title: Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors.
abstract: 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.
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: martacamarasan@gmail.com.
authors.forename: Marta
authors.initials: M
authors.lastname: Camarasa
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: raimonpc@gmail.com.
authors.forename: Raimon
authors.initials: R
authors.lastname: Puig de la Bellacasa
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: alejandro.lopez@iqs.url.edu.
authors.forename: Àlex L
authors.initials: ÀL
authors.lastname: González
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: raulondonom@iqs.url.edu.
authors.forename: Raül
authors.initials: R
authors.lastname: Ondoño
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: roger.estrada@iqs.url.edu.
authors.forename: Roger
authors.initials: R
authors.lastname: Estrada
authors.affiliation: Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. Electronic address: sfranco@irsicaixa.es.
authors.forename: Sandra
authors.initials: S
authors.lastname: Franco
authors.affiliation: Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. Electronic address: rbadia@irsicaixa.es.
authors.forename: Roger
authors.initials: R
authors.lastname: Badia
authors.affiliation: Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. Electronic address: jaeste@irsicaixa.es.
authors.forename: José
authors.initials: J
authors.lastname: Esté
authors.affiliation: Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. Electronic address: MMartinez@irsicaixa.es.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Martínez
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: jordi.teixido@iqs.url.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixidó
authors.affiliation: Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. Electronic address: bclotet@irsicaixa.es.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain. Electronic address: j.i.borrell@iqs.url.edu.
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000187:drug effects*; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines
keywords: HCV genotype 1b replicon; Hepatitis C; Pyrido[2,3-d]pyrimidin-7-(8H)-ones; Small molecule inhibitor