Identification of Phenylisoxazolines as Novel and Viable Antibacterial Agents Active against Gram-Positive Pathogens

Michael R. Barbachyn,*† Gary J. Cleek,† Lester A. Dolak,† Stuart A. Garmon,† Joel Morris,‡ Eric P. Seest,† Richard C. Thomas,† Dana S. Toops,† William Watt,† Donn G. Wishka,† Charles W. Ford,§ Gary E. Zurenko,§ Judith C. Hamel,§ Ronda D. Schaadt,§ Douglas Stapert,§ Betty H. Yagi,§ Wade J. Adams, Janice M. Friis, J. Gregory Slatter, James P. Sams, Nancee L. Oien,§ Matthew J. Zaya, Larry C. Wienkers, and Michael A. Wynalda
Pharmacia Corporation, 7000 Portage Road, Kalamazoo, Michigan 49001
J. Med. Chem., 2003, 46 (2), pp 284–302
DOI: 10.1021/jm020248u
Publication Date (Web): December 13, 2002
Copyright © 2003 American Chemical Society
*

 To whom correspondence should be addressed. Phone:  269-833-7726. Fax:  269-833-9629. E-mail:  michael.r.barbachyn@pharmacia.com.

,
†

 Combinatorial and Medicinal Chemistry; Medicinal Chemistry; Structural, Analytical & Medicinal Chemistry.

,
‡

 Present address:  Pfizer Central Research, Groton, CT.

,
§

 Infectious Diseases Biology.

,

 Global Metabolism and Investigative Sciences.

Abstract

Abstract Image

A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure−activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C−C or N−C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.

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History

  • Published In Issue January 16, 2003
  • Received June 7, 2002

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