Chloramphenicol nitro group

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... 

Chloramphenicol, a broad-spectrum antibiotic, has probably received more attention in the polarographic literature than any other pharmaceutical. The aromatic nitro group is quite easily reduced. Studies [76] employing polarog-raphy, cyclic voltammetry, and constant-potential coulometry have suggested that... 

Metabolism is almost always an oxidative process. Reductive metabolism is much more limited. Functional groups that are reduced are, naturally, in a higher oxidation state. The more common examples include nitro groups, which are reduced to amines, and ketones, which reduce to alcohols. Chloramphenicol (8.28), an antibiotic that has fallen out of favor because of serious side effects, contains a nitro group that is reduced to the corresponding amine (8.29) (Scheme 8.9).7 Warfarin (Coumadin, 8.30), an anticlotting agent, is at least partially metabolized by reduction of its ketone to an alcohol. 

Operation of amperometric detectors in the reductive mode is more difficult because dissolved oxygen in the sample and mobile phase will interfere. Nevertheless, the quinone of doxorubicin and the nitro group of chloramphenicol have been reduced [94]. 

Florfenicol was believed to be more like thiamphenicol (XI), which appeared to be free of the blood toxicity problems associated with chloramphenicol. The toxicity of chloramphenicol was loosely linked to the presence of the nitro group. Nevertheless, Schering regarded Florfenicol as too risky to develop for human use, leaving the compound to be picked up by Schering s Animal Health Division for use as an animal antibiotic. 

At present nitration is one of the most widely applied direct substitution reactions. This is due to several factors. For example nitration usually proceeds easily, its products can readily be separated from the spent acid, said there is a wide range of possibilities in the practical use of nitro compounds, both as intermediates and end products. The presence of a nitro group in the starting product made it possible to obtain a number of basic organic intermediates such as aniline said benzidine. Dyes with more than one nitro group, such as picric acid were obtained. It has been found that higher nitrated nitro compounds and nitric acid esters have explosive properties and are of practical importance. Some nitro compounds are used in perfumes. Medicinal properties have lately been discovered in certain nitro compounds, eg. chloramphenicol. 

The electron-attracting nitro group in the antibiotic chloramphenicol (Tab. 1.1) has been replaced by other electron-attracting functions such as methyl-sulfonyl (thiamphenicol) or an acetyl (or cetophenicol). Apparently, the dominant feature is of electronic nature. 

Much of Landsteiner s pioneer work was carried out with haptens that were aromatic amines. The compounds were converted to diazonium salts with nitrous acid and aUowed to react with proteins at alkaline pH (approximately 9). Reaction occurred primarily with histidine, tyrosine, and tryptophan residues of the protein carrier. For a representative procedure, see Kabat (p. 799 seq.). An interesting application of this procedure was the preparation of a chloramphenicol-protein conjugate which was used to elicit antibodies specific for chloramphenicol. In this case, a prior reduction of the nitro group of chloramphenicol to an amino group was required. As early as 1937, carcinogenic compounds were conjugated to protein carriers by means of their isocyanate derivatives which were prepared from amines. Immune sera were raised, and their properties were studied. - ... 

Since thiamphenicol, which causes very few cases of aplastic anemia, differs from chloramphenicol by substitution of the para-nitro group by a methylsulfonyl group, interest has been focused on the para-nitro group and metabolites of that part of the molecule, nitrosochlor-amphenicol and chloramphenicol hydroxylamine. In human bone marrow, nitrosochloramphenicol inhibited DNA synthesis at 10% of the concentration of chloramphenicol required for the same effect, and prohferation of myeloid progenitors was irreversibly inhibited. The covalent binding of nitrosochloramphenicol to marrow cells was 15 times greater than that of chloramphenicol... 

Idiosyncratic aplastic anemia occurs only in humans exposed to chloramphenicol. The reaction is rare (1 in 30000) and not dose related. The toxic effects are related to the presence of the para-nitro group on the chloramphenicol molecule. Florfenicol lacks this group and is not associated with aplastic anemia in any species. Long-term chloramphenicol therapy (>14 days) is associated with dose-related anemia and pancytopenia through a decrease in protein synthesis in the bone marrow, especially in cats. Florfenicol may cause similar reversible suppression of the myeloid series in bone marrow, but this does not appear to be clinically significant during shortterm treatment regimens. 

Several studies of the biosynthesis of chloramphenicol have led to the conclusion that it is formed via the shikimic acid pathway, specifically from chorismic acid. An arylamine synthetase promotes formation of p-amino-L-phenyl alanine (1 ) 50>51. This product is converted to chloramphenicol (15) by oxidation of the amine function to a nitro group, by hy-droxylation of the benzylic methylene group, reduction of the carboxyl... 

Nitro groups present in a molecule are usually indicative of bitter taste (chloramphenicol, picric acid)... 

Hi) The presence of a nitro group was revealed by the reduction of chloramphenicol with tin (Sn) and hydrochloric acid, followed by diazotization and then coupling to yield an orange precipitate with P-naphthol (Rebstoek et al. 1949). 

As a successor to chloramphenicol, florfenicol is now used extensively in food-producing species, particularly calves, chickens, and young pigs. It lacks the para-nitro group of chloramphenicol, which seems to be an essential molecular feature for causing aplastic anaemia. Therefore, there is no public health risk relating to aplastic anaemia arising from the use of florfenicol. 

Miller NE, Halpert J. Analogues of chloramphenicol as mechanism-based inactivators of rat liver cytochrome P-450 Modifications of the propanediol side chain, the p-nitro group, and the dichloromethyl moiety. Mol Pharmacol 1986 29(4) 391-398. 

Chloramphenicol has the common Ce-Cs skeleton which appears in amino acids such as phenylalanine and its C3 fragment is also structurally related to serine, but it contains a nitro group and dichloroacetyl group which are unusual in natural products. The condensation of />-nitrophenylserinol and dichloroacetic acid appears to have been excluded as a step in the biosynthesis of this antibiotic . However, dechloro analogues of chloramphenicol are produced by a Streptomyces sp. in a culture medium to which no chloride ion has been added. These analogues include compounds in which the dichloroacetyl group of XXVII is replaced by acetyl, propionyl, butyryl, and pentanoyl or hexanoyl . 

Chloramphenicol Analogs - From studies on the biosynthesis of chloramphenicol using l c-iabeled compounds it was concluded that p-aminophenylalanine is a specific precursor. Oxidaticm of the amino function gives rise to the nitro group in chloramphenicol. 69... 

Cetophenicol an analog of chloranqphenicol having an acetyl group in place of the p-nitro group in chloramphenicol was selected for clinical evaluation as an antimicrobial agent. 0... 

Chloramphenicol. Only chloramphenicol and a few closely related analogues fall iato this group. Chloramphenicol, a nitro benzene derivative of dichloroacetic acid, inhibits proteia biosyathesis. 

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