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

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

Journal of medicinal chemistry (2007-01-19)
Qiuping Wang, Edlaine Lucien, Akihiro Hashimoto, Godwin C G Pais, David M Nelson, Yongsheng Song, Jane A Thanassi, Christopher W Marlor, Christy L Thoma, Jijun Cheng, Steven D Podos, Yangsi Ou, Milind Deshpande, Michael J Pucci, Douglas D Buechter, Barton J Bradbury, Jason A Wiles
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Levofloxacin, 98.0-102.0% anhydrous basis (HPLC)
Sigma-Aldrich
Ciprofloxacin, ≥98% (HPLC)
Sigma-Aldrich
Isoquinoline-6-boronic acid pinacol ester, 95%