Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies

• Published in: European journal of medicinal chemistry 2019-11, Vol.182, p.111635-111635, Article 111635
• Main Authors: Ye, Jiqing, Yang, Xiao, Xu, Min, Chan, Paul Kay-sheung, Ma, Cong
• Format: Article
• Language: English
• Subjects: 150-cavity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Computer Simulation; Derivative; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Influenza virus; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Neuraminidase; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; Orthomyxoviridae - drug effects; Orthomyxoviridae - enzymology; Oseltamivir; Oseltamivir - chemical synthesis; Oseltamivir - chemistry; Oseltamivir - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111635

The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents. [Display omitted] •Hybridization of oseltamivir with heteroaryl groups generated novel anti-influenza agents.•Compound 6f and 10i displayed IC50 values at nM level against neuraminidase of a clinical isolate.•In silico ADME predictions showed that 6f and 10i had comparable properties with oseltamivir.•Molecular docking studies showed 6f and 10i adopted different binding modes with neuraminidase.