2 Nitroimidazole

‘azomycin’) and the problems involved in their synthesis (usually via the 2-aminoim-
idazole) it seemed worthwhile to attempt to prepare these compounds by thermal
rearrangement of the N-nitro compounds (by analogy with the well-known reactions
of 1-nitro-pyrazoles and -indazoles) (Chapter 4.04).

From: Comprehensive Heterocyclic Chemistry, 1984

Related terms:

Nanoparticle, Doxorubicin, Tracer, Insulin, Hydrogen Peroxide, Neoplasm, Glucose,

Fluorine 18, Hypoxia

View all Topics

DNA and Aspects of Molecular Biology

Kent S. Gates, in Comprehensive Natural Products Chemistry, 1999

7.14.2.9.1 Azomycin
Azomycin (87) is an antimicrobial agent first isolated in 1953 and structurally charac-
terized in 1955.213 Studies with (87), as well as with substituted 2-nitroimidazoles,
strongly suggest that (87) may be capable of covalently modifying DNA by several
different pathways.

Four-electron enzymatic reduction of 2-nitroimidazoles converts the nitro group

to a hydroxyamine (88).214 These hydroxyamine derivatives of imidazoles are elec-
trophilic and undergo hydrolysis to produce the known DNA-damaging agent gly-
oxal (89) (Scheme 21) (see Section 7.14.2.2.1).214 Reductive activation of 2-nitroim-
idazoles, including (87), in the presence of DNA results in the formation of glyoxal
adducts with guanine.215,216 It is possible that electrophilic 2-hydroxyaminoimi-
dazoles may directly alkylate DNA, although this has not been demonstrated.
Scheme 21.

2-Nitroimidazoles also can cause DNA damage by enzyme-driven redox cycling

of the nitro functional group.217,218 In this process, single-electron enzymatic
reduction of the nitro group yields a radical anion that can be oxidized by molecular
oxygen to generate superoxide radicals and regenerate the starting nitro compound
(Scheme 22). Although enzyme systems protect cells from its deleterious effects,
superoxide radical can lead to DNA damage through a cascade of reactions involving
dismutation to hydrogen peroxide followed by generation of hydroxyl radical via the
Fenton reaction (see Section 7.14.2.15).

Scheme 22.

> Read full chapter

Antiparasitic drugs
Stephen W Page, in Small Animal Clinical Pharmacology (Second Edition), 2008

Benznidazole
N-benzyl-2-(2-nitroimidazole-1-yl)acetamide.

Benznidazole, a 2-nitroimidazole and analog of the more familiar 5-nitroimidazole

metronidazole, acts by interfering with polymerases and DNA templates of suscep-
tible protozoa, inhibiting RNA and protein synthesis. The nitro group is reduced by
parasite metabolic pathways, resulting in the formation of reactive anion species,
toxic to a parasite that is deficient in catalase and peroxidase activity.

Following oral administration, benznidazole is absorbed rapidly and completely,

with peak plasma concentrations achieved in 3–4 h. Benznidazole appears to be
extensively metabolized, with only 5% of unchanged drug excreted in urine. The
elimination half-life is approximately 12 h.

Benznidazole is indicated for the treatment of infection with Trypanosoma cruzi.

In humans it is administered orally at 2–4 mg/kg q.12 h for 30–60 days. The dose
regimen in dogs has not been clearly defined. Relapses are frequent and parasito-
logical cure is not reliably achieved. Best results are associated with treatment of
early infections.

Adverse effects include vomiting, skin reactions and encephalopathy, frequently

leading to cessation of treatment.

> Read full chapter

Chemical Modifiers of Radiation Re-

sponse
Cameron J. Koch PhD, ... Raul C. Urtasun MD, FASTRO, in Leibel and Phillips
Textbook of Radiation Oncology (Third Edition), 2010

Misonidazole and Nimorazole

Misonidazole, a 2-nitroimidazole, was developed as a more efficient radiosensitizer
because of its known increased electron affinity. In the oral form, the dose-limiting
toxicity was again manifested in gastrointestinal effects (nausea, vomiting) and
peripheral neuropathy, which limits the effective SER.23,24 Not surprisingly, almost
all of the clinical trials of radiotherapy combined with misonidazole turned out to
be negative,25 an outcome consistent with the small degree of radiosensitization
expected with the clinically used low doses.26 Once more the inability to deliver a
sufficient dose may have been one of the reasons that a significant proportion
of large international clinical trials showed no benefit to misonidazole (Table 4-2).
However, it has been shown that selected populations of patients with specific
tumors did benefit by using this compound.27 This observation was made in pa-
tients with head and neck cancers. Overgaard and colleagues28 reported that not
only with misonidazole but also with nimorazole (a 5-nitroimidazole), there was a
significant benefit in a cohort of patients with stage T1 and T4 pharynx carcinoma
in terms of local regional control (Fig. 4-3). Patients with hemoglobin levels lower
than 9 mmol/L showed particular improvement. These two studies also showed
that the compounds had a similar benefit, despite the fact that fewer fractions
of radiation were “sensitized” in the misonidazole groups than in the nimorazole
groups, in which the drug was administrated with every fraction of radiation (first
30 fractions). The significant improvement of the effect of the radiotherapeutic
management of supraglottic and pharynx tumors was again demonstrated in a
randomized double-blind phase III study of 414 patients receiving nimorazole or
placebo in association with conventional primary radiotherapy (62-68 Gy, 2 Gy per
fraction, 5 fractions per week).28 Of interest is that in this study the nimorazole could
be given without major side effects. Nimorazole is currently standard treatment for
patients in Denmark receiving radiation therapy for head and neck cancer.29 The
benefit of misonidazole was not observed in another large clinical trial conducted
in North America under the Radiation Therapy Oncology Group (RTOG) in patients
with stage III and IV head and neck tumors, in which misonidazole was used with
two of the five radiation fractions per week. In this study, the administration of the
radiosensitizer was limited by neurologic complications, and the use of efficient
doses was prevented.30 A prospective randomized trial was initiated afterward in the
same cooperative group with a newer third-generation compound, etanidazole. A
significantly greater dose of etanidazole than misonidazole could be administered
for a sensitizer effect with acceptable gastrointestinal and neurologic toxicity.31

> Read full chapter

Approaches to Design and Synthesis of

Antiparasitic Drugs
Satyavan Sharma, Nitya Anand, in Pharmacochemistry Library, 1997

4.2 5-Nitroimidazoles
Extensive SAR studies on 2-nitroimidazoles did not result in getting a clinically
acceptable drug, but focussed attention to investigate the potential of other nitroim-
idazoles. Consequently, Rhone-Poulenc set out to carry out structural modifications
in 5-nitroimidazoles, which are more readily accesible than 2-nitroimidazoles. By the
end of the 1950s, the discovery of metronidazole (22) was announced [23,24], which
is now the drug of choice for treating amoebiasis, giardiasis and trichomoniasis in
humans [25–27].

The discovery of metronidazole stimulated a vigorous search for better nitroimi-

dazole drugs in different laboratories over the world, and led to a new generation
of antiprotozoal drugs. Variation of the alkyl chain at 1-position of 2-methyl-5-ni-
troimidazole provided a number of compounds with high order of antiamoebic
and antitrichomonal activities. Some of these are used in clinical practice and in-
clude benzoylmetronidazole (23), tinidazole (24), ornidazole (25), bamnidazole (26),
carnidazole (27), panidazole (28), secnidazole (29) and dimetridazole (30) [20].
Variations in the 2-position of 2-substituted-l-methyl-5-nitroimidazoles also pro-
vided compounds with promising activity, which include ipronidazole (31), ronida-
zole (32), azanidazole (33), fexinidazole (34) satranidazole (35), pirinidazole (36) and
chloronidazole (37) [20,28].

The demonstration of high antiprotozoal activity in chloronidazole (37) [29] and

nimorazole (38) [20] indicated that an alkyl group at the 2-position of 5-nitro-1-sub-
stituted imidazoles is not essential for biological activity, though the large majority
of antiprotozoal drugs of this class carry a substituent at 2-position, which seems to
modulate their activity. Some of the later drugs in this group include MCA-nitroimi-
dazole (39), MF-nitroimidazole (40), flunidazole (41), moxnidazole (42) and HOE-316
(43) [20].
> Read full chapter

Trypanosoma cruzi
Thaisa Lucas Sandri, ... Iara Jose de Messias-Reason, in Encyclopedia of Infection
and Immunity, 2022

Treatment
Benznidazole (N-benzyl-2-nitroimidazole-1-acetamide) and nifurtimox (5-nitrofu-
ran derivative) are the only options for effective treatment of T. cruzi infection.
Benznidazole is a prodrug metabolized by parasite enzymes to become active;
metabolites seem to act through several mechanisms to block T. cruzi glutathione
and trypanothione pathways (Müller Kratz et al., 2018). Nifurtimox impedes T. cruzi
carbohydrate metabolism through the inhibition of pyruvic acid synthesis (Forsyth
et al., 2016; Bern et al., 2020). Both antiparasitic drugs must be administered at the
onset of the acute phase, including congenital transmission and reactivation due to
immunosuppression. During early chronic phase, in adults, regardless symptoms,
some guidelines recommend antiparasitic treatment in order to prevent or cure
disease progression and in pregnant women (Dias et al., 2016).

Benznidazole is the first-choice drug in most Latin American countries due to the
high toxicity of nifurtimox. Even so, treatment has a suspension rate of around
20% due to poorly tolerated side effects (Jackson et al., 2010; Pinazo et al., 2013).
Unfortunately, less than 10% of CD patients in the Americas have been diagnosed
and only around 1% of them have access to antiparasitic treatment (DNDI, 2018).
Importantly, the potential benefits of medication should be weighed against the du-
ration of treatment (up to 2 months), contraindications (such as pregnant women),
and possible adverse reactions which occurs in up to 40% of adult patients (Bern et
al., 2007; Torrico et al., 2018). Thus, these drugs have been effective mainly during
early infection and their benefits in the chronic CD phase remain questionable.

Important concerns associated with the use of benznidazole and nifurtimox need to
be addressed such as the severe collateral effects that lead to treatment interruption;
T. cruzi resistance to the drugs; effectiveness in the chronic phase; and specific
formulations for children and pregnant women are still an emerging need (Menezes
et al., 2011; Morillo et al., 2015; Ribeiro et al., 2020). In this context, development
of new drugs against T. cruzi targeting novel mechanisms of action in order to
minimize toxicity and adverse effects have been carried out by several research
groups (Bernatchez et al., 2020; Ribeiro et al., 2020). Additionally, specific supportive
therapy for cardiac, digestive or neurological manifestations may be required.

> Read full chapter

Drugs for Protozoal Infections Other

Than Malaria
James S. McCarthy, ... Louis V. Kirchhoff, in Mandell, Douglas, and Bennett's Prin-
ciples and Practice of Infectious Diseases (Eighth Edition), 2015
Benznidazole
Benznidazole (N-benzyl-2-nitroimidazole-1-acetamide; Rochagan, Radanil) (Fig.
41-3) is a nitroimidazole derivative that is the drug of choice for treating infections
with Trypanosoma cruzi. The mechanism of action of benznidazole is not known.
Benznidazole is readily absorbed, highly lipophilic, and extensively metabolized, with
only 5% of the dose excreted unchanged in the urine.92,93

Benznidazole is only available in oral form. The dose and duration of treatment
are the same regardless of the stage of the infection. No assays are available
commercially to determine blood levels, and no data are available to guide dose
adjustments in patients with renal or hepatic insufficiency, pregnancy, or in
lactating women. It is recommended that benznidazole not be given to such patients.
Resistance to benznidazole has been reported94; efforts to understand the molecular
mechanisms underlying resistance are underway.95,95a The clinical significance of
resistance is unknown, in large measure because compliance is often an issue, and
also because assessment of parasitologic cure after treatment is difficult. No
assays for testing for resistance to benznidazole are available, and no data regarding
drug-drug interactions have been published.

Adverse effects occur in a substantial proportion of patients treated with benznida-

zole, but predisposing factors that increase the risk for side effects have not been
established.96 Limited data suggest that there is no relationship between benznida-
zole levels and risk for adverse drug reactions.97 Peripheral neuropathy and rash are
the most common. Granulocytopenia can also occur. On occasion, the latter can be
severe, and because of this, blood counts should be monitored weekly during the
first few weeks of treatment. Adverse effects usually disappear with dose reduction or
stopping the drug, although granulocytopenia may take several weeks to resolve. It is
noteworthy that patients with Chagas' disease who undergo cardiac transplantation
and who are given benznidazole for management of reactivation of T. cruzi have an
increased incidence of malignant tumors.98 However, the incidence of tumors in the
general population of patients treated with benznidazole has not been studied.

In the United States benznidazole is available from the CDC Drug Service.

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A New Era for Chagas Disease Drug Dis-

covery?
Martine Keenan, Jason H. Chaplin, in Progress in Medicinal Chemistry, 2015
6.4.2 Other Nitro Heterocycles
A diverse range of 3-nitro-1H-1,2,4-triazole and 2-nitro imidazole-based aromatic
and aliphatic amines was synthesised and evaluated against T. cruzi amastigotes,
T. b. rhodesiense trypomastigotes and Leishmania donovani axenic amastigotes, e.g.,
(29) [97]. The activity of these compounds was shown to be enhanced against those
T. brucei parasites over-expressing an NADH-dependent Type 1 nitroreductase,
consistent with a role for this enzyme in bioactivation of the compounds, similar to
(3) and nifurtimox (5). Nine of the compounds possessing the interesting and novel
triazole pharmacophore were identified as candidates for in vivo studies based on
their potency, selectivity over host cells (SI > 200) and compliance with Lipinski's rule
of 5. The symmetrically bis-benzylated derivative (29) was of particular interest due
to its high activity against all three organisms.

SAR expansion of the nitro triazoles identified a range of other potent structures
including piperazine, benzothiazole, amide and sulfonamide derivatives [98,99]. A
representative set of 13 compounds were progressed to in vivo mouse studies utilis-
ing the previously described fast luminescence assay involving luciferase-expressing
transgenic parasites. Eleven of the thirteen compounds exhibited significant anti-T.
cruzi activity. Three compounds were identified for further development (30–32)
[100].

The hydroxymethylated derivative (33) of the more toxic anti-microbial nitrofurazone

(34) was shown to provide high cure rates equivalent to (3) as assessed by PCR,
serology and tissue sampling analysis in an acute mouse infection model with the
Tulahuen strain [101]. No signs of toxicity were evident, and mouse survival rates
were higher for (33) than for (3) (although not deemed statistically significant
in the study). The dosage of (33) was substantially higher than that of (3) (150 vs.
60 mg/kg, respectively), and both compounds were considerably more effective
than (34), which showed significant signs of toxicity and led to high mortality
(75%). Pharmacokinetic studies of (33) in rat demonstrated its conversion over time
to parent compound (34), indicating a likely contribution of both species to the
anti-trypanosomal activity [102]. Interestingly, (33) displayed a considerably larger
volume of distribution than (34), which may contribute to its improved efficacy by
enabling access to deeper tissue reservoirs of the parasite.

> Read full chapter

RELEVANCE OF PRECLINICAL PHAR-

MACOLOGY AND TOXICOLOGY TO
PHASE I TRIAL EXTRAPOLATION
TECHNIQUES: RELEVANCE OF ANI-
MAL TOXICOLOGY
Joseph E. Tomaszewski, ... Karen M. Schweikart, in Anticancer Drug Development,
2002

1. Introduction
EF5 [2-(2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl)acetamide] is a
fluorinated 2-nitroimidazole (Fig. 6) that is currently undergoing clinical evaluation
as a diagnostic agent to detect and quantify oxygen levels in tumors and other tis-
sues. This compound, an analogue of the radiation-sensitizing agents misonidazole
and etanidazole, was designed to optimize a number of chemical and pharmacologic
properties that maximize its usefulness for the determination of tissue hypoxia
(Koch et al., 1995). The reductive metabolism of EF5 and other 2-nitroimidazoles
in cells leads to the production of reactive nitroso and hydroxylamine species that
form adducts with cellular proteins. For EF5, this process has been shown to be
consistently dependent on oxygen tension. The introduction of five fluorine atoms
into the molecule results in increased lipophilicity and broad distribution into tissues
(Laughlin et al., 1996). In addition, the fluorine-containing side chain facilitated
the development of avid and specific monoclonal antibodies for detection of tissue
adducts and may also allow detection by MRI and PET imaging.

FIGURE 6. Structure of EF5.

> Read full chapter

Imidazoles and their Benzo Derivatives:

(ii) Reactivity
M.R. Grimmett, in Comprehensive Heterocyclic Chemistry, 1984

4.07.1.4.2 Nitration
When imidazole is treated with a mixture of concentrated nitric and sulfuric acids the
4-nitroimidazole is formed by nitration of the imidazole conjugate acid. There is no
substitution at C-2 and so the important antibiotic 2-nitroimidazole (azomycin) can-
not be prepared by direct nitration. Variations in reaction conditions such as heating
imidazole nitrate with sulfuric acid or addition of sodium or potassium nitrates to
imidazole give the same 4-nitro product. Exhaustive nitration in ‘mixed acids’ gives
successively 4-nitro- and 4,5-dinitroimidazoles, but not 2,4,5-trinitroimidazole. The
last-named compound can, however, be prepared by nitration of 2,4-dinitroimida-
zole 73CHE465 . A chloro substituent is no hindrance to the nitration process:
both 1-methyl-4- and 1-methyl-5-chloroimidazoles are readily nitrated in sulfuric
acid. While nitric acid in acetic anhydride (nitronium acetate) seems to form only
the nitrate salt in many instances, dinitrogen tetroxide in acetonitrile is reported to
convert 4-substituted imidazoles bearing electron-withdrawing substituents into a
mixture of 5- and 2-nitro derivatives. Such nitrations at C-2 are unexpected. With
nitric–sulfuric acid mixtures 1-methyl- and 1,2-dimethyl-imidazoles give mixtures
of the 4-and 5-nitro isomers in the approximate ratios of 5 : 2 and 2 : 1, respectively.

The kinetics of nitration of imidazole have been studied in sulfuric acid medium. The
yields of 4-nitroimidazole are dependent on the acidity, e.g. %H2SO4, yield (%): 83.7,
46; 89.6, 26; 93.8, 19; 98.8, 19; 1% SO3, 90. Ring opening accompanies the process
giving rise to ammonia and, presumably, oxidation products. The kinetic results
which could be separated indicate that the species being nitrated is the imidazole
cation, but side reactions complicate matters. The suggested mechanism is outlined
in Scheme 30 B-76MI40701 .

Scheme 30.

Both benzimidazoles and aryl-substituted imidazoles are commonly substituted by

nitro in the aryl rings, and consequently such reactions will be treated as reactions
of substituents (Sections 4.07.3.1 and 4.07.3.2). On occasions, though, reaction can
occur in the heterocyclic nucleus. Thus, when 2-(p-fluorophenyl)imidazole is nitrated
under mild conditions an 80% yield of the 4-nitro product (78) results. Yet a further
nitro group can be introduced by the use of nitric and acetic acids at 95 °C. More
acidic nitrating agents tend to attack the benzene ring or may result in oxidation.
The observation that nitric acid in 20% oleum at −10 °C still nitrates (presumably) the
deactivated imidazolium species in preference to the electron-deficient fluorophenyl
group must reflect the relative stabilities of the Wheland intermediates (Scheme 31)
79JHC1153 .
Scheme 31.

Attention is also drawn to the conditions under which N-nitration (Section

4.07.1.3.11) and NNO2 → CNO2 migrations (Section 4.07.1.2.2) take place.

‘ipso’-Nitration of iodoimidazoles has been reported 80AHC(27)241 , but recent

studies 79CC523, 81JOC1781 have demonstrated that some compounds, report-
ed to be 2-iodo derivatives, are in fact 4-iodoimidazoles. Accordingly, when the
results reported earlier are amended in the light of these findings it can be seen
that iodo groups in the 4- and 5-positions of imidazole may be replaced by the nitro
group (Scheme 32). It had been reported earlier that 4,5-dibromoimidazole could
not be nitrated, but that 4-chloro- and 4-bromo-imidazoles undergo nitration at
the vacant C-5 (or -4) position. The formation of 2,4,5-trinitroimidazole (80) from
2,4,5-triiodoimidazole (79) is unexpected as it involves nitration at C-2. An analogous
nitration (in 50% HNO3) of 4,5-diiodoimidazole to give 5-iodo-2,4-dinitroimidazole
must be viewed with suspicion since the authors thought their starting material was
2,4-diodoimidazole. Furthermore, the suggestion 76JCS(P2)1089 that the facility
of nitrodehalogenation decreases with an increase in acid strength (because water
is needed to remove the halogen cation from the Wheland intermediate) is not in
accordance with the use of 100% nitric acid for the conversion of (79) into (80).
Repetition of this sequence of reactions will be required to clarify the anomalies.
 Scheme 32.

> Read full chapter

Nitroimidazoles
Peter J. Jenks, in Antibiotic and Chemotherapy (Ninth Edition), 2010

An imidazole ring is an important feature of many natural compounds with a wide

range of biological activities. Nitroimidazoles with antimicrobial activity emerged
from a search for a drug that would provide an effective treatment for infections
caused by protozoa of the Trichomonas genus, including the human pathogen,
Trichomonas vaginalis. The first active compound was an antibiotic, azomycin (2-ni-
troimidazole) produced by a streptomycete. It was soon abandoned, but led to the
synthesis of several hundred related compounds, one of which, the 5-nitroimidazole
metronidazole, combined activity against the parasites with acceptable animal tox-
icity. The compound was marketed in 1960 and 2 years later was fortuitously found
also to possess potent activity against anaerobic bacteria.

Numerous 5-nitroimidazoles were subsequently developed. Metronidazole and

tinidazole are in widespread clinical use; others include nimorazole, ornidazole and
secnidazole. The 2-nitroimidazole, benznidazole, is uniquely used in the treatment
of South American trypanosomiasis (Chagas disease); fexinidazole is under inves-
tigation in African trypanosomiasis (sleeping sickness). Carnidazole, dimetridazole,
ipronidazole and ronidazole are used in veterinary medicine and are not discussed
further here.

Other imidazole derivatives are used as antifungal agents (Chapter 32) and an-
thelmintics (Chapter 34). Some, chiefly 2-nitroimidazoles, have been examined as
possible radiosensitizers for the treatment of hypoxic tumors.

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