Isothiazoloquinolones with Enhanced Antistaphylococcal Activities against Multidrug-Resistant Strains:  Effects of Structural Modifications at the 6-, 7-, and 8-Positions

• Published in: Journal of medicinal chemistry Vol. 50; no. 2; pp. 199 - 210
• Main Authors: Wang, Qiuping, Lucien, Edlaine, Hashimoto, Akihiro, Pais, Godwin C. G., Nelson, David M., Song, Yongsheng, Thanassi, Jane A., Marlor, Christopher W., Thoma, Christy L., Cheng, Jijun, Podos, Steven D., Ou, Yangsi, Deshpande, Milind, Pucci, Michael J., Buechter, Douglas D., Bradbury, Barton J., Wiles, Jason A.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25-01-2007
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cell Line, Tumor; Drug Resistance, Multiple, Bacterial; Female; Humans; Medical sciences; Methicillin Resistance; Mice; Pharmacology. Drug treatments; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Topoisomerase II Inhibitors; Rodentia; In vitro; Meticillin; Resistance; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Multiple resistance; Bacteria; Micrococcales; Micrococcaceae; Antibacterial agent; Clinical isolate; Staphylococcus aureus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060844e

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 (7 g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 μg/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.