ABSTRACT
An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1'-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.
Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Ferrous Compounds/pharmacology , Hepacivirus/drug effects , Metallocenes/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Cell Line, Tumor , Ferrous Compounds/chemical synthesis , Ferrous Compounds/chemistry , Ferrous Compounds/pharmacokinetics , Humans , Macaca fascicularis , Male , Metallocenes/chemical synthesis , Metallocenes/chemistry , Metallocenes/pharmacokinetics , Microsomes, Liver/metabolism , Molecular Structure , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Organoselenium Compounds/chemical synthesis , Piperidines/chemical synthesis , Quinolines/chemical synthesis , Staphylococcus aureus/drug effects , Topoisomerase II Inhibitors/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cell Line, Tumor , DNA Topoisomerase IV/antagonists & inhibitors , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/enzymology , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Staphylococcus aureus/enzymology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacologyABSTRACT
A novel 5,4-dialkyl substituted thiophene was discovered by in silico screening of the 3D polymerase crystal structure (1GX6) that demonstrated single digit micromolar HCV inhibition activity in the replicon assay and dose-dependent inhibition in the replicase complex assay. Subsequently, SAR was explored with a small set of dialkyl and tetrahydro-benzo thiophenes. Since these thiophenes inhibit synthesis of both, single- and double-stranded RNAs, their mechanism of action is distinct from other known HCV inhibitors.
Subject(s)
Hepacivirus/drug effects , Thiophenes/pharmacology , Viral Nonstructural Proteins/drug effects , Hepacivirus/enzymology , Models, Biological , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
Bacterial primase is essential for DNA replication in Gram-positive and Gram-negative bacteria. It is also structurally distinct from eukaryotic primases, and therefore an attractive, but under-explored, target for therapeutic intervention. We applied virtual screening to discover primase inhibitors, and subsequently several commercially available analogs of these initial hits showed potent primase inhibition and in vitro antibacterial activity. This work provides a 3D pharmacophore for primase ligands, SAR trends, and leads that can be further optimized.
