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

作者：Camarasa Marta; Puig de la Bellacasa Raimon; Gonzalez Alex L; Ondono Raul; Estrada Roger; Franco Sandra; Badia Roger; Este Jose; Angel Martinez Miguel; Teixido Jordi; Clotet Bonaventura; Borrell Jose I^*

来源：European Journal of Medicinal Chemistry, 2016, 115: 463-483.

DOI：10.1016/j.ejmech.2016.03.055

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

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 mu M (CC50 = 5.3 mu M) and EC50 = 0.034 mu M (CC50 = 13.5 mu M), respectively] and high selectivity indexes, 196 and 397. These values are similar to the EC50 reported for sofosbuvir (2) (0.048 mu M) 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.

• 出版日期2016-6-10