Design, in silico studies, synthesis and in vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1

Rocío M. Neri-Bazán, Jazmín García-Machorro, David Méndez-Luna, Luis E. Tolentino-López, Federico Martínez-Ramos, Itzia I. Padilla-Martínez, Leopoldo Aguilar-Faisal, Marvin A. Soriano-Ursúa, José G. Trujillo-Ferrara, M. Jonathan Fragoso-Vázquez, Blanca L. Barrón, José Correa-Basurto

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Since the neuraminidase (NA) enzyme of the influenza A virus plays a key role in the process of release of new viral particles from a host cell, it is often a target for new drug design. The emergence of NA mutations, such as H275Y, has led to great resistance against neuraminidase inhibitors, including oseltamivir and zanamivir. Hence, we herein designed a set of derivatives by modifying the amine and/or carboxylic groups of oseltamivir. After being screened for their physicochemical (Lipinski's rule) and toxicological properties, the remaining compounds were submitted to molecular and theoretical studies. The docking simulations provided insights into NA recognition patterns, demonstrating that oseltamivir modified at the carboxylic moiety and coupled with anilines had higher affinity and a better binding pose for NA than the derivatives modified at the amine group. Based on these theoretical studies, the new oseltamivir derivatives may have higher affinity to mutant variants and possibly to other viral subtypes. Accordingly, two compounds were selected for synthesis, which together with their respective intermediates were evaluated for their cytotoxicity and antiviral activities. Their biological activity was then tested in cells infected with the A/Puerto Rico/916/34 (H1N1) influenza virus, and virus yield reduction assays were performed. Additionally, by measuring neuraminidase activity with the neuraminidase assay kit it was found that the compounds produced inhibitory activity on this enzyme. Finally, the infected cells were analysed with atomic force microscopy (AFM), observing morphological changes strongly suggesting that these compounds interfered with cellular release of viral particles.

Original languageEnglish
Pages (from-to)154-167
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume128
DOIs
StatePublished - 2017

Keywords

  • Atomic force microscopy
  • Influenza
  • Neuraminidase inhibitors
  • Oseltamivir
  • π-cation interactions

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