Discovery of N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as HCV NS5B polymerase inhibitors |
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Authors: | 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 |
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Affiliation: | School of Pharmacy, National Taiwan University, Taipei, Taiwan, ROC. |
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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. |
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Keywords: | antiviral agents HCV NS5B polymerase inhibitors pyrophosphate mimics structure–activity relationships |
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