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

Aim: The purpose of this study is to design and synthesize a new series of sulfamethazine derivatives as potent neuraminidase inhibitors. Materials & methods: A sulfamethazine lead compound, ZINC670537, was first identified by structure-based virtual screening technique, then some novel inhibitors X1–X10 based on ZINC670537 were designed and synthesized. Results: Compound X3 exerts the most good potency in inhibiting the wild-type H5N1 NA (IC50 = 6.74 μM) and the H274Y mutant NA (IC50 = 21.09 μM). 150-cavity occupation is very important in determining activities of these inhibitors. The sulfamethazine moiety also plays an important role. Conclusion: Compound X3 maybe regard as a good anti-influenza candidate to preform further study. A series of novel sulfamethazine neuraminidase inhibitors were designed and synthesized. A novel lead compound ZINC670537 was screened out by means of structure-based virtual screening, molecular dynamic simulation and bioactivity test. A series of novel sulfamethazine neuraminidase inhibitors were designed and synthesized. Compound X3 has the best inhibitory activity, and its activity inhibiting the H274Y mutant NA is comparable to that of OSC. Molecular docking studies have shown that the 150-cavity plays an important role in discovery of novel sulfamethazine NA inhibitors. The sulfamethazine moiety interacts tightly with three key residues (Arg118, Arg292, Arg371) by forming hydrogen bondings, which is beneficial to improve activity of compound. The results of this work provide new insights into the design of more potent NA inhibitors.