Discovery of a non-zwitterionic oseltamivir analogue as a potent influenza a neuraminidase inhibitor

The most of potent neuraminidase inhibitors as zwitterions with poor lipophilicity suffered from the poor oral bioavailability. Herein, we describe a rational journey to discover a non-zwitterionic neuraminidase inhibitor 24a containing urea. It showed potent inhibitions against neuraminidases from group 1(H5N1 and H1N1) and group 2 (H3N2) subtypes and exhibited more strong inhibitory activities against neuraminidases from H274Y mutants than oseltamivir carboxylate. Whether administrated by orally or intravenous injection, the pharmacokinetic profile of compound 24a in SD rats were improved compared to oseltamivir carboxylate. [Display omitted] •Oseltamivir analogues containing thiourea or urea were designed and synthesized.•Compound 24a as a non-zwitterionic inhibitor showed potent activities against wild-type and H274Y mutant neuraminidases.•Compound 24a showed high metabolic stability in liver microsomes and plasma in vitro.•The oral bioavailability of 24a was 8.8% in rats.