Metronidazole, synthesis

Chromosome function Quinolones Metronidazole (also ) Nitrofu rantoin Rifampicin (also ) 5-Fluorocytosine Inhibit DNA gyrase DNA strand breakage DNA strand breakage Inhibits RNA polymerase Inhibits DNA synthesis No action on mammalian equivalent Requires anaerobic conditions not present in mammalian cells No action on mammalian equivalent Converted to active form in fungi... 

N. M. Mahfouz, M. A. Hassan, Synthesis, Chemical and Enzymatic Hydrolysis, and Bioavailabihty Evaluation in Rabbits of Metronidazole Amino Acid Ester Prodrugs with Enhanced Water Solubility , J. Pharm. Pharmacol. 2001, 53, 841-848. 

Inhibition of nncleic acid synthesis or their function in microorganisms (sulfonamides, trimethoprim, metronidazole, qninolones, and rifampicin). 

Metronidazole Inhibits DNA replication Affects synthesis or structure... 

Metronidazole — see also Imidazole, l-(2-hydroxy-ethyl)-2-methyl-5-nitro-antiprotozoal activity, 1, 180 veterinary use, 1, 208 mode of action, 1, 208 Metyrapol metabolism, 1, 234 Metyrapone metabolism, 1, 234 Mevaloladone synthesis, 1, 490 Mevalonolactone synthesis, 3, 846 MG18755... 

Mechanism of Action. The exact mechanism of action of metronidazole is not known. It is believed that this drug is reduced chemically within the parasitic cell to a metabolite that impairs nucleic acid and DNA synthesis.32 The exact nature of this metabolite, however, and other features of the cytotoxic effects of this drug remain to be determined. 

In spite of extensive investigations into the electrophilic substitution of imidazoles, no rational explanation has yet been found for certain features of the reaction [78], The nitration of imidazoles takes place exclusively at position 4 or 5. In reaction with the sulfuric-nitric acid mixture imidazole itself forms the 4(5)-nitro derivative [79-85], A large number of papers have been devoted to the production of 2-methyl-4(5)-nitroimidazole by the nitration of 2-methylimidazole [79, 82, 86-94], This is due to the fact that 2-methyl-4(5)-nitroimidazole is an important intermediate product in the synthesis of highly effective medical products (metronidazole, tinidazole, dimetridazole, etc.). 

Metronidazole and clindamycin are protein synthesis inhibitors that inhibit bacteria by interacting with the DNA to cause a loss of helical DNA structure and strand break-... 

Metronidazole possesses selective bactericidal and an-tiparasitic activity. Its mechanism of action is complex and not thoroughly understood but is thought to include interference with nucleic acid synthesis. Metronidazole is also capable of producing a disulfiram-type reaction with ethanol ingestion. This reaction is hypothesized to occur due to metronidazole inhibition of aldehyde dehydrogenase. 

Metronidazole Nucleic acid synthesis Activation in the parasite Giardia. Trichomonas, Entamoeba... 

Inhibition of nucleic acid synthesis. Fluoroquinolones block the action of DNA gyrase rifampin binds strongly to DNA-dependent RNA polymerase metronidazole, following chemical reduction of the nitro group of the molecule within anaerobic bacteria or sensitive protozoal cells, produces a bactericidal effect by reacting with various intracellular macromolecules. 

All the evidence reviewed above points to an interesting possibility that the primary action of metronidazole and nitrofurans in T. vaginalis may be the inhibition of synthesis of proteins. Whether reduction of the nitro group is the prerequisite for this activity remains to be seen. 

Interference with nucleic acid synthesis Quinolones Rifampin Metronidazole... 

The interaction of reduced metronidazole species with DNA of microorganisms causes iirhibition of DNA and RNA synthesis. The DNA double helix is destroyed and the strand is broken. Both the antiprotozoal activity and mutagenicity of metronidazole has been attributed to the abihty of its nitro group to get reduced to form short living toxic intermediates [84,92,96,97]. 

Emetine (Fig. 7-9) in the form of the crude drug obtained from the roots and rhizomes of Ipecac (Cephaelis ipecacuanha) has been in use since the seventeenth century. The alkaloid, as the hydrochloride, has been used parenterally to treat amebic dysentery. It is also effective in hepatic infestation, but not against amebic cysts. Because of its cardiac toxicity and emetogenic properties, it has been superseded by metronidazole and chloroquine, but it is still used as an alternative. The amebicidal mechanism of emetine is protein synthesis inhibition by interference of peptidyl-RNA translocation. Since this action is general to eukaryotic cells, its relative selectivity in the presence of mammalian cells is not well understood. Unrelated uses of Ipecac (presumably due to its alkaloid content) are as an expectorant in cough preparations and an emergency emetic (Syrup of Ipecac). 

Mechanisms Metronidazole is an imidazole derivative with activity against protozoa and bacteria. The drug undergoes a reductive bioactivation of its nitro group by ferredoxin (present in anaerobic parasites) to form reactive cytotoxic products that interfere with nucleic acid synthesis. 

Metronidazole (e.g., Flagyl) Cidal Inhibits nucleic acid synthesis. Trichomonas, Giardia, Entamoeba histolytica. 

The chemical synthesis and biological testing of numerous nitroimidazoles occurred following the discovery in 1955 of azomycin, a 2-nitroimidazole compound, and the demonstration of its trichomonacidal properties a year later. The trichomonacidal activity of metronidazole, a... 

The reduction of intestinal ammonia synthesis can also be achieved by the administration of non-absorbable disaccharides-like lactulose and lactitol or antibiotics like neomycin, paramomycin, metronidazole or rifaximin. Lactulose exerts several effects (1). acidification of the intestinal content resulting in a reduction of ammonia absorption and net movement of ammonia from the blood into the bowel and (2). reduced bacterial production of ammonia in the colonic lumen due to environmental changes with promotion of the growth of non-urease producing bacteria and (3). the cathartic effect. The daily dose of lactulose is between 30 and 60 g per day. The goal is to obtain 2-3 soft bowel movements per day. Recently lactulose has been proven to be effective even in patients with minimal HE (Prasad et al., 2007). 

Nowadays, antibiotics are primarily classified according to the mechanism of their action, with similarity of chemical structure as a secondary factor. Penicillin and its derivatives inhibit the formation of bacterial cell walls (Fig. 3.38). Cephalosporins have the same active mechanism. Other compounds are taken up into bacterial DNA to form unstable molecules (quinolones, metronidazole) or inhibit peptide synthesis (tetracychnes, aminoglycosides, macrolides). Some antibiotics (e.g. glycopeptides) exert a complex effect. 

Azelaic acid is a saturated dicarboxylic acid. Its therapeutic effect in rosacea is likely based on the inhibition of the synthesis of reactive oxygen species by neutrophils. The efficacy of 15% azelaic acid gel is similar to that of 1% metronidazole gel [39, 40]. 

The two antibiotics with which PPIs synergize are amoxicillin and clarithromycin. The former antibiotic inhibits cell wall biosynthesis by inhibiting peptidyl transferase and by binding to other proteins in the cell wall biosynthesis pathways. Cell division is therefore required for the bactericidal action of this class of antibiotic. Clarithromycin binds to the 23S RNA and thereby inhibits protein synthesis. Hence, protein synthesis is required for the action of this antibiotic. Metronidazole is reduced to the hydroxylamine derivative, which then binds to DMA, hence not requiring cell division or protein synthesis for its efficacy. PPIs do not synergize with this antibiotic. Resistance to metronidazole develops by decrease of the level of reducing enzyme and, therefore, may be relative or absolute. Resistance to clarithromycin occurs by a base mutation at the binding site on the RNA and is usually absolute. 

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