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 describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Quinolones/chemical synthesis , Staphylococcus aureus/drug effects , Thiazoles/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cell Line, Tumor , Drug Resistance, Multiple, Bacterial , Female , Humans , Methicillin Resistance , Mice , Quinolones/chemistry , Quinolones/pharmacology , Staphylococcus aureus/enzymology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Topoisomerase II InhibitorsABSTRACT
We synthesized a diverse series of 9H-isothiazolo[5,4-b]quinoline-3,4-diones containing heteroaromatic groups at the 7-position via palladium-catalyzed cross-coupling. Many of these compounds demonstrated potent antistaphylococcal activity (MICs 2 microg/mL) against a multi-drug-resistant strain (ATCC 700699) and low cytotoxic activity (CC(50)>100 microM) against the human cell line Hep2 (laryngeal carcinoma).
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Azo Compounds/pharmacology , Methicillin Resistance , Quinolones/pharmacology , Staphylococcus aureus/drug effects , Sulfhydryl Compounds/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Azo Compounds/chemical synthesis , Azo Compounds/chemistry , Azo Compounds/toxicity , Cell Line, Tumor , Cyclization , Fluorine/chemistry , Humans , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/toxicity , Staphylococcus aureus/physiology , Structure-Activity RelationshipABSTRACT
This report describes 9H-isothiazolo[5,4-b]quinoline-3,4-diones (ITQs) containing aromatic groups at the 7-position that were prepared using palladium-catalyzed cross-coupling and tested against a panel of susceptible and resistant bacteria. In general, these compounds were more effective against Gram-positive than Gram-negative organisms. Many of the ITQs were more potent than contemporary quinolones and displayed a particularly strong antistaphylococcal activity against a clinically important, multi-drug-resistant strain. In contrast with ITQs reported previously, several of the analogues described in this Letter demonstrated low cytotoxic activity against a human cell line.
