Discovery andsynthesis of novel benzoylhydrazone neuraminidase inhibitors

Abstract

Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC₅₀ = 0.13 μM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC₅₀ = 0.44 μM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.

Keywords: 150-cavity; 430-cavity; Benzoylhydrazone; Neuraminidase inhibitor.