Nursing

Biology

Oseltamivir

Virology

Neuraminidase

Zanamivir

Biochemistry

Potency

Docking (animal)

Coronavirus disease 2019 (COVID-19)

Stereochemistry

Structure–activity relationship

In vitro

Orthomyxoviridae

Enzyme

Influenza A virus subtype H5N1

Infectious disease (medical specialty)

Pharmacology

Medicine

Chemistry

Virus

Influenza A virus

Neuraminidase inhibitor

Disease

Pathology

European Journal of Medicinal Chemistry

From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5-NH2 position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5-NH2 position of oseltamivir. All the compounds were evaluated for in vitro antiviral activity against H5N1 and H5N8. Encouragingly, compounds 9a and 11e were exhibited prominent activity, which is similar to oseltamivir carboxylate (OSC) and in NAs inhibitory assay, 11e showed remarkable potency against N1 (H5N1), N2 (H5N2), N6 (H5N6) and N8 (H5N8). In addition, 11e demonstrated low cytotoxicity and no obvious toxicity at the dose of 1500 mg/kg in mice. Molecular docking studies of 9a and 11e provided a plausible rationale for the high potency against group-1 NAs. This work provided new insights to design further neuraminidase inhibitors, which can help to investigate new potent inhibitors for group-1 and group-2 shortly.

Discovery of novel “Dual-site” binding oseltamivir derivatives as potent influenza virus neuraminidase inhibitors