Dual targeting of DNA gyrase and topoisomerase IV: target interactions of heteroaryl isothiazolones in Staphylococcus aureus.

Heteroaryl isothiazolones (HITZs) are antibacterial agents that display excellent in vitro activity against Staphylococcus aureus. We recently identified a series of these compounds that show potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA). We report here the results of in vitro resistance studies that reveal potential underlying mechanisms of action.

In vitro and in vivo antibacterial activities of heteroaryl isothiazolones against resistant gram-positive pathogens.

The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibiotic-resistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains.

Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions.

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.

Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells.

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.

Biological evaluation of isothiazoloquinolones containing aromatic heterocycles at the 7-position: In vitro activity of a series of potent antibacterial agents that are effective against methicillin-resistant Staphylococcus aureus.

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).