Synthesis and antibacterial activity of some aryloxy/thioaryloxy oxazolidinone derivatives Vishal Arora, a Manikrao M. Salunkhe, a Neelima Sinha, b Rakesh K. Sinha c and Sanjay Jain b, * a Department of Chemistry, The Institute of Science, 15 Madam Cama Road, Mumbai 400 032, Maharashtra, India b Medicinal Chemistry Division, New Chemical Entity Research, Lupin Research Park, 46/47A,Village Nande, Taluka Mulshi, Pune 411 042, Maharashtra, India c Microbiology Division, New Chemical Entity Research, Lupin Research Park, 46/47A, Village Nande, Taluka Mulshi, Pune 411 042, Maharashtra, India Received 24 May 2004; revised 29 June 2004; accepted 30 June 2004 Available online 24 July 2004 Abstract—A series of aryloxy/thioaryloxy oxazolidinone derivatives has been synthesized and tested for in vitro antibacterial activity by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms, some of which are resistant to methicillin and vancomycin. Compounds 12a, 12b, 14a, and 14b from this series were found to be equipotent or more potent than linezolid in vitro. Ó 2004 Elsevier Ltd. All rights reserved. The oxazolidinones, a new class of synthetic antimicro- bial agents, are active against numerous multi- drug-resistant Gram-positive organisms. 1 Particularly, problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), penicillin- and cephalosporin-resist- ant Streptococcus pneumoniae. Their mode of action has been found to inhibit protein synthesis in the initial stage. 2 Due to this novel mechanism of action, oxazolid- inones are not cross resistant with other types of antibi- otics. This class was discovered through broad screening and is exemplified by the erstwhile clinical candi- date DuP 721 (1, Fig. 1). 3–5 Early studies of DuP 721 revealed a number of attractive features but despite these attractive features, the devel- opment of DuP 721 was terminated. 6 Pharmacia group found Linezolid (2, Fig. 1), 7,8 which is well known as the first promising candidate of oxazolidinone and works effectively against numerous serious Gram-posi- tive human pathogens caused by MRSA and VRE. The potential of this new antibacterial class has stimu- lated an exploratory chemical analog program in our discovery research laboratories. In the present commu- nication, we wish to report the synthesis and microbio- logical evaluation of a series of hitherto unknown substituted aryloxy/thioaryloxy oxazolidinone deriva- tives 12, 14–18. Compounds 12, 14–18 were synthesized in various steps as shown in Scheme 1. Compound 7 was synthesized starting from 1,2-difluoro-4-nitrobenzene (3). Com- pound 3 on condensation with 4-acetamidophenol/thio- phenol in the presence of K 2 CO 3 in DMF at 80 °C gave N-(4-[2-fluoro-4-nitro-phenoxy/phenylthio]phenyl)acet- amide (5) in excellent yields, which on reduction by Pd–C/H 2 followed by condensation with benzyl chloro- formate gave benzyl 4-(4-[acetylamino]phenoxy/ phenylthio)-3-fluorophenyl-carbamate (7). Conversion 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.06.096 Keywords: Antibacterial; Oxazolidinone; Aryloxy/thioaryloxy deriva- tives; Resistant bacteria. * Corresponding author. Tel.: +91-20-25126689; fax: +91-20- 25863630; e-mail addresses: sanjayjain@lupinpharma.com; sanjayjain_ ran@hotmail.com N N O O O NHAc F N O O H 3 C O NHAc 1 DuP 721 2 Linezolid Figure 1. Bioorganic & Medicinal Chemistry Letters 14 (2004) 4647–4650