Photochemistry of Oxazolidinone Antibacterial Drugs^†

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 (Phidec approximately 0.25) and in methanol (Phidec approximately 0.03), reasonably via the triplet. The chemical processes observed are reductive defluorination 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.

Comparison of photoreactions of flutamide in acetonitrile and 2-propanol solvents in the absence of cage-forming compounds

“…However, the UV spectra indicated that the photoreaction was faster in deaerated 2-propanol than in aerated 2-propanol. In previous studies, the elimination of fluorine atoms in photoreactions is accelerated by the presence of alcohol and water [31][32][33][34]. In the case of trifluoromethyl benzene derivatives, an electron donor binding to the phenyl ring likely will induce solvolysis [31,33].…”

“…In previous studies, it has been shown that some benzotrifluoride derivatives are photoreactive and that the fluorine atoms can easily be eliminated via solvolysis [31][32][33]. Furthermore, it has been found that fluorobenzene derivatives can undergo photodissociation to release fluorine atoms [34]. This is remarkable because the fluorine atom is generally unreactive in thermal dissociation reactions.…”

Singlet versus Triplet Excited State Mediated Photoinduced Dehalogenation Reactions of Itraconazole in Acetonitrile and Aqueous Solutions

“…However, ITR has also been reported to cause heartburn, headaches, sweating and other unwanted side effects . Indeed, many side effects of photosensitive agents have been reported due to the reactive intermediates generated under exposure to solar radiation, such as radicals or ions, especially for drugs that contain an aryl halide structure. − Photoinduced dehalogenation reactions can occur when exposed to light and then cause the carbon–halogen bond to cleave and generate halogen ion or radical intermediates. − The generation of these halogen ions or radicals may be responsible for many relevant photosensitivity disorders, such as fever, headache, or even cutaneous adverse reactions. ,− More importantly, the carbon–halogen bond exists widely in many drug molecules, , thus a detailed understanding of the photoinduced dehalogenation process is needed to develop a better understanding of how unwanted photoinduced drug side effects occur.…”

Aqueous photochemical behavior of oxazolidinone antibiotic linezolid

“…前人已经研究了磺胺类 [12,13] 、四环素类 [14] 、 氟喹诺酮类 [11,15] 等抗生素的环境光化学行为, 但其 光解过程的微观机理鲜有报道, Chen 研究组 [16,17] [18] . 此类抗生素光化学行为的 研究目前仅局限于药品光稳定性方面 [19] , 如光照下, 利奈唑酮在水和甲醇中均发生了光致脱氟, 量子产 率分别为 0.25 和 0.03. 值得注意的是, 此类抗生素的 光解可能引起光化学遗传毒性 [19] .…”

“…此类抗生素光化学行为的 研究目前仅局限于药品光稳定性方面 [19] , 如光照下, 利奈唑酮在水和甲醇中均发生了光致脱氟, 量子产 率分别为 0.25 和 0.03. 值得注意的是, 此类抗生素的 光解可能引起光化学遗传毒性 [19] . 因此, 考虑到光 [6,20] .…”