Of chloramphenicol

Dichloroacetic acid is used in the synthesis of chloramphenicol [56-75-7] and aHantoin [97-59-6]. Dichloroacetic acid has vimcidal and fungicidal activity. It was found to be active against several staphylococci (36). The oral toxicity is low the LD q in rats is 4.48 g/kg. It can, however, cause caustic bums of the skin and eyes and the vapors are very irritating and injurious (28). 

Table 1. Minimum Inhibitory Concentration (MIC) of Chloramphenicol and Thiamphenicol Against Sensitive Organisms...

Plasmid-mediated bacterial inactivation of chloramphenicol and thiamphenicol can potentially lead to three products, the 3- 0-acetyl (3), 1-0-acetyl (4), and 1,3-di-O-acetyl (5) derivatives as shown in Figure 1. 

Fig. 1. CAT (catalyzed acetylation) of chloramphenicol (1, R = NO2), and thiamphenicol (1, R = CH2SO2) where Ac-CoA is acetyl coenzyme A [72-89-9].

Table 3. Activity of Chloramphenicol and Analogues Against Chloramphenicol-Sensitive and -Resistant Organisms...

Veterinary Potential or Fiorfenicol. The absolute ban on the use of chloramphenicol ia food producing animals ia the United States and Canada has accentuated the need for an effective broad spectmm antibiotic ia animal food medicine. Fiorfenicol and other antibiotics commonly used ia veterinary medicine have been evaluated in vitro against a variety of important veterinary and aquaculture pathogens. Some of these data ate shown in Tables 4 and 5, respectively. Fiorfenicol was broadly active having MICs lower than those of chloramphenicol in each of the genera tested (Table 4). Florfenicol was also superior to chloramphenicol, thiamphenicol, oxytetracycline [79-57-2] ampicillin [69-53-4] and oxolinic acid [14698-29-4] against the most commonly isolated bacterial pathogen of fish in Japan (Table 5) (37). 

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

Liquid chromatographic determination of chloramphenicol in kidney tissue homogenates using valve-switching techniques , 113 171 -174(1988). 

Briefly stated, the production of chloramphenicol by the surface culture method involves inoculating a shallow layer, usually less than about 2 cm, of a sterile, aqueous nutrient medium with Streptomyces ver)ezuelae and incubating the mixture under aerobic conditions at a temperature between about 20° and 40°C, preferably at room temperature (about 25°C), for a period of about 10 to 15 days. The mycelium is then removed from the liquid and the culture liquid is then treated by methods described for Isolating therefrom tne desired chloramphenicol. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

The major mechanism of resistance to chloramphenicol is mediated by the chloramphenicol acetyltransferases (CAT enzymes) which transfer one or two acetyl groups to one molecule of chloramphenicol. While the CAT enzymes share a common mechanism, different molecular classes can be discriminated. The corresponding genes are frequently located on integron-like structures and are widely distributed among Gramnegative and - positive bacteria. 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

Serious and sometimes fatal blood dyscrasias (patiiologic condition of blood disorder of cellular elements of blood) are die chief adverse reaction seen witii the adiniiiistration of chloramphenicol, hi addition to blood dyscrasias superinfection, hypersensitivity reactions, nausea, vomiting, and headache may be seen. It is recommended that patients receiving oral chloramphenicol be hospitalized so that patient observation and frequent blood studies can be performed during treatment witii this drug. 

It is important to monitor closely serum blood levels of chloramphenicol, particularly in patients with impaired liver or kidney function or when administering chloramphenicol with other drugs metabolized by the liver. Blood concentration levels exceeding 25 mcg/mL increase the risk of the patient developing bone marrow depression. 

A famous example of the use of nitro compounds in synthesis was the original synthesis of the antibiotic chloramphenicol (8), which is still used to treat tropical diseases. This synthesis also confirmed the structure of chloramphenicol and established that the (-)-thrco compound was the biologically active stereoisomer. 

Of the fonr possible optical isomers of chloramphenicol, only the o-threo form is active. This antibiotic selectively inhibits protein synthesis in bacterial ribosomes by binding to the 50S subunit in the region of the A site involving the 23 S rRNA. The normal binding of the aminoacyl-tRNA in the A site is affected by chloramphenicol in such a... 

These agents bind selectively to a region of the SOS ribosomal subunit close to that of chloramphenicol and erythromycin. They block elongation of the peptide chain by inhibition of peptidyl transferase. 

Three ofher mechanisms of chloramphenicol resisfance have been described. Firsf, a fransposon-encoded chloramphenicol efflux protein has been idenfified in E. coli. Second, some bacterial sfrains have been found to possess drug-resisfanf ribosomes, and fhird, low level resisfance can arise by chromosomal mufafions which reduce fhe amounf ofporins and fherefore impair uptake. This last mechanism is essentially that described for the AG AC antibiotics. 

Feedback inhibition of amino acid transporters by amino acids synthesized by the cells might be responsible for the well known fact that blocking protein synthesis by cycloheximide in Saccharomyces cerevisiae inhibits the uptake of most amino acids [56]. Indeed, under these conditions, endogenous amino acids continue to accumulate. This situation, which precludes studying amino acid transport in yeast in the presence of inhibitors of protein synthesis, is very different from that observed in bacteria, where amino acid uptake is commonly measured in the presence of chloramphenicol in order to isolate the uptake process from further metabolism of accumulated substances. In yeast, when nitrogen starvation rather than cycloheximide is used to block protein synthesis, this leads to very high uptake activity. This fact supports the feedback inhibition interpretation of the observed cycloheximide effect. 

Mosher RH, DJ Camp, K Yang, MP Brown, WV Shaw, LC Vining (1995) Inactivation of chloramphenicol by O-phosphorylation. J Biol Chem 270 27000-27006. 

Several extraction techniques have also been described that use enzymatic or chemical reactions to improve extraction efficiency. A technique that has been used to increase the overall recovery of the marker residue is enzymatic hydrolysis to convert specific phase II metabolites (glucuronides or sulfates) back into the parent residue. Cooper etal used a glucuronidase to increase 10-fold the concentration of chloramphenicol residues in incurred tissue. As an example of a chemical reaction, Moghaddam et al. used Raney nickel to reduce thioether bonds between benomyl and polar cellular components, and as a result achieved a substantially improved recovery over conventional solvent extraction. In choosing to use either of these approaches, thorough characterization of the metabolism in the tissue sample must be available. 

Antibiotics may be classified by chemical structure. Erythromycin, chloramphenicol, ampicillin, cefpodoxime proxetil, and doxycycline hydrochloride are antibiotics whose primary structures differ from each other (Fig. 19). Figure 20 shows potential oscillation across the octanol membrane in the presence of erythromycin at various concentrations [23]. Due to the low solubility of antibiotics in water, 1% ethanol was added to phase wl in all cases. Antibiotics were noted to shift iiB,sDS lo more positive values. Other potentials were virtually unaffected by the antibiotics. On oscillatory and induction periods, there were antibiotic effects but reproducibility was poor. Detailed study was then made of iiB,sDS- Figure 21 (a)-(d) shows potential oscillation in the presence of chloramphenicol, ampicillin, cefpodoxime proxetil, and doxycycline hydrochloride [21,23]. Fb.sds differed according to the antibiotic in phase wl and shifted to more positive values with concentration. No clear relationship between activity and oscillation mode due to complexity of the antibacterium mechanism could be discovered but at least it was shown possible to recognize or determine antibiotics based on potential oscillation measurement. 

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