Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors

Marta Camarasa, Raimon Puig De La Bellacasa, Àlex L. González, Raül Ondoño, Roger Estrada, Sandra Franco, Roger Badia, José Esté, Miguel Ángel Martínez, Jordi Teixidó, Bonaventura Clotet, José I. Borrell

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10 Citations (Scopus)

Abstract

© 2016 Elsevier Masson SAS. All rights reserved. The design and selection of a combinatorial library of pyrido[2,3-d]pyrimidin-7(8H)-ones (4) has allowed the synthesis of 121 compounds, using known and new synthetic methodologies, and the evaluation of the inhibitory activity against hepatitis C virus (HCV) genotype 1b replicon. Among these compounds, 21{4,10} and 24{2,10} presented very high activities [EC50 = 0.027 μM (CC50 = 5.3 μM) and EC50 = 0.034 μM (CC50 = 13.5 μM), respectively] and high selectivity indexes, 196 and 397. These values are similar to the EC50 reported for sofosbuvir (2) (0.048 μM) using a similar methodological approach and the same virus subtype. 21{4,10} and 24{2,10} are obtained through shorter synthetic itineraries than sofosbuvir and 24{2,10} is achiral contrary to sofosbuvir which presents 4 stereogenic centers. In silico studies suggest that 21{4,10} and 24{2,10} inhibits NS5B polymerase through allosteric site binding.
Original languageEnglish
Pages (from-to)463-483
JournalEuropean Journal of Medicinal Chemistry
Volume115
DOIs
Publication statusPublished - 10 Jun 2016

Keywords

  • HCV genotype 1b replicon
  • Hepatitis C
  • Pyrido[2,3-d]pyrimidin-7-(8H)-ones
  • Small molecule inhibitor

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