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

• Published in: European journal of medicinal chemistry 2016-06, Vol.115, p.463-483
• Main Authors: Camarasa, Marta, Puig de la Bellacasa, Raimon, González, Àlex L., Ondoño, Raül, Estrada, Roger, Franco, Sandra, Badia, Roger, Esté, José, Martínez, Miguel Ángel, Teixidó, Jordi, Clotet, Bonaventura, Borrell, José I.
• Format: Article
• Language: English
• Subjects: Drug Design; Drug Evaluation, Preclinical; HCV genotype 1b replicon; Hepacivirus - drug effects; Hepatitis C; Molecular Docking Simulation; Pyrido[2,3-d]pyrimidin-7-(8H)-ones; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Small molecule inhibitor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.03.055

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. [Display omitted] •New pyrido[2,3-d]pyrimidin-7-(8H)-ones are active against HCV genotype 1b replicon.•21{4,10} and 24{2,10} presented very high activities against HCV genotype 1b replicon.•21{4,10} and 24{2,10} presented very good selectivity indexes.•Computational studies suggest that 21{4,10} and 24{2,10} can potentially inhibit NS5B polymerase.•21{4,10} and 24{2,10} are likely to interact with RNA riboses of the primer strand.