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Discovery of N ‐Arylalkyl‐3‐hydroxy‐4‐oxo‐3,4‐dihydroquinazolin‐2‐carboxamide Derivatives as HCV NS5B Polymerase Inhibitors
Author(s) -
Deore Ravindra Ramesh,
Chen Grace Shiahuy,
Chang PeiTeh,
Chern TingRong,
Lai ShinYu,
Chuang MingHsieh,
Lin JungHsin,
Kung FanLu,
Chen ChienShu,
Chiou ChunTang,
Chern JiWang
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200058
Subject(s) - carboxamide , chemistry , ns5b , pharmacophore , stereochemistry , quinazolinone , active site , polymerase , binding site , enzyme , biochemistry , hepacivirus , gene , genotype
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 μ M ). Compound 9 k possesses selectivity toward HCV1b replicon Ava.5 cells (EC 50 =17.5 μ M ) over parent Huh‐7 cells (CC 50 =187.5 μ M ). 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.