Design, synthesis and biological evaluation of oxalamide derivatives as potent neuraminidase inhibitors

Abstract

Neuraminidase (NA) is an effective target for research and development of anti-influenza drugs. Herein, based on structure-based virtual screening, it was found that ZINC05250774, an oxalamide derivative, was a lead NA inhibitor. In this paper, a series of novel inhibitors (Z1–Z10) were designed and synthesized through modification and transformation of ZINC05250774. From the inhibition results, compound Z2 had the best inhibitory activity against NA (IC₅₀ = 0.09 μM), which was better than that of the positive control oseltamivir carboxylate (OSC) (IC₅₀ = 0.10 μM) and lead ZINC05250774 (IC₅₀ = 1.91 μM). Molecular docking results indicate that the good potency of Z2 may be attributed to the 3-chloro-substituted phenyl, which can be extended into the 430-cavity by the oxalamide chain. Furthermore, the oxalamide group is also important for this series of compounds, which can form strong hydrogen bond interactions with the three essential positively charged arginine residues (Arg118, Arg292, and Arg371) at the active site. The results of this work may contribute to developing more potent NA inhibitors to fight the influenza virus.