ABSTRACT
A series of potent anthranilic acid-based inhibitors of the hepatitis C NS5B polymerase has been identified. The inhibitors bind to a site on NS5B between the thumb and palm regions adjacent to the active site as determined by X-ray crystallography of the enzyme-inhibitor complex. Guided by both molecular modeling and traditional SAR, the enzyme activity of the initial hit was improved by approximately 100-fold, yielding a series of potent and selective NS5B inhibitors with IC50 values as low as 10 nM. These compounds were also inhibitors of the HCV replicon in cultured HUH7 cells.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , ortho-Aminobenzoates/chemical synthesis , Allosteric Regulation , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Cell Line , Crystallography, X-Ray , Hepacivirus/enzymology , Hepacivirus/genetics , Humans , Models, Molecular , Replicon , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry , Virus Replication/drug effects , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacologyABSTRACT
A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery of compound 16, a highly potent and selective inhibitor that is active in the replicon system.
Subject(s)
Antiviral Agents/chemical synthesis , DNA-Directed RNA Polymerases/antagonists & inhibitors , Hepacivirus/enzymology , Indoles/chemical synthesis , Pyrans/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Crystallography, X-Ray , DNA-Directed RNA Polymerases/chemistry , Indoles/chemistry , Pyrans/chemistry , Stereoisomerism , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.