Synthesis and in vitro antibacterial activity of novel methylamino piperidinyl oxazolidinones q Brijesh Kumar Srivastava, * Rina Soni, Jayendra Z. Patel, Manish Solanki, Darshan Valani, Sunil Gupta, Bhupendra Mishra, Vijay Takale, Purvi Pandya, Mukul R. Jain and Pankaj R. Patel Zydus Research Centre, Sarkhej-Bavla N. H.8A, Moraiya, Ahmedabad 382210, India Received 3 May 2007; revised 22 June 2007; accepted 27 June 2007 Available online 30 June 2007 Abstract—Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram-positive strains. (S)-N- {3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl)-acryloyl]-piperidin-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2–4 lg/mL against linezolid resistant Staphylococcus aureus (linezolid P16 lg/mL). Ó 2007 Elsevier Ltd. All rights reserved. Bacterial infections have been a serious concern both in the hospital and community settings. The mortality and morbidity caused by Gram-positive bacteria has world- wide alarming impact on the human population. Oxazo- lidinones have been remarkable antibacterials, which act with a novel mechanism by inhibiting the protein synthe- sis at the bacterial ribosomal level. 1 The only drug of oxazolidinone class linezolid (Zyvox TM ) 1 (Fig. 1) has been approved by USFDA in April 2000. 2 The multidrug resistance is another challenge to medical fraternity. Unfortunately the linezolid is also not spared from resis- tance, however only few cases have been reported. 3 Several pharmaceutical industries and academic institu- tions have witnessed the pace of oxazolidinone antibac- terial research to get efficacious and safer drug. 4,5 Recently, we have disclosed our oxazolidinone antibac- terial findings but due to unfavorable pharmacokinetic and pharmacodynamic profile none of the compounds could be selected for further development 6 . Weidner-Wells et al. investigated 4-piperidinyloxy oxazo- lidinone 3 (Fig. 1) with antibacterial activity against vari- ety of susceptible as well as resistant Gram-positive organisms. 7 The results from the SAR developed by them demonstrated that replacement of piperazinyl ring of eperezolid 2 (Fig. 1) by 4-piperidinyloxy moiety is tolera- ble for imparting antibacterial activity. We have devel- oped a novel series of oxazolidinones 4a–4i,(Fig. 2) where piperazinyl ring of eperezolid is replaced by meth- ylamino piperidinyl system. Ranbaxy Research Labora- tories has optimized piperazinyloxazolidinones to get 5-nitrofuryl derivative 5 (RBx-7644), 5m (Fig. 2) which is safer and currently in clinical development. 8 Similarly we have developed SAR and identified compound 6, (Fig. 2) which bears 5-nitrofuryl on the distant nitrogen atom of the piperazinyl ring of the eperezolid system, show impressive in vitro MIC values against all the strains tested. 6a Looking on the promising drugability of 5-nitro- furyl derivative, we modified methylamino piperidinyl oxazolidinone series to get 5-nitrofuryl derivative 4i. The oxazolidinones 1, 2, 4a–4i, 5, and 16 were evaluated for their in vitro antibacterial activities in MIC assay by Clinical & Laboratory Standards Institute Guidelines. 9 The syntheses of methylamino piperidinyl substituted oxazolidinones 4a–4i and 16 have been outlined in Scheme 1 and achieved as reported in the literature. 6b,10 4-Hydroxy piperidine was converted into N-Boc-4-pipe- 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.06.075 Keywords: N-Methylamino piperidinylaryloxazolidinones; In vitro MIC assay; Gram-positive organism; Linezolid resistant Staphylococ- cus aureus. q ZRC Communication # 226. * Corresponding author. Tel.: +91 2717 250801; fax: +91 2717 250603; e-mail addresses: brijeshsrivastava@zyduscadila.com, bksri2000@yahoo.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 5227–5232