Design, Synthesis, Biological Evaluation and In Silico Studies of Pyrazole-Based NH₂-Acyl Oseltamivir Analogues as Potent Neuraminidase Inhibitors

Abstract

Oseltamivir represents one of the most successful neuraminidase (NA) inhibitors in the current anti-influenza therapy. The 150-cavity of NA was identified as an additional binding pocket, and novel NA inhibitors have been designed to occupy the 150-cavity based on the structure information of oseltamivir carboxylate (OC) in complex with NA. In this study, a series of C-5-NH2-acyl derivatives of OC containing the pyrazole moiety were synthesized. Several derivatives exhibited substantial inhibitory activity against NA. Moreover, in silico ADME evaluation indicated that the derivatives were drug-like with higher oral absorption rates and greater cell permeability than OC. Additionally, molecular docking studies revealed that the derivatives interacted with both the NA enzyme active site and 150-cavity as expected. The results provided useful information for further structural optimization of OC.

Keywords

• influenza virus
• neuraminidase inhibitor
• 150-cavity
• oseltamivir derivatives
• pyrazole