TY - JOUR
T1 - Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors
AU - Camarasa, Marta
AU - De La Bellacasa, Raimon Puig
AU - González, Àlex L.
AU - Ondoño, Raül
AU - Estrada, Roger
AU - Franco, Sandra
AU - Badia, Roger
AU - Esté, José
AU - Martínez, Miguel Ángel
AU - Teixidó, Jordi
AU - Clotet, Bonaventura
AU - Borrell, José I.
N1 - Funding Information:
Financial support by the Spanish Ministerio de Economia y Competividad project SAF2010-C21617-C02 is greatly acknowledged. M. Camarasa wants to thank IQS for a scholarship. R. Puig de la Bellacasa wants to thank Generalitat de Catalunya for a grant within the Talent empresa (TEM) 2009 program ( 2009 TEM 00128 ).
Publisher Copyright:
© 2016 Elsevier Masson SAS. All rights reserved.
PY - 2016/6/10
Y1 - 2016/6/10
N2 - 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.
AB - 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.
KW - HCV genotype 1b replicon
KW - Hepatitis C
KW - Pyrido[2,3-d]pyrimidin-7-(8H)-ones
KW - Small molecule inhibitor
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UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000375360800040&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1016/j.ejmech.2016.03.055
DO - 10.1016/j.ejmech.2016.03.055
M3 - Article
C2 - 27054294
AN - SCOPUS:84962384885
SN - 0223-5234
VL - 115
SP - 463
EP - 483
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -
