Short communicationNovel Mannich ketones of oxazolidinones as antibacterial agents
Introduction
Oxazolidinones are new class of synthetic antibacterials [1]. Linezolid (Fig. 1) has been the first and the only candidate of oxazolidinone class in the market [2]. However, there are reports that linezolid resistant organisms have started appearing in hospital isolates [3], [4], [5]. Eperezolid (Fig. 2) is a follow up molecule of Pharmacia, which has been exploited by several research organizations to get superior molecules [6], [7], [8].
We have earlier reported a few rational approaches to get better antibacterial agents [9], [10], [11], [12]. Antibacterial activity of several fused Mannich ketones has been reported in literature with significant antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus saprophyticus, Micrococcus letucs and Bacillus subtilis [13], [14].
In the present communication we report for the first time the synthesis and activity of substituted Mannich ketones (5–12) of piperazinyl oxazolidinones (3–4) and their antibacterial activities in in-vitro MIC assay have been evaluated against selected Gram-positive organisms (Table 1 and Fig. 3).
The Mannich ketones (5–12) (Table 1) were synthesized using our earlier reported method [15] and characterized [16], where piperazinyl phenyl oxazolidinone 3 or 4 template were taken in methanol and treated with 37% formaldehyde solution at 0–5 °C. After removal of the solvents under reduced pressure the resulting residue was treated with ethereal HCl at 0–5 °C followed by refluxing with appropriate ketone in methanol (Scheme 1).
The piperazinyl phenyl oxazolidinone derivatives 3 and 4 (Fig. 3) used for the synthesis of Mannich ketones have been synthesized according to literature methods [17], [18]. The in-vitro MIC antibacterial activity of the compounds 5–12 against Gram-positive bacteria (S. aureus, S. epidermidis, B. subtilis, Enterococcus faecalis) was tested as growth inhibition using microdilution broth method according to NCCLS standards [19]. Compounds were dissolved in concentrated DMSO and water was added to get stock solution in 80% DMSO. The working solution was prepared by diluting the stock solution 1:10 times in 4–8% DMSO in water or medium and the dissolved compounds were evaluated in the concentrations of 0.25, 0.5, 1, 2, 4, 8, 16, 32 and 64 μg/ml.
Section snippets
Results and discussion
The Mannich ketone analogues of oxazolidinones 3 and 4, were screened for in-vitro activity against a panel of Gram-positive organisms. The analog 5 showed inferior activity than linezolid as well as eperezolid (Table 1). Thus in an attempt to improve potency, we prepared several analogues by modifying the ketone part A (see Fig. 3). However, all such resulting compounds 6–9 lost their in-vitro antibacterial activity. It has been reported that thioacetamide at the 5th position of the
Conclusion
A moderately active compound 5 has been taken as a lead to get active compounds 10–12. It has been shown that thio compounds are more potent than their oxygen counterpart.
Acknowledgements
We thank Dr. Braj Bhushan Lohray, President, Zydus Research Centre for his valuable suggestions, Mr. Pankaj R. Patel, CMD and the management of Zydus group for encouragement. We thank the analytical department for support and Mr. Binu Philip for his help in preparing the manuscript.
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