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

Abstract

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.

Keywords: 150-cavity; H5N1; anti-flu drugs; neuraminidase inhibitor; sulfamethazine derivatives; virtual screening.

Figure 1.

The lead compound discovery process by way of structure-based virtual screening. MD: Molecular dynamics.

Figure 2.

The chemical structures of Data set 4 and the lead compound 5.

Figure 3.

Binding mode of lead compound 5 (ZINC670537) with neuraminidase (Protein Data Bank ID: 2HU0).

Figure 4.

Synthesis of target compounds X1–X10. Reagents and conditions: (A) Chloroacetyl chloride, K₂CO₃, DMF, 0°C, 1.5 h; (B) K₂CO₃, DMF, 60°C, 10 h; (C) K₂CO₃, DMF, rt, 6 h; (D) KOH, ethanol, rt, 4 h; (E) DMF, 1-hydroxybenzotriazole,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, rt, 6 h. rt: Room temperature.

Figure 5.

Binding modes of some representative compounds X3, X4, X6 and X10 with neuraminidase (Protein Data Bank: 2HU0).