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.

Ligand-Based Drug Design of Novel Antimicrobials against Staphylococcus aureus by Targeting Bacterial Transcription

“…Finally, four compounds, J098-0498, 1067-0401, M013-0558, and F186-0261 displayed acceptable parameters in the ADME/T calculation (Figure 7). The values of the Qikprop descriptors for the four hit compounds were depicted in Table 6 and all of them fell in the standard range of parameters [49,50]. The aqueous solubility (QPlogS) of these compounds was predicted satisfactory and the percentages of oral absorption very high (80%).…”

“…Results revealed that all the molecules were druggable without any violation of Lipinski's rule of five (Table S2). The values of the Qikprop descriptors for the four hit compounds were depicted in Table 6 and all of them fell in the standard range of parameters [49,50]. The aqueous solubility (QPlogS) of these compounds was predicted satisfactory and the percentages of oral absorption very high (>80%).…”