- Progress towards a stable cephalosporin-halogenated phenazine conjugate for antibacterial prodrug applications
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Resistant bacteria successfully evade the action of conventional antibiotic therapies during infection, often leading to significant illness and death. Our lab has discovered halogenated phenazine (HP) analogues which demonstrate potent antibacterial activities through a unique iron-starving mechanism. Herein, we describe synthetic efforts towards a stable cephalosporin-HP conjugate prodrug with the aim of translating HPs into useful clinical agents. Cephalosporin-antibiotic conjugates offer multiple advantages for antibacterial design, including the release of active agents through the targeting of intracellular cephalosporinase following selective ring-opening of the beta-lactam warhead. During these studies, carbonate-linked cephalosporin-HP conjugate 16 was synthesized; however, we were unable to successfully remove the ester group required for cephalosporinase processing. Cephalosporin-HP 16 was then utilized as a probe to investigate the stability of the carbonate linker in antibacterial assays and, as predicted, this compound proved to be inactive against Staphylococcus aureus (MIC > 100 μM). The lack of 16’s antibacterial activity can be attributed to the carbonate linker remaining intact throughout the MIC assay, thus not liberating the active HP moiety. These efforts have led to a more stable cephalosporin-HP conjugate joined through a carbonate linker compared to a highly unstable ether linked analogue we previously reported.
- Xiao, Tao,Liu, Ke,Huigens, Robert W.
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- Cephalothin: Hydrolysis of the C-3'-acetoxy moiety of a 7-aminocephalosporanic acid; observation of both acyl-oxygen bond cleavage and reversible alkyl-oxygen bond cleavage
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The aqueous solution chemistry of the C-3'-acetoxy moiety of cephalothin sodium (1b) was examined with the use of isotopically labeled H218O and [2-13C]acetate anion. The 18O incorporation studies indicate that the hydrolysis (at pH 4.7 ± 0.1) of 1b to the deacetyl derivative of cephalothin (2b) proceeds via two pathways: alkyl-oxygen bond cleavage (55-63%) and acyl-oxygen bond cleavage accounting for the remainder. The incorporation of [2-13C]acetate into 1b suggests that the alkyl-oxygen cleavage pathway is a reversible reaction.
- Indelicato,Engel,Occolowitz
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- Preparation method of cefoxitin lactone
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The invention discloses a preparation method of a cefoxitin lactone. The method comprises the following steps: (1) under catalysis of N,O-bis(trimethylsilyl)acetamide or triethylamine, 2-thiopheneacetyl chloride and 7-ACA are subjected to an amidation reaction in an organic solvent to obtain a compound 2; (2) the compound 2 is subjected to a hydrolysis reaction under enzyme catalysis to obtain an[(6R,7R)-3-methylol-8-oxo-7-(2-thiopheneacetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid] compound 1; and (3) the compound 1 is subjected to an intramolecular esterification reaction in an alcohol solvent under the action of an acid, and after the reaction is completed, the cefoxitin lactone is obtained by post-treatment. The preparation method has mild reaction conditions, simpleoperation, and high reaction yield, and the obtained cefoxitin lactone has high purity, and can be used as an impurity reference substance in the process of drug consistency re-research.
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Paragraph 0016; 0044; 0047-0050; 0051; 0054; 0055; 0058
(2020/02/08)
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