Nitroimidazole compounds

Chagas disease is caused by a kinetoplastid trypanosoma parasite and affects millions of people in Latin America. The disease is currently incurable. Chemotherapy is based mainly on nitrofuran and nitroimidazole compounds and sterol biosynthesis inhibitors such as ketoconazole (337). Toxicity and high doses are the major problems for these organic drugs. Urbina et al. (338, 339) have found that com-plexation of antiparasitic organic agents such as chloroquine (78)... 

Recently85, the first example of S l substitution involving a nitroimidazole compound in which the nitro group is o- to the side-chain at which the substitution occurs was described (equation 18). 

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. ... 

Diloxanide often causes flatulence and, occasionally, nausea, vomiting, diarrhea, urticaria, and pruritus. It is an excellent luminal amebicide and is indicated after treatment with the 5-nitroimidazole compounds, which have relatively weak activity on the cyst stage. Experience over 14 years has been summarized by the Centers for Disease Control and Prevention (CDC, Atlanta), confirming the minimal toxicity of diloxanide. Fewer adverse effects were reported in patients aged 20 months to 10 years than in those aged over 10 years. There is no record of interactions between diloxanide and either metronidazole or tinidazole (SEDA-13, 830) (SEDA-17, 333). 

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... 

Niles JC, Wishnok JS, Tannenbaum SR (2001) A novel nitroimidazole compound formed during the reaction of peroxynitrite with 2 ,3 ,5 -tri-0-acetyl-guanosine. J Am Chem Soc 49 12147-12151... 

S. Kizaka-Kondoh, and H. Konse-Nagasawa, Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia. Cancer Sci, 100 (8), 1366-73, 2009. 

The introduction of a formyl or acyl group can be achieved by transformation of VNS products. Hydrolysis of dichloromethylnitroarenes, VNS products between heteroaromatic nitro compounds and chloroform, is a method of choice for the preparation of heterocyclic aldehydes, as shown in Eq. 9.41, in which 4-nitroimidazole is converted into 5-formyl-4-nitroimidazole.69... 

Raney nickel reduction of 4(5)-nitroimidazole (27 R = H) in a mixture of acetic anhydride and acetic acid gave a diacetylated compound (35%) that was identified as 1- (or 3-) acetyl-4-acetamidoimidazole (57JA2188). 

Gamma-ray-induced reduction of both 4(5)-nitroimidazole (27 R = H) and 2-methyl-4(5)-nitroimidazole (27 R = H) in aqueous sodium formate or isopropanol solutions has been studied (83MI2) at neutral pH under inert conditions. Both compounds (27 R = H, Me) were reduced stepwise with the consumption of six electrons. 

Hunter and Nelson (41 Mil) attempted the preparation of 4(5)-aminoimidazole (25 R = H) from its acetyl derivative (28 R = H, R1 = Me), which they obtained by reduction of 4(5)-nitroimidazole (27 R = H) with tin(II) chloride in acetic anhydride. The authors noted that hydrolysis of compound (28 R = H, R = Me) with aqueous acids resulted in fission of the imidazole ring and formation of acetic acid, formic acid, ammonia, and glycine. Base hydrolysis gave similar results (41 Mil), although a trace of 4(5)-aminoimidazole (25 R = H) was detected. 

The use of hydrazine hydrate in anhydrous methanol with 5% palladium on charcoal under an inert atmosphere gave excellent results for the reduction of l-benzyl-4-nitroimidazole (72 R1 = CH2Ph, R2 = H) with compound (71 R1 = CH2Ph, R2 = H) being isolated as its hydrochloride salt (96%) (74JMC1168). 

Catalytic hydrogenation of methanolic solutions of the 4-nitroimidazoles (72 R1 = D-glucopyranosyl, D-arabinopyranosyl, D-xylopyranosyl R2 = H) using platinum oxide as catalyst gave the corresponding 4-aminoimidazole nucleosides (71 R1 = D-glucopyranosyl, D-arabinopyra-nosyl, D-xylopyranosyl R2 = H) (yields 16, 33, and 25%, respectively), which were apparently isolated as the free bases but no mention of the stability of these compounds was made (72LA67). 

Polarographic reduction of l-methyl-5-nitroimidazole (97 R = Me, R2 = H) has been shown to proceed in two distinct steps, probably via the hydroxylamine derivative (102), to give the amino compound (96 R = Me, R2 = H) (62CR2603). 

The instability of 5-aminoimidazoles (96) has led to in situ acylation being used to obtain stable compounds and using this approach several derivatives have been prepared. For example, a solution of the appropriate 5-nitroimidazole (97) in ethyl acetate was reduced with Raney nickel, and the resulting solution of 5-aminoimidazole (96) then treated with an acid chloride to give the amides (118 R1 = Me, R2 = S02Me, COPh, R3 = alkyl, aryl, hetaryl) (25-45%) [82IJC(B)1087],... 

The antitrichomonal compound l-methyl-5-nitro-2-(2 -pyrimidyl)imida-zole (97 R = Me, R2 = pyrimid-2-yl) has been shown to be metabolized to the corresponding acetamide (118 R1 = Me, R2 = pyrimid-2-yl, R3 = Me) in both rats and humans (74JPS293). The acetamide (118 R1 = Me, R2 = pyrimid-2-yl, R3 = Me) was also produced synthetically by reduction of a solution of the nitroimidazole (97 R1 = Me, R2 = pyrimid-2-yl) in acetic acid with zinc powder and subsequent treatment of the aminoimidazole (96 R1 = Me, R2 = pyrimid-2-yl) in situ with acetic anhydride to give the acetamide (118 R = Me, R2 = pyrimid-2-yl, R3 = Me) (4%) (74JPS293). 

The TV-protected nitrosoimidazole carbonitrile 42 - which can easily be obtained from the commercially available 4-nitroimidazole in 4 reaction steps - was treated with phenyl methylcarbazate 43 to give a substituted triazenyli-midazole 44. The cyano group of this compound was first hydrolyzed to an amide function to produce 45, and then irradiation yielded the end product 9a in high yield (79%). 

In an attempt to understand further the carcinogenicity of azathioprine, recent work in the authors laboratory has concentrated on the photodegradation of two compounds associated with the drug. l-Methyl-4-nitro-5-thioimid-azole is a metabolite and 5-hydroxy- l-methyl-4-nitroimidazole a hydrolysis product. Both gave, on irradiation at wavelengths greater than 300 nm, 1-methylparabanic acid (248) [152], The primary metabolites of azathioprine had previously been shown to be more potent than the parent drug as photosensitizers. Both 6-mercaptopurine and these imidazoles may play roles in its neoplastic action [151]. 

Several studies have reported the influence of nitroimidazole derivatives on biological systems. Thus the influence of Misonidazole, l-(2-nitro-l-imidazoyl)-3-methoxy-propan-2-ol, on strand breaking in calf thymus DNA under ionizing radiation conditions has been assessed70. Pulse-radiolysis studies of nitroheterocyclic compounds have examined... 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

The same regiochemistry is observed when nitroimidazole (48-2, 48-3) acts as a nucleophile in unionized form. Thus, the reaction of a compound with benzoyl-aziridine (49-1) in the presence of boron trifluoride probably involves an initial salt formation with an amide attack by the imidazole results in a ring opening and the formation of the alkylated product (49-2) the free primary amine (49-3) is obtained on basic hydrolysis. Acylation of the primary amine with methyl thiochloroformate gives the corresponding thiourethane, carnidazole (49-4) [52]. 

---