Chloramphenicol analogs

Chloramphenicol Analogs. — Microbial kinetics have permitted a more precise quantification of substituent effect on antimicrobial activity in a series of chloramphenicol analogs. 

From the point of view of importance and chemical feasibility, chloramphenicol (Figure 9) presented an excellent subject for structural modification. It was the first truly broad-spectrum antibiotic isolated, and its structure and total synthesis were both reported two years after the discovery was announced (40, 41, 42). The synthesis of chloramphenicol analogs proved to be one of the great disappointments of early chemical research in the antibiotic field. Hundreds of analogs were synthesized, but none was found superior to the parent drug in terms either of antimicrobial activity or therapeutic index (43). The palmitate and hemisuccinate esters have provided superior dosage forms for oral and parenteral use. One synthetic analog, thiamphenicol (44) has achieved limited use in human and veterinary medicine. 

More extensive parameter variations have been reported in the approximation of electronic substituent parameters. In addition to the widely used aliphatic systems with varying degrees of success (2, 4, 8, 94, 95). McFarland has suggested the use of group dipole moments (fx) and electronic polarizability parameters (a) in addition to Hammett electronic interactions between drugs and receptors (96, 97). He obtained excellent results in correlating inhibitory rate constants of E. coli by chloramphenicol analogs (Equation 29) (96). 

Stevens, J.C. and J. Halpert (1988). Selective inactivation of four rat liver microsomal androstene-dione hydroxylases by chloramphenicol analogs. Mol. Pharmacol. 33, 103-110. 

Figure 1 A hypothetical binding site model for chloramphenicol analogs. Note that the dichloroacetyl group is postulated to interact with a positively charged gua-nidinium group of the protein and the nitrophenyl group with the it cloud of an uncharged imidazole.

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... 

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. ... 

Drugs that may interact with zalcitabine include antacids, chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, vincristine, cimetidine, metoclopramide, amphotericin, aminoglycosides, foscarnet, antiretroviral nucleoside analogs, pentamidine, and probenecid. 

Yes. Chloramphenicol inhibits the peptidyltransferase of the 50S ribosomal subunit of bacteria, while cycloheximide inhibits the analogous enzyme in the 60S subunit of eukaryotic ribosomes. Their structures are shown below. 

The three antibiotic inhibitors of translation that will be used in this experiment are chloramphenicol, cycloheximide, and puromycin (Fig. 23-10). Chloramphenicol is specific for prokaryotic ribosomes, blocking the transfer of the peptide on the tRNA at the P site to the amino acid linked to the tRNA at the A site (the peptidyl transfer reaction). Since the source of the ribosomes used in this experiment is wheat germ (eukaryotic), we would predict that chloramphenicol would not have a great effect on translation. The mechanism of cycloheximide-mediated inhibition is the same as that described above for chloramphenicol, except for the fact that it is specific for the 80S eukaryotic ribosome. Puromycin is a more broad translational inhibitor, effective on both eukaryotic and prokaryotic ribosomes. It acts as a substrate analog of aminoacyl tRNA. When it binds at the A site of the ribosome, it induces premature termination of translation (Fig. 

Chloramphenicol phosphotransferase from the producing bacterium Streptomyces venezuelae (47) is unrelated to the protein kinase family but rather shows more similarity to small-molecule kinases such as shikimate kinase (48). Analogous to the CAT strategy, phosphorylation occurs at the hydroxyl position 3, blocking this essential group from interacting with the ribosome (Fig. 10). 

Zidovudine is a synthetic nucleoside analog that blocks replication of the human immunodeficiency virus (HIV) by inhibiting reverse transcriptase. The primary indication for zidovudine administration in newborns is the prevention of vertical transmission of HIV. Like chloramphenicol, zidovudine is eliminated in adults primarily by glucuronide conjugation, suggesting that newborns may have a reduced capacity to eliminate zidovudine. However, unlike... 

Synthetic applications of AD which have already appeared and which are of potential industrial interest include the synthesis of propranolol (9) [48], diltiazem (10) [49], carnitine, and 4-amino-3-hydroxybutyric acid (11) [50], azole anti-fungals (12) [51], chloramphenicol (13) [52], reticuline intermediates (14) [53], camptothecin analogs (15) [54], khellactone (16) derivatives [55], taxol C-13 side chain (17) [56], halosarin [64], dehydro- xo-brevicomin [65], and antimalar-ial active cyclopenteno-l,2,4-trioxanes [57], as summarized in Figure 4. 

Syriopoulou, V.P., Harding, A.L., Goldman, D.A. Smith, A.L. (1981) In vitro antibacterial activity of fluorinated analogs of chloramphenicol and thiamphenicol. Antimicrobial Agents and Chemotherapy, 19, 294-297. 

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