Structure of Chloramphenicol

The structure of chloramphenicol has been established on the basis of the following vital chemical evidences. They are  

However, these produets may be accounted for provided the base is assumed to be 2-amino-l-nitrophenyl propane-1, 3-diol (Rebstoek et al. 1949). Thus  

D-threo-(-)-2, 2-Dichloro-N-[P-hydroxy-a-(hydroxy methyl)-/)-nitrophenyl] acetamide Acetamide, 2,z-dichloro-N-[2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophenyl) etheryl]-, [R-(R, R )]- BP USP Eur. P Int. P Ind. P  

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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. 

Figure 1.17. Chemical structure of chloramphenicol, the first broad-spectrum antibiotic to gain clinical...

Two crystal structures of chloramphenicol bound to the ribosome are available. In one structure, chloramphenicol is observed to bind only at the active site hydro-phobic crevice of the bacterial (D. radiodurans) ribosome [4]. In the other structure chloramphenicol binds only at the hydrophobic crevice at the entrance to the exit tunnel of an archaeal (H. marismortui) ribosome [7]. Both of these sites are surrounded by nucleotides implicated in chloramphenicol binding either by nucleotide protection studies or by mutational studies (Fig. 4.12). They probably correspond to the two sites inferred from biochemical experiments. 

Leslie AG, Moody PC, Shaw WV. Structure of chloramphenicol acetyltransferase at 1.75-A resolution. Proc. Natl. Acad. Sci. 

Izard T, Ellis 1. The crystal structures of chloramphenicol phos- 68. photransferase reveal a novel inactivation mechanism. EMBO 1. 

FIGURE 16.3 Chemical structures of chloramphenicol and thiamphenicol. Thiamphenicol, in which the nitroso group of chloramphenicol is replaced by a methylsulfone group, retains antibiotic activity, but does not cause the aplastic anemia that is a major concern with chloramphenicol therapy. 

Figure 7.16. The structure of chloramphenicol. The hydroxyl groups can be acetylated...

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. ... 

Chirality center, 292 detection of, 292-293 Eischer projections and, 975-978 R,S configuration of, 297-300 Chitin, structure of, 1002 Chloral hydrate, structure of, 707 Chloramphenicol, structure of, 304 Chlorine, reaction with alkanes, 91-92,335-338 reaction with alkenes, 215-218 reaction with alkynes, 262-263 reaction with aromatic compounds, 550 Chloro group, directing effect of, 567-568... 

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. 

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. 

FIG. 19 Chemical structures of (a) erythromycin, (b) chloramphenicol, (c) ampicillin, (d) cefpo-doxime proxetil, and (e) doxycycline hydrochloride. 

Fig. 1 Chemical structures of some of the most important antibiotics used nowadays divided into the most representative families fluoroquinolones, sulfonamides, penicillins, macrolides, and tetracyclines. Another important antibiotic, chloramphenicol, is also shown...

Chloramphenicol, thiamphenicol, and florfenicol are broad-spectrum antibacterials with closely related chemical structures (Fig. 3.2). In thiamphenicol, the p-nitro group on the benzene ring of chloramphenicol is replaced with a methyl sulfonyl group. In florfenicol, the hydroxyl group on the side chain of thiamphenicol is replaced with a fluorine. They are all potent antibacterial agents acting... 

Despite the fact that the preparation of chloramphenicol-specific antibodies was reported as early as in 1966 (36), it was 1984 before the first immunoassay was published for the determination of chloramphenicol residues in swine muscle, eggs, and milk (37). This first-published method was a radioimmunoassay that required an extraction procedure and special laboratory facilities to attain a quantification limit of 1 ppb. Employed polyclonal antibodies showed insignificant crossreactivity with structurally related compounds, except that thiamphenicol that did not interfere with the analysis. However, cross-reactivity was significant for metabolites deviating from the parent compound in the acyl side chain. 

Fig. 1. CAT activities in seeds of transgenic tobacco plants containing hs promoter-CAT constructs. A, Schematic structure of chimaeric genes introduced into tobacco. Details of the construction are described by Schoffl et al. (1989,1991). HSE sequences with the consensus C-GAA-TTC-G are symbolised by boxes the synthetic HSE2 is represented by two overlapping soybean HSEs. The CaMV promoter is a truncated silent version of the 35S promoter, providing only the TATA box and the transcription start site. B, CAT assays were performed as described by Schoffl et al. (1989), using 50 pg protein from seed extracts and 10 jig from leaf extracts. Dry seeds (ds) without imbibition and 20 h imbibed seeds (is), derived from the same plant, were used. Heat treatment (hs) was carried out for 2h at 40 °C prior to protein extraction. Control extracts (c) were prepared from leaves incubated at 25 °C. cm, WC-chloramphenicol acm, acetylated form of cm.

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