Inhibition of Influenza Virus Replication by Oseltamivir Derivatives

Characterized by the high morbidity and mortality and seasonal surge, the influenza virus (IV) remains a major public health challenge. Oseltamivir is commonly used as a first-line antiviral. As a neuraminidase inhibitor, it attenuates the penetration of viruses through the mucus on the respiratory tract and inhibits the release of virus progeny from infected cells. However, over the years, oseltamivir-resistant strains have been detected in the IV surveillance programs. Therefore, new antivirals that circumvent the resistant strains would be of great importance. In this study, two novel secondary amine derivatives of oseltamivir CUHK326 (6f) and CUHK392 (10i), which bear heteroaryl groups of M2-S31 proton channel inhibitors, were designed, synthesized and subjected to biological evaluation using plaque assay. Influenza A virus (A/Oklahoma/447/2008, H1N1), influenza B viruses (B/HongKong/CUHK33261/2012), an oseltamivir-resistant influenza A virus (A/HongKong/CUHK71923/2009, H1N1) and an oseltamivir-resistant influenza B virus (B/HongKong/CUHK33280/2012) were included in the antiviral effect assessment compared to oseltamivir carboxylate (OC). Both novel compounds significantly reduced the plaque size of seasonal IV A and B, and performed similarly to OC at their corresponding half-maximal inhibitory concentration (IC₅₀). CUHK392 (10i) functioned more effectively than CUHK326 (6f). More importantly, these compounds showed an inhibitory effect on the oseltamivir-resistant strain under 10 nM with selective index (SI) of >200.