Discovery of novel acylhydrazone neuraminidase inhibitors

• Published in: European journal of medicinal chemistry 2019-07, Vol.173, p.305-313
• Main Authors: Zhao, Zhi Xiang, Cheng, Li Ping, Li, Meng, Pang, Wan, Wu, Fan Hong
• Format: Article
• Language: English
• Subjects: 430-Loop; Acylhydrazone; Neuraminidase inhibitor; Virtual screening
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.04.006

Neuraminidase (NA) plays a crucial role in the replication and transmission of influenza virus. NA inhibitors have been developed as effective treatments for influenza A and B infections. In this paper, a new lead neuraminidase inhibitor 6a (IC50 = 7.10 ± 0.2 μM) was discovered by ligand-based virtual screening, receptor-based virtual screening, molecular dynamics simulation (MD), and bioassay validation. MD simulation indicates that the morpholinyl group of 6a could be embedded in 430-loop of NA. To exploit the 430-loop in the active site, a series of novel acylhydrazone NA inhibitors 6b-6g were designed and synthesized based on the lead compound 6a. Compound 6e exerts the most potency, with IC50 value of 2.37 ± 0.5 μM against NA, which is lower than that of oseltamivir carboxylate (OC) (IC50 = 3.84 μM). Overall, this work provided unique insights in the discovery of potent inhibitors against NA. A series of novel acylhydrazone neuraminidase inhibitors were designed and synthesized based on virtual screening. [Display omitted] •Discovery of novel acylhydrazone neuraminidase (NA) inhibitors targeting 430-loop based on virtual screening.•The synthesized inhibitors show excellent inhibitory activity against NA.•430-loop plays an important role in discovery of novel acylhydrazone NA inhibitors.•This work provides unique insights in the discovery of potent inhibitors against NA.