909192-02-5Relevant academic research and scientific papers
Discovery of N-Arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide Derivatives as HCV NS5B Polymerase Inhibitors
Deore, Ravindra Ramesh,Chen, Grace Shiahuy,Chang, Pei-Teh,Chern, Ting-Rong,Lai, Shin-Yu,Chuang, Ming-Hsieh,Lin, Jung-Hsin,Kung, Fan-Lu,Chen, Chien-Shu,Chiou, Chun-Tang,Chern, Ji-Wang
, p. 850 - 860 (2012/07/14)
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 hepatitisC virus (HCV) NS5B polymerase inhibitors. Lead optimization led to the identification of N-phenylpropyl carboxamide 9k (IC50=8.8μM). Compound 9k possesses selectivity toward HCV1b replicon Ava.5 cells (EC50=17.5μM) over parent Huh-7 cells (CC50=187.5μM). Compound 9k effects a mixed mode of NS5B inhibition, with NTP-competitive displacement properties. The interaction between 9k and NS5B is stabilized by the presence of magnesium ions. Docking studies showed that the binding orientation of 9k 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.
