10.1016/j.ejmech.2019.05.076
Design, synthesis and biological evaluation of "Multi-Site"-binding influenza virus neuraminidase inhibitors.
Jia R1, Zhang J1, Ai W1, Ding X1, Desta S1, Sun L1, Sun Z1, Ma X2, Li Z1, Wang D1, Huang B3, Zhan P4, Liu X5.
Author information
Abstract
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-NH2 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 EC50 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.
KEYWORDS:
150-Cavity; 430-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives
PMID: 31176096 DOI: 10.1016/j.ejmech.2019.05.076