2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid with inbuilt β-N-hydroxy-γ-keto-acid pharmacophore as HCV NS5B polymerase inhibitors.
The inbuilt 2-N-hydroxy-1-oxo-3-carboxylic acid of isoquinolone was designed as pyrophosphate mimic for hepatitis C NS5B polymerase. Various 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives 11a-p were synthesized and evaluated as HCV NS5B polymerase inhibitors. Compound 11c exhibited moderate inhibitory potency based on the inorganic pyrophosphate generation (IC₅₀ = 9.5 μM) and based on NTP incorporation by NS5B enzyme (IC₅₀ = 5.9 μM). Compound 11c demonstrated antiviral activity (EC₅₀ = 15.7 μM) and good selectivity in HCV genotype 1b replicon Ava.5 cells. Compound 11c reduced the interaction of NTP to NS5B polymerase. Docking model showed that 11c situated in similar orientation to the bound uridine triphosphate in the active site of NS5B polymerase. As a result, 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was disclosed as a novel inbuilt β-N-Hydroxy-γ-keto-acid pharmacophore for HCV NS5B polymerase inhibitors.
School of Pharmacy, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 10051, Taiwan, ROC.
R R
RR
Deore
G S
GS
Chen
C-S
CS
Chen
P-T
PT
Chang
M-H
MH
Chuang
T-R
TR
Chern
H-C
HC
Wang
J-W
JW
Chern
D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007651:Keto Acids; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D007651:Keto Acids; D017361:Viral Nonstructural Proteins; C574950:2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid; C574951:beta-N-hydroxy-gamma-keto-acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase