Discovery of N-Arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide Derivatives as HCV NS5B Polymerase Inhibitors

• Published in: ChemMedChem 2012-05, Vol.7 (5), p.850-860
• Main 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
• Format: Article
• Language: English
• Subjects: antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Catalytic Domain; Drug Discovery; HCV NS5B polymerase; Hepacivirus; Humans; inhibitors; Models, Molecular; Molecular Structure; Polymerase Chain Reaction; pyrophosphate mimics; Quinazolinones - chemistry; Quinazolinones - pharmacology; Structure-Activity Relationship; structure-activity relationships; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200058

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 (IC50=8.8 μM). Compound 9 k possesses selectivity toward HCV1b replicon Ava.5 cells (EC50=17.5 μM) over parent Huh‐7 cells (CC50=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. Inbuilt pyrophosphate mimic: A β‐N‐hydroxy‐γ‐ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold to yield inhibitors of hepatitis C virus (HCV) NS5B polymerase. N‐phenylpropyl carboxamide 9 k (IC50=8.8 μM) possesses selective cytotoxicity in favor of HCV1b replicon Ava.5 cells (EC50=17.5 μM) over parent Huh‐7 cells (CC50=187.5 μM).