TY - JOUR
T1 - Design, in silico studies, synthesis and in vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1
AU - Neri-Bazán, Rocío M.
AU - García-Machorro, Jazmín
AU - Méndez-Luna, David
AU - Tolentino-López, Luis E.
AU - Martínez-Ramos, Federico
AU - Padilla-Martínez, Itzia I.
AU - Aguilar-Faisal, Leopoldo
AU - Soriano-Ursúa, Marvin A.
AU - Trujillo-Ferrara, José G.
AU - Fragoso-Vázquez, M. Jonathan
AU - Barrón, Blanca L.
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Atomic force microscopy
KW - Influenza
KW - Neuraminidase inhibitors
KW - Oseltamivir
KW - π-cation interactions
UR - http://www.scopus.com/inward/record.url?scp=85011629383&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.01.039
DO - 10.1016/j.ejmech.2017.01.039
M3 - Artículo
C2 - 28182988
SN - 0223-5234
VL - 128
SP - 154
EP - 167
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -