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

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, and Jason A. Wiles*
Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, Connecticut 06511
J. Med. Chem., 2007, 50 (2), pp 199–210
DOI: 10.1021/jm060844e
Publication Date (Web): December 20, 2006
Copyright © 2007 American Chemical Society
*

 To whom correspondence should be addressed. Telephone:  203-624-7000. Fax:  203-752-5454. E-mail:  jwiles@achillion.com.

Abstract

Abstract Image

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 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.

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History

  • Published In Issue January 25, 2007
  • Received July 19, 2006

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