title: Discovery of N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as HCV NS5B polymerase inhibitors.
abstract: The metal ion chelating β-N-hydroxy-γ-ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold, leading to N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as hepatitis C virus (HCV) NS5B polymerase inhibitors. Lead optimization led to the identification of N-phenylpropyl carboxamide 9 k (IC(50) =8.8 μM). Compound 9 k possesses selectivity toward HCV1b replicon Ava.5 cells (EC(50) =17.5 μM) over parent Huh-7 cells (CC(50) =187.5 μM). Compound 9 k effects a mixed mode of NS5B inhibition, with NTP-competitive displacement properties. The interaction between 9 k and NS5B is stabilized by the presence of magnesium ions. Docking studies showed that the binding orientation of 9 k occupies the central portions of both magnesium-mediated and NTP-ribose-response binding sites within the active site region of NS5B. As a result, 3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives are disclosed herein as novel, mainly active site inhibitors of HCV NS5B polymerase.
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Ravindra Ramesh
authors.initials: RR
authors.lastname: Deore
authors.forename: Grace Shiahuy
authors.initials: GS
authors.lastname: Chen
authors.forename: Pei-Teh
authors.initials: PT
authors.lastname: Chang
authors.forename: Ting-Rong
authors.initials: TR
authors.lastname: Chern
authors.forename: Shin-Yu
authors.initials: SY
authors.lastname: Lai
authors.forename: Ming-Hsieh
authors.initials: MH
authors.lastname: Chuang
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.forename: Fan-Lu
authors.initials: FL
authors.lastname: Kung
authors.forename: Chien-Shu
authors.initials: CS
authors.lastname: Chen
authors.forename: Chun-Tang
authors.initials: CT
authors.lastname: Chiou
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D055808:Drug Discovery; D016174:Hepacivirus; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D016133:Polymerase Chain Reaction; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D052999:Quinazolinones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase