2-Methyl-5-nitroimidazole Metronidazole

Thymine) ) -1- l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (metronidazole)-- products... 

Considerable interest has been reported in the radiolytic reactions of radiosensitiz-ing nitroimidazoles such ns Metronidazole, 2-methyl-5-nitro-l//-imidazole-1-ethanol (52). Again loss of the nitro function as nitrite appears to be one of the principal events. The formation of nitrite from /-irradiation of the Ni(II) complex of the imidazole 52 arises by hydroxy radical attack to form the radical anion. This either eliminates nitrite or undergoes a four-electron reduction to a hydroxylamino derivative68,69. 

Metronidazole Metronidazole, 2-methyl-5-nitroimidazol-l-ethanol (37.2.10), is made by nitrating 2-methylimidazole to make 2-methyl-5-nitroimidazole (37.2.9), which is then reacted with 2-chloroethanol or ethylenoxide, which is easily transformed to the desired metronidazole [49,50]. 

Fig-1 Metronidazole, l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, and side chains in positions 1 and 2 of related compounds tinidazole and ornidazole. Metronidazole and tinidazole are approved by the FDA for treatment of trichomoniasis, and ornidazole is used for this purpose outside the USA. Both tinidazole and ornidazole have been used with variable success in attempts to cure metronidazole-resistant infections... 

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.). 

Flash photolysis of misonidazole, metronidazole, and nitrobenzothiazoles has been carried out in [1369-1371], Laser flash-photolysis (355 nm) allows to determine relatively stable anion-radicals of misonidazole and metronidazole in aqueous solutions [1370], Solvated electrons have been formed at harder irradiation, the result of which interaction with nitroimidazole molecules is generation of their radical anions [1372], The authors [1372] have also found that fluorescence intensity of metronidazole is about 20 times more than that of misonidazole in same conditions. Photochromic properties of benzothiazole derivatives containing nitro and methyl groups in the ortho positions with respect to each other were studied by flash photolysis [1371], The application of the thermodynamic approach to predict the kinetic stability of formed nitronic acids is limited owing to specific intramolecular interactions. The lifetime of photoinduced nitronic acid anions tends to increase with rise in the chemical shift of the methyl protons. The rate constants photoinduced nitronic acids and their anions increase as the CH3C-CN02 bond becomes longer [1371],... 

Jokipii L, Jokipii AM. Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole, metronidazole, secnidazole, ornidazole, tinidazole, carnidazole, and panidazole against Bacteroides fragilis and other bacteria of the Bacteroids fragilis group. Antimicrob Agents chemother 1985 28(4) 561. ... 

The key intermediate for preparing various l-substituted-2-methyl-5-nitroimi-dazole drugs like metronidazole (22), tinidazole (24), ornidazole (25) etc. is 2-methyl-5-nitroimidazole (55), which is conveniently prepared by nitration of 2-methylimida-zole (54) [45]. Nucleophilic reaction with various substrates in presence of acids... 

Flagyl I.V. lmidazole-1-ethanol, 2-methyl-5-nitro-, hydro-chloride 1H-lmldazole-1-ethanol, 2-methyl-5-nitro-, hydrochloride 2-Methyl-5-nitroimidazole-1-ethanol monohydrochloride 2-Methyl-5-nilroimidazole-1-ethanol hydrochloride Metronidazole hydrochloride SC 32642. Antiprotozoal against Trichomonas. Antiamebic and antibacterial. SCS Pharm. 

The most commonly reported nitroimidazoles in the literature include dimetridazole (DMZ), metronidazole (MNZ), ronidazole (RNZ), and ipronidazole (IPZ) (Fig. 7.7). More recently, additional members of this class such as carnidazole (CNZ), ornidazole (ONZ), tinidazole (TNZ), and ternidazole (TRZ) have also been incorporated into analytical methods. Extensive studies on the metabolism of nitroimidazoles in poultry, beef, swine, and fish have shown that the hydroxy metabolites of the parent compounds, formed by oxidation of the side-chain in the C2 position of the imidazole ring, are of additional concern. These compounds have been shown to have toxicity equal to that of their parent forms and are often rapidly formed by metabolism within the animal. Studies in both poultry and rainbow trout have shown that the distribution of parents to metabolites is analyte- and species-specific. As a result, it has been suggested that it is imperative that a residue control program considers both the parent and the metabolites. The metabolites indicated in the literature include MNZ-OH, IPZ-OH, and HMMNI (2-hydroxymethyl-l-methyl-5-nitroimidazole) as the hydroxy metabolites of MNZ, IPZ, and DMZ, respectively. HMMNI has also been identified as a metabolite of RNZ, but through a different pathway. HMMNI is not a major metabolite of RNZ, however, and is therefore not suitable on its own for use as a marker of RNZ use. 

The reaction between 2-methyl-5-nitroimidazole and ethylene chlorohydrin at an elevated temperatures ranging from 128° to 130°C for a period of 18 hours results into the formation of metronidazole with the elimination of one mole of HCl. 

Tinidazole is chemically l-(2-ethylsulfonyl-ethyl)-2-methyl-5-nitroimidazole (Figure 1). It is active against protozoa and anaerobic bacteria and is used like metronidazole in a range of infections [1]. The drug is reported to hydrolyze quantitatively in alkaline conditions to 2-methyl-5-nitroimidazole and under photolytic conditions, the drug yields intermediate, rearrangement, and degradation products [2]. 

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