Oxazolidinonas

Bioorganic & Medicinal Chemistry 20 (2012) 3422–3428

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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc

Syntheses and biological studies of novel spiropiperazinyl oxazolidinone antibacterial agents using a spirocyclic diene derived acylnitroso DielsÀAlder reaction
Cheng Ji a, Weimin Lin a, Garrett C. Moraskia, Jane A. Thanassi b, Michael J. Pucci b, Scott G. Franzblau c, Ute Möllmann d, Marvin J. Miller a,⇑
a

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA d LeibnizInstitute for Natural Product Research and Infection Biology, Hans Knoell Institute, Beutenbergstrasse 11a, 07745 Jena, Germany
b c

a r t i c l e

i n f o

a b s t r a c t
Several novel oxazolidinone antibiotics with a spiropiperazinyl substituent at the 40 -position of the phenyl ring were synthesized through nitroso Diels–Alder chemistry and the in vitro antibacterial activities wereevaluated against various Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and mycobacteria (Mycobacterium vaccae, Mycobacterium tuberculosis). Analogs (8a and 12) were active against selected drug resistant microbes, like methicillin-resistant Staphylococcus aureus (MRSA) andvancomycin-resistant enterococci (VRE) and had no mammalian toxicity in a Hep-2 cellular assay (CC50 >100 lM). Ó 2012 Elsevier Ltd. All rights reserved.

Article history: Received 15 February 2012 Revised 3 April 2012 Accepted 9 April 2012 Available online 18 April 2012 Keywords: Oxazolidinone Antibiotics Nitroso DielsÀAlder reaction Spirocyclic diene MRSA

1. Introduction The rate of antimicrobial resistancehas increased dramatically in the past few decades due to the misuse and overuse of antibiotics.1,2 Infections caused by resistant organisms such as methicillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP) are often extremely difficult to treat. Therefore, efforts towards the discovery of new antibiotics areof great significance. The oxazolidinones are a class of wholly synthetic, orally active antibiotics that has excellent activity against a variety of susceptible and resistant Gram-positive bacteria.3–6 Targeting bacterial protein synthesis, this class of compounds possesses a unique mode of action by preventing binding of the aminoacyl-tRNA to the A site of the ribosome.7,8 This unique activityindicates the potential for oxazolidinones to have low cross-resistance with existing protein synthesis inhibitors.9–11 To date, linezolid (ZyvoxTM, Fig. 1) is the only oxazolidinone that has been approved for clinical use for the treatment of pneumonia and skin infections due to drug resistant Gram-positive bacteria such as MRSA, VRE and PRSP.3,12,13 Unfortunately, though in only a few cases,resistance against
⇑ Corresponding author. Tel.: +1 574 631 7571; fax: +1 574 631 6652.
E-mail address: mmiller1@nd.edu (M.J. Miller). 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.04.026

linezolid was observed not long after it was put into use.14–17 The development of resistance encourages the design, syntheses, studies andhopefully development of novel oxazolidinone derivatives. Extensive structure–activity relationships have been established for oxazolidinone derivatives (Fig. 1).3 The S-configuration at the C-5 position of the oxazolidinone ring is necessary and the acetamide is good for antibacterial activity. Meanwhile, electrondonating nitrogen substituents at the 40 -position of the phenyl ring are well tolerated...