Photochemistry of Oxazolidinone Antibacterial Drugs † Elisa Fasani*, Fedele Tilocca and Angelo Albini Department of Organic Chemistry, University of Pavia, Pavia, Italy Received 23 December 2008, accepted 15 January 2009, DOI: 10.1111 ⁄ j.1751-1097.2009.00546.x ABSTRACT The photochemistry of six N3-(3-fluoro-4-dialkylaminophenyl)- oxazolidinones known for their antimicrobial activity has been examined. All of these compounds are defluorinated in water (F dec  0.25) and in methanol (F dec  0.03), reasonably via the triplet. The chemical processes observed are reductive defluori- nation and solvolysis, depending on the structural variation introduced (thus, tethering the dialkylamino group to the aromatic ring and introducing a highly polar group in the oxazolidinone moiety have an effect). A likely mechanism involves the fragmentation of the C–F bond yielding the corresponding triplet phenyl cation. This intermediate either is reduced or, under appropriate conditions, intersystem crosses to the singlet state that adds the solvent. These data demonstrate a sizeable photodecomposition of these drugs that causes a decrease in the therapeutic activity. Furthermore, the likely formation of phenyl cations may cause a photogenotoxic effect. INTRODUCTION In the last decades, the development of antibacterials has been largely based on the improvement of existing classes, as the introduction of a new family requires major investments. Therefore, the emerging of oxazolidinones after a long interval and after brilliant work by chemists and biologists is to be considered a major advancement (1–5), culminating in the licensing of the first clinically useful antibacterial of this class, linezolid 1. In this molecule the heterocyclic moiety bears an aliphatic side chain in position 5 (S configuration necessary for drug activity) and a phenyl group on the nitrogen atom, likewise required for activity. In turn, the phenyl moiety is functionalized by fluorination (that increases the potency and enhances the oral pharmacokinetic performance) and by introducing an electron donating group (morpholino), well tolerated and improving the safety profile. This drug is used for the treatment of infections caused by multi-resistant bacteria including streptococci (6) and methicillin-resistant Staphylococcus aureus (7) and has many therapeutic indica- tions, including the treatment of tuberculosis. Although this is a rather expensive drug, treatments are considered more cost effective than using competing drugs (8). Linezolid is considered a relatively safe drug and the main toxicity issue reported to date refers to the possible develop- ment of thrombocytopenia upon prolonged treatment (9–11). However, the presence of the fluoroaminophenyl motif is reminiscent of the high photoreactivity of fluoroanilines (12) and of the fact that other antimicrobials likewise with a fluorine atom flanking an amino group such as lomefloxacin and other fluoroquinolones are known for their high photo- lability (13,14) and phototoxicity (15). Linezolid is known to be liable to degradation under photochemical conditions (16– 18) and a recent detailed study has shown that the main photoprocess does in fact involve the aromatic fluorine (19). The reaction proceeded from the triplet state and was well rationalized on the basis of a phenyl cation as the intermediate. As mentioned above, the research on new oxazolidinones is quite active at present (20–25) and several new derivatives are candidates to the introduction in therapy. This encouraged us to extend the photochemical study on some further derivatives in order to understand whether structural variations had an important effect on the photochemical properties. The choice of the derivatives for the study was based on the significance of the pharmacological properties. MATERIALS AND METHODS H (300 MHz) and C (75.4 MHz) NMR spectra were registered by means of a Brucker instrument and IR spectra by using a Perkin Elmer Fourier transform spectrophotometer. Flash silica gel was used for column chromatographic separation. Reverse-phase HPLC analysis was carried out by using a C 18 PHENOMENEX Gemini, 25 cm · 4.6 mm, 5 lm column and eluting with H 2 O ⁄ MeCN 70 ⁄ 30 for 2, 6 and 7, 60 ⁄ 40 for 4 and 5, 50 ⁄ 50 for 3. The same setup was used for HPLC ⁄ MS experiments. Fluorescence and phosphorescence spec- tra were measured by means of a Perkin Elmer LS 55 luminescence spectrometer under the conditions indicated in Table 4. Starting materials. (S)-3-[3¢-Fluoro-4¢-(N-morpholino)phenyl]- 5-(N-acetamidomethyl)-oxazolidin-2-one (linezolid, 1) was prepared according to the published procedure (5). N1-{(5S)-3-[(6aS)-1-Fluoro- 6a,7,8,9-tetrahydro-6H-azolo-[1,2-d]benzo[b][1,4]oxazin-3-yl]-2-oxo- 1,3-oxazolan-5-yl}methylacetamide 2 and N1-{(5S)-3-[(6aS)-6a,7,8,9- tetrahydro-6H-azolo-[1,2-d]benzo[b][1,4]oxazin-3-yl]-2-oxo-1,3-oxazo- lan-5-yl}methylacetamide 7 were prepared essentially according to the published procedure (26) but because of low yields and difficult application two of the intermediates involved were synthesized in a different way as indicated below. (6aS)-1-fluoro-6a,7,8,9-tetrahydro-6H-azolo-[1,2-d]benzo[b][1,4] oxazine-3-amine: To a solution of 9.00 g (37.8 mmol) of (6aS)-1- fluoro-3-nitro-6a,7,8,9-tetrahydro-6H-azolo-[1,2-d]benzo[b][1,4]oxazine (26) in 50 mL of tetrahydrofuran and 90 mL of methanol, ammonium formate was added (19.00 g). The flask was maintained under argon atmosphere and cooled to 0°C. Ten percent palladium on carbon (0.44 g) was added and the suspension was stirred overnight. The reaction was monitored by TLC, water and ethyl acetate were added, the phases separated, and the aqueous portion was extracted with ethyl acetate. The combined organic portions were washed with saturated †This invited paper is part of a Symposium-in-Print on Pharmaceutical Photochemistry. *Corresponding author email: elisa.fasani@unipv.it (Elisa Fasani) Ó 2009 The Authors. Journal Compilation. The American Society of Photobiology 0031-8655/09 Photochemistry and Photobiology, 2009, 85: 879–885 879