Design and synthesis of heterocyclic hydroxamic acid derivatives as inhibitors of Helicobacter pylori urease

Article abstract of DOI:10.1081/SCC-120021024

Helicobacter pylori produces ammonia to help counter the acidic environment in the human stomach. The production of ammonia, essential for the microorganism's survival and virulence, is the product of enzymatic conversion of urea by the H. pylori's urease. Inhibition of urease activity by dipeptide hydroxamic acids has previously been demonstrated using a variety of fluorides, thiols and hydroxamic acids. Studies employing computer-aided drug design techniques have been utilized to suggest a novel series of heterocyclic hydroxamic acid derivatives as potential as urease inhibitors. The heterocyclic compounds 7a,b, 10b, 12b, 16b, and 19b have been designed, synthesized, and preliminarily tested as dipeptide mimics which offer a structure that is more biologically stable than that of the reported dipeptide inhibitors.

Full text of DOI:10.1081/SCC-120021024

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Design and Synthesis of Heterocyclic Hydroxamic Acid
Derivatives as Inhibitors of Helicobacter pylori Urease
Estela Maris F. Muri a , Hetal Mishra a , Mitchell A. Avery a & John S. Williamson a
a Department of Medicinal Chemistry, University of Mississippi, University, Mississippi, USA
Version of record first published: 17 Aug 2006
To cite this article: Estela Maris F. Muri, Hetal Mishra, Mitchell A. Avery & John S. Williamson (2003): Design and Synthesis
of Heterocyclic Hydroxamic Acid Derivatives as Inhibitors of Helicobacter pylori Urease, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:12, 1977-1995
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 1977–1995, 2003
Design and Synthesis of Heterocyclic
Hydroxamic Acid Derivatives as Inhibitors of
Helicobacter pylori Urease
Estela Maris F. Muri, Hetal Mishra, Mitchell A. Avery,
*
and John S. Williamson
Department of Medicinal Chemistry, University of
Mississippi, University, Mississippi, USA
ABSTRACT
Helicobacter pylori produces ammonia to help counter the acidic
environment in the human stomach. The production of ammonia,
essential for the microorganism’s survival and virulence, is the
product of enzymatic conversion of urea by the H. pylori’s urease.
Inhibition of urease activity by dipeptide hydroxamic acids has pre-
viously been demonstrated using a variety of fluorides, thiols and
hydroxamic acids. Studies employing computer-aided drug design
techniques have been utilized to suggest a novel series of heterocyclic
hydroxamic acid derivatives as potential as urease inhibitors. The
heterocyclic compounds 7a,b, 10b, 12b, 16b, and 19b have been
*Correspondence: John S. Williamson, Faser Hall, School of Pharmacy,
Department of Medicinal Chemistry, University of Mississippi, University, MS
38677, USA; E-mail: mcjsw@olemiss.edu.
1977
DOI: 10.1081/SCC-120021024
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1978
Muri et al.
designed, synthesized, and preliminarily tested as dipeptide mimics
which offer a structure that is more biologically stable than that of
the reported dipeptide inhibitors.
INTRODUCTION
Almost 90% of the world population is believed infected with the
spiral-shaped, gram-negative bacterium Helicobacter pylori, making this
one of the most prevalent disease-causing bacterial infections known.
H. pylori infections have been linked to a variety of gastric health pro-
blems including chronic gastritis and peptic ulcer disease. This wide-
spread infection, which is already showing signs of antibiotic resistance,
may serve as a model for the treatment and control of potential multi-
drug-resistant infectious disease pandemics. While the clinical manifesta-
tions associated with H. pylori infection do not present an immediate, or
generally life-threatening complication, drug design and development,
treatment, and potential eradication of the infectious agent may yield
valuable insight into processes that may become more frequent and
critical to man’s survival in the future.[1]
In 1982, the bacteria later assigned as H. pylori, was implicated in the
etiology of common peptic ulcer disease.[2] Today, H. pylori is believed to
be associated with the development of up to 90% of duodenal ulcer cases
and approximately 70% of gastric ulcer cases, especially in under-
developed countries.[3] Although the relationship is somewhat controver-
sial, H. pylori is believed to be an etiological factor in chronic
active-gastritis, gastric esophageal reflux disease (GERD), mucosa-
associated lymphoid tissue (MALT)-type gastric carcinoma and
other gastric cancers.[4] Antibiotic eradication therapies in the clinic
have been shown to heal gastritis, provide a cure for many patients
suffering from peptic ulcers, and even generate a remission of MALT
carcinomas. While the majority of H. pylori infections can be controlled
by currently available antibiotic therapies,[5] antibiotic resistant strains
of the microorganism are becoming frequent.[6] Infection of the
human gastrointestinal tract, specifically the mucous lining of the
stomach, by H. pylori requires that the microorganism neutralize or
adapt to the otherwise lethally acidic environment. H. pylori utilizes
its own metabolism of urea to ammonia by the enzyme urease to
counteract the harsh environment of the stomach. By analogy,
inhibition of this urea to ammonia catalysis should halt this vital
neutralization mechanism.[7] Molecules designed to specifically inhibit

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Inhibitors of Helicobacter pylori Urease
1979
the H. pylori urease target offer the potential of both an effective and
selective chemotherapy.
In general, ureases are inhibited by a variety of agents including
fluorides,[8] thiols,[9] and hydroxamic acids.[10,11] In previous studies,
hydroxamic acid dipeptide inhibitors of H. pylori urease were used to
create a model template for the design of selective inhibitors of H. pylori
urease.[12,13] We now report the design and synthesis of a series of hetero-
cyclic hydroxamic acid derivatives, which are currently being tested in a
series of in vitro H. pylori urease binding assays. The heterocyclic com-
pounds designed as inhibitors are represented by structures 7a,b, 10b, 12b,
16b, and 19b. Based on a rational drug design approach, each of the
compounds would possess the required pharmacophore groups necessary
to increase selective urease binding stability, with both hydroxamic acid
and ionizable amine moieties. In addition to binding selectivity, the struc-
tural design was directed towards the synthesis of potential hydroxamic
acid inhibitors that would be likely to exhibit increased biological stability
as compared with the dipeptide and amino acid derivatives.
RESULTS AND DISCUSSION
In order to explore the binding parameters associated with various
hydroxamic acid inhibitors, we have created a computer-generated
homology model obtained from the combination of H. pylori urease
sequence data and the x-ray crystal structure of Klebsiella aerogenes
urease (EC 3.3.1.5).[12,14] Acetohydroxamic acid was docked into the
active pocket of this homology-modeled urease and the most probable
configuration of the enzyme-inhibitor complex was assessed by molecular
dynamics studies. Comparative Molecular Field Analysis (CoMFA) was
then carried out on a variety of dipeptide hydroxamic acid derivatives.
The resulting conformation was used as a template to construct 24
potential dipeptide hydroxamic acid inhibitors on which CoMFA analy-
sis was performed. The resulting model provided a q2LOO of 0.610,
a conventional r2 of 0.988, and an F value of 294.88. Validation of the
CoMFA model was obtained using the IC50 values of 6 compounds not
included in the construction of the model. A very good structural corre-
lation was observed between amino acids in the model urease’s active
pocket and the CoMFA contour maps.[12] This correlation, as along
with the CoMFA data, validated the model as a computational design
tool for H. pylori urease inhibitors.[15]
Based on the results of the computational design studies, several
novel heterocyclic hydroxamic acid derivatives were synthesized and

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1980
Muri et al.
are currently undergoing in vitro H. pylori urease inhibition analyses. The
heterocyclic hydroxamic acids, represented as 7a,b, 10b, 12b, 16b, and
19b, were specifically designed as mimics of the dipeptide inhibitors to
produce compounds with increased biological stability, as well as a
greater binding stability of the ionizable acid and amine moieties.
Preparation of the imidazole hydroxamic acid derivatives 7a,b
(Sch. 1) was initially accomplished by nitration of the commercially avail-
able imidazole (1) to yield the 4(5)-nitro-1H-imidazole (2).[16] This
compound exists in solution as an equilibrium mixture of two tautomeric
forms and N-alkylation can result in different products according to the
reaction conditions. Alkylation of 2 in the presence of base has been
reported to yield predominantly the 1,4-disubstituted isomer.[17] The
esters 3a,b were obtained by alkylation with methyl chloroacetate and
methyl-3-bromo propionate, respectively, in the presence of K2CO3 and
TBAI as a phase-transfer catalyst.[18] Catalytic reduction of the nitro-
ester compounds 3a,b yielded the unstable 4-amino-imidazoles 4a,b
that were directly protected with
a tert-butoxycarbonyl (BOC)
group.[19,20] Several methods for the synthesis of hydroxamic acids are
documented in literature, including the strategy of activating carboxylic
acids then coupling these with O/N-protected hydroxylamines such as
NH2-O-Bn, N-t-BOC-O-THP, N-t-BOC-O-TBDMS.[21] Another popular
variation of this strategy includes activation of the carboxylic acid using
dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT)
then coupling with an O-benzylhydroxylamine.[22] The mosteconomical,
and hence the most commonly used, method for synthesis of hydroxamic
acids is the reaction of hydroxylamine with acid chlorides or esters. The
treatment of esters 5a,b with hydroxylamine resulted into nucleophilic
displacement of the ester functionality to give the hydroxamates 6a,b in
good yields.[23] The formation of the resulting hydroxamate was initially
confirmed by the appearance of a distinctive purplish color on TLC using
FeCl3–conc. HCl as an indicator. The removal of the BOC group was
achieved using acid catalysis, which provided the salts of 7a,b.[24] Itis
important to note that an ionizable NH2 group is required for significant
pharmacological activity (Sch. 1).
A thiazole series of compounds was prepared by the esterification of
the commercially available thiazole acetic acid 8 with an excess of thionyl
chloride in methanol at 0ꢀC.[25] This provided the ester 9, which was
treated with freshly prepared hydroxylamine in methanol.[26] After react-
ing overnight, the solution was shown to contain the corresponding
hydroxamic acid 10a, which was subjected to HCl treatment to produce
the salt 10b. The outline sequence of the reaction strategy is shown
in Sch. 2.

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Inhibitors of Helicobacter pylori Urease
1981
Scheme 1. (a) Conc. H2SO4, HNO3, 40–45ꢀC, 2 h, 56%; (b) ClCH2CO2Me (3a)
BrCH2CH2CO2CH3 (3b), K2CO3, TBAI, CH3CN, 80ꢀC, 30 min, 78% (3a), 90%
(3b); (c) H2, 10% Pd/C, MeOH, 2 h; (d) (BOC)2O, MeOH, r.t., overnight, 56%
(5a, 2 steps), 59% (5b, 2 steps); (e) H2NOH 50% aqueous solution, MeOH, reflux,
overnight, 74% (6a), 65% (6b); (f ) CH2Cl2, 2 M HCl ether solution, r.t., 4 h,
70% (7a), 66% (7b).
For the synthesis of the adenine hydroxamate derivative 12b, t he
commercially available (6-amino-purin-9-yl)-acetic acid ethyl ester (11)
was employed (Sch. 3). By varying the reagent-substrate ratios and
temperature, standard reaction conditions were found for an efficient con-
version of the ester group of 11 to the hydroxamic acid functionality.[23]
Synthesis of the indazole derivative 16b (Sch. 4) was accomplished
by alkylation of 6-nitroindazole (13) with ethyl 2-bromoacetate, then
hydrogenation of the nitro function to form the amine ester 15.[27]
The conversion of the ester to the hydroxamic acid has been outlined
in Schs. 1 and 3.
The pyrazole hydroxamic acid derivative 19b was obtained by solid–
liquid phase-transfer-catalyzed alkylation of the ring NH of 3-amino-4-
carbetoxy-pyrazole (17). Alkylation with methyl chloroacetate provided
the N-alkylated product 18a in 70% yield (Sch. 5).[18,28] The desired
alkylated product was easily separated from the NH-alkylated product

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1982
Muri et al.
Scheme 2. (a) SOCl2, MeOH, 0ꢀC, overnight, 83%; (b) H2NOHꢁHCl, KOH,
MeOH, r.t., 24 h, 70%; (c) 2 M HCl ether solution, CH2Cl2, 75%.
Scheme 3.
18b (25% yield) by chromatography. As a means of avoiding the undesir-
able NH-alkylation associated with the synthesis of 18a, a second syn-
thetic route was established where the primary amine of 17 was selectively
protected with a trityl moiety affording the compound 20. The protecting
group has the advantages of being easily removed by acid catalysis as well
as increased stability at basic pH.[29] The NH-trityl pyrazole 20 was alky-
lated with methylchloroacetate to afford the ester 21. The removal of the
trityl group was accomplished using mild acid to provide the amine ester
18a.[30] Direct conversion of the ester 18a to the hydroxamic acid 19a was
effected using hydroxylamine in aqueous solution. Finally, the hydroxa-
mic acid 19a was transformed to its corresponding salt with an HCl-ether
solution (Sch. 5). Proof of the conversion of the ethyl ester of 18a to the
hydroxamic acid 19a was accomplished when the reaction of hydroxyl-
amine and 3-amino-4- carbetoxy-pyrazole (17) under identical condi-

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Inhibitors of Helicobacter pylori Urease
1983
Scheme 4. (a) BrCH2CO2Et, K2CO3, DMF, 18 h, r.t., 80%; (b) MeOH, CHCl3,
H2, 10% Pd/C, 2 h, 50%; (c) 50% H2NOH aqueous solution, r.t., overnight,
80%; (d) 2 M HCl ether solution, CH2Cl2, 80%.
tions, failed to produce any reaction product. Heterocycles with ester
substituents on thiophene and furan rings were examined as potential
substrates of this direct conversion to the hydroxamic acid under a vari-
ety of reaction conditions without success.[31]
CONCLUSIONS
Computer-aided molecular design methods were successfully used to
produce a homology model of H. pylori urease, a potential drug target for
the treatment of a variety of gastric-related illnesses. The model was used
to determine various protein-ligand interactions, which were subse-
quently used in the design of novel heterocyclic hydroxamic acid urease
inhibitors. Here we report our successful synthesis approach for the
production of the rationally designed urease inhibitors via the transami-
nation of heterocyclic esters. Compounds 7a,b, 10b, 12b, 16b, and 19b are
examples of hydroxamic acid derivatives possessing the pharmacophoric
requirements, as predicted by our design model, to increase stability and
inhibitor efficiency. Although inconclusive results were obtained during
the in vitro testing using crude fractions of H. pylori urease, current
refinements of the bioassay procedures are underway.

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Muri et al.
Scheme 5. (a) ClCH2CO2Me, K2CO3, TBAI, CH3CN, reflux, overnight, 70%
(18a), 25% (18b); (b) 50% H2NOH aqueous solution, r.t., 1.5 h, reflux, 65%;
(c) 2 M HCl ether solution, CH2Cl2, 85%; (d) Et3N, trityl chloride, ꢂ10ꢀC t o
r.t., overnight, 75%; (e) ClCH2CO2Me, K2CO3, TBAI, CH3CN, reflux, 1 h, 55%;
(f) 1.5% HCl in acetone, r.t., 4 h, 72%.
EXPERIMENTAL
All solvents were purchased as a reagent grade, dried using standard
conditions, and stored over molecular sieves. Solvent and reagent trans-
fers were accomplished either via syringe or cannula, and all reactions
were routinely conducted under argon atmosphere, unless otherwise indi-
cated. The formation of the hydroxamate was confirmed by the appear-
ance of purple color on TLC with mixture of FeCl3 and concentrated
hydrochloric acid. Purification of products was accomplished using silica
gel flash chromatography (Whatman 60, 230–400 mesh). Routine NMR

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Inhibitors of Helicobacter pylori Urease
1985
analyses were accomplished in CDCl3 and DMSO-d6 on a Bruker
Advance DPX-400. Melting points were obtained on Thomas-Hoover
capillary melting point apparatus and are uncorrected. Mass spectral
measurements were made on Waters 2690 mass spectrometer.
Analytical results are within ꢃ0.40% of the theoretical values and were
determined by QTI, Whitehouse, NJ.s.
4(5)-Nitro-1H-imidazole (2)
To a mixture of 1 g (14.68 mmol) of 1H-imidazole in 6.6 mL of
concentrated H2SO4 was added 2.1 mL (94.38 mmol) of 70% HNO3 at
a rate to maintain the temperature at 40–45ꢀC. The resulting solution was
stirred at 40ꢀC for 2 h and poured onto ice and the mixture adjusted
to pH 2 with Na2CO3. The solids were collected and crystallized from
boiling acetic acid to give 0.924 g (56%) of 2, m.p. 310–311ꢀC,
(lit. 312–313ꢀC).[16] 1H NMR (DMSO-d6, 400 MHz): ꢀ 13.20 (br s, 1H,
NH), 8.29 (s, 1H, 2-H), 7.83 (s, 1H, 5-H). 13C NMR: ꢀ 162.7 (C), 136.6
(CH), 119.7 (CH). ESMS m/z 114 (M þ 1).
(4-Nitro-imidazol-1-yl)-acetic Acid Methyl Ester (3a)
A mixture of 4(5)-nitro-1H-imidazole 1 g (8.85 mmol), 0.93 mL
(10.6 mmol) of methyl chloroacetate, 1.8 g (13.27 mmol) of potassium
carbonate, 0.070 g (0.185 mmol) of TBAI and 10 mL of acetonitrile was
stirred vigorously at 80ꢀC for 30 min. After cooling to room temperature,
the inorganic salts were filtered off and washed with acetonitrile. The
combined acetonitrile solution was evaporated and the residue was
recrystallized from ethyl acetate to give 1.27 g (78%) of (4-nitro-
imidazol-1-yl)-acetic acid methyl ester as
a yellow solid (m.p.
133–134ꢀC). H NMR (DMSO-d6, 400 MHz): ꢀ 8.35 (s, 1H, 2-H), 7.82
(s, 1H, 5-H), 5.08 (s, 2H, CH2), 3.70 (s, 3 H, OCH3). 13C NMR: ꢀ 168.8
(C¼O), 147.6 (C), 139.1 (CH), 123.4 (CH), 53.4 (CH3), 49.1 (CH2).
ESMS m/z 186 (M þ 1).
1
3-(4-Nitro-imidazol-1-yl)-propionic Acid Methyl Ester (3b)
The procedure is similar to the general procedure for 3a. The product
was obtained as a yellow solid (m.p. 116–117ꢀC) in 90% yield. H NMR
(DMSO-d6, 400 MHz): ꢀ 8.38 (s, 1H, 2-H), 7.83 (s, 1H, 5-H), 4.30
1

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1986
Muri et al.
(t, J ¼ 6.7 Hz, 2H, CH2), 3.58 (s, 3H, OCH3), 2.95 (t, J ¼ 6.7 Hz, 2H,
CH2). 13C NMR: ꢀ 171.3 (C¼O), 147.7 (C), 138.4 (CH), 122.4 (CH),
52.4 (CH3), 43.9 (CH2), 34.9 (CH2). ESMS m/z 200 (M þ 1).
(4-Amino-imidazol-1-yl)-acetic Acid Methyl Ester (4a)
A solution of 3a, 1 g (5.4 mmol) in 20 mL of MeOH and 0.052 g
of 10% Pd/C were vigorously shaken under an atmosphere of H2
(40 psi) for 2 h. The catalyst was filtered off and the solution was
concentrated (ca. 10 mL) and used immediately to the next step.
(4-Amino-imidazol-1-yl)-propionic Acid Methyl Ester (4b)
The procedure is similar to the general procedure for 4a.
(4-tert-Butoxycarbonylamino-imidazol-1-yl)-acetic Acid
Methyl Ester (5a)
To a solution of 4a, 0.8 g (5.16 mmol) in 10 mL of MeOH was added
2.24 g (10.3 mmol) of di-tert-butyl-dicarbonate. The mixture was stirred
at room temperature overnight, and the solvent was evaporated.
Purification by florisil column chromatography (3% CHCl3/MeOH)
gives 0.768 g (56%, 2 steps) of the product as a yellow solid (m.p.
184–185ꢀC). 1H NMR (CDCl3, 400 MHz): ꢀ 9.16 (s, 1H, NH), 7.23
(s, 1H, 2-H), 7.01 (s, 1H, 5-H), 4.60 (s, 2H, CH2), 3.74 (s, 3H, OCH3),
1.48 (s, 9H, Boc). 13C NMR: ꢀ 168.1 (C¼O), 153.3 (C¼O), 139.5 (C),
133.9 (CH), 105.7 (CH), 80.1 (C), 53.1 (OCH3), 48.7 (CH2), 28.7 (3CH3).
ESMS m/z 256 (M þ 1).
3-(4-tert-Butoxycarbonylamino-imidazol-1-yl)-propionic Acid
Methyl Ester (5b)
The procedure is similar to the general procedure for 5a. The product
was obtained as an orange solid in 59% yield in 2 steps (m.p. 148–149ꢀC).
1H NMR (CDCl3, 400 MHz): ꢀ 9.80 (s, 1H, NH), 7.32 (s, 1H, 2-H), 6.98
(s, 1H, 5-H), 4.14 (t, J ¼ 6.3 Hz, 2H, CH2), 3.56 (s, 3H, OCH3), 2.80
(t, J ¼ 6.3 Hz, 2H, CH2), 1.42 (s, 9H, Boc). 13C NMR: ꢀ 172.0 (C¼O),
153.3 (C¼O), 139.2 (C), 134.0 (CH), 105.4 (CH), 79.2 (C), 52.3 (OCH3),
42.9 (CH2), 35.7 (CH2), 28.9 (3CH3). ESMS m/z 300 (M þ 1).

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Inhibitors of Helicobacter pylori Urease
1987
(1-Hydroxycarbamoylmethyl-1H-imidazol-4-yl)-carbamic Acid
tert-Butyl Ester (6a)
To a solution of 5a, 1 g (3.92 mmol) in 15 mL of MeOH was added
1.19 mL (19.6 mmol) of 50% H2NOH aqueous solution. The mixture
was refluxed overnight. After cooling to room temperature the product
was extracted with AcOEt (3 ꢄ 100 mL). The combined organic
layers were washed with brine and dried over Na2SO4. Concentration
under reduced pressure yielded the crude product. After purification
by silica gel column chromatography (20% CHCl3/MeOH), the
product 6a was obtained as a white solid (0.74 g, 74%, m.p.
164–165ꢀC). H NMR (DMSO-d6, 400 MHz): ꢀ 10.80 (bs, 1H), 9.32 (bs,
1
1H), 9.08 (bs, 1H), 7.30 (s, 1H, 2-H), 6.87 (s, 1H, 5-H), 4.42 (s, 2H, CH2),
1.40 (s, 3H, Boc). 13C NMR: ꢀ 164.5 (C¼O), 153.4 (C¼O), 139.0 (C),
134.8 (CH), 106.2 (CH), 79.4 (C), 48.0 (CH2), 28.9 (3CH3). ESMS m/z
257 (M þ 1).
[1-(2-Hydroxycarbamoyl-ethyl)-1H-imidazol-4-yl]-carbamic
Acid tert-Butyl Ester (6b)
The procedure is similar to the general procedure for 6a. The product
was obtained as a white solid in 65% yield (m.p. 70–71ꢀC). H NMR
1
(DMSO-d6, 400 MHz): ꢀ 10.50 (bs, 1H), 9.75 (bs, 1H), 9.00 (bs, 1H),
7.26 (s, 1H, 2-H), 6.95 (s, 1H, 5-H), 4.11 (t, J ¼ 6.3 Hz, 2H, CH2), 2.41
(t, J ¼ 6.3 Hz, 2H, CH2), 1.41 (s, 3H, Boc). 13C NMR: ꢀ 167.3 (C¼O),
153.4 (C¼O), 139.0 (C), 134.0 (CH), 105.5 (CH), 79.3 (C), 43.2 (CH2),
34.5 (CH2), 29.0 (3CH3). ESMS m/z 271 (M þ 1).
1-Hydroxycarbamoylmethyl-1H-imidazol-4-yl-ammonium
Chloride (7a)
To a mixture of 0.5 g (1.95 mmol) of 6a in 20 mL of CH2Cl2
was added 8 mL of 2 M HCl ether solution. The mixture was stirred
at room temperature for 4 h. The solvent was evapored and the salt
was obtained as a white solid by recrystallization from MeOH (0.262 g,
1
70%). H NMR (DMSO-d6, 400 MHz): ꢀ 10.40 (bs, 1H), 8.40 (s, 1H,
2-H), 6.60 (s, 1H, 5-H), 4.68 (s, 2H, CH2), 4.50 (bs, 4H). 13C NMR: ꢀ
163.1 (C¼O), 137.9 (C), 131.8 (CH), 104.1 (CH), 49.2 (CH2). ESMS m/z
157 (M þ 1).

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1988
Muri et al.
1-(2-Hydroxycarbamoyl-ethyl)-1H-imidazol-4-yl-ammonium
Chloride (7b)
The procedure is similar to the general procedure for 7a. The product
was obtained as a white solid in 66% yield. 1H NMR (DMSO-d6,
400 MHz): ꢀ 10.42 (bs, 1H), 8.42 (s, 1H, 2-H), 6.90 (bs, 4H), 6.61 (s,
1H, 5-H), 4.21 (s, 2H, CH2), 2.50 (s, 2H, CH2). 13C NMR: ꢀ 166.7
(C¼O), 140.0 (C), 130.1 (CH), 102.2 (CH), 45.4 (CH2), 33.4 (CH2).
ESMS m/z 171 (M þ 1).
(2-Amino-thiazol-4-yl)-acetic Acid Methyl Ester (9)
(2-Amino-thiazol-4-yl)-acetic acid (8) (3 g, 17.4 mmol) was dissolved
in an ice-cooled solution of excess thionyl chloride in methanol. The ice
was allowed to melt and the reaction mixture was stirred overnight. The
solvent was evaporated and the residue was dissolved in water and
extracted with CH2Cl2 (3 ꢄ 200 mL). The organic layer was then evapo-
rated to give 2.5 g (83%) of ester 9 as a white crystalline solid (m.p.
124–126ꢀC). 1H NMR (DMSO-d6, 400 MHz): ꢀ 6.88 (bs, 2H, NH2),
6.29 (s, 1H, CH), 3.57 (s, 3H, CH3), 3.44 (s, 2H, CH2). 13C NMR: ꢀ
171.4 (C), 169.1 (C¼O), 145.1 (C), 104.0 (CH), 52.5 (OCH3), 37.6
(CH2). ESMS m/z 173 (M þ 1). Anal. calcd. for C6H8N2O2S: C, 41.85;
H, 4.68; N, 16.27. Found: C, 41.63; H, 4.64; N, 16.24.
2-(2-Amino-thiazol-4-yl)-N-hydroxy-acetamide (10a)
A
solution of hydroxylamine was prepared by dissolving
H2NOH ꢁ HCl (3.22 g, 46 mmol) in 14 mL of methanol and stirring it
with a solution of KOH (5.2 g, 92 mmol) in 14mL of methanol for
20 min. The KCl precipitated out was filtered, and the solution of the
hydroxylamine was added dropwise to the ice cooled solution of the
aminoester 9 (1 g, 5.8 mmol). The mixture was kept standing at room
temperature for 24 h. The solvent was evaporated, and the resulting
crude solid was dissolved in water. The pH was neutralized using
1.25 N aq. CH3COOH. The solid that precipitated out was filtered and
dried using reduced pressure to furnish pure product, which was further
recrystallized from methanol to give 0.7 g (70%) of 10 as a pale brown
solid (m.p. 171–172ꢀC). H NMR (DMSO-d6, 400 MHz): ꢀ 6.81 (s, 2H,
1
disappeared with D2O), 6.20 (s, 1H, CH), 3.34–3.42 (bs, 2H, disappeared
with D2O), 3.10 (s, 2H, CH2). 13C NMR: ꢀ 175.4 (C), 168.9 (C¼O),

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Inhibitors of Helicobacter pylori Urease
1989
146.6 (C), 103.3 (CH), 36.7(CH2). ESMS m/z 174 (M þ 1). Anal. calcd.
for C5H7N3O2S: C, 34.76; H, 4.07; N, 24.26. Found: C, 34.44; H, 4.33;
N, 24.13.
4-Hydroxycarbamoylmethyl-thiazol-2-yl-ammonium
Chloride (10b)
The procedure is similar to the general procedure for 7a. The product
was obtained in 75% yield. 1H NMR (DMSO-d6, 400 MHz): 8.27 (s, 1H),
6.17 (s, 1H, CH), 3.13 (s, 2H, CH2). 13C NMR: ꢀ 176.6 (C), 169.2 (C¼O),
159.9 (C), 106.3 (CH), 49.2(CH2). ESMS m/z 174 (M þ 1).
2-(6-Amino-purin-9-yl)-N-hydroxy-acetamide (12a)
The procedure is similar to the general procedure for 6a. The product
was obtained as a white solid in 70% yield (m.p. 244–245ꢀC). H NMR
1
(DMSO-d6, 400 MHz), ꢀ 11.2 (bs, 1H, NH), 9.3 (bs, 2H, NH2), 8.10 (s,
1H, CH), 7.28 (s, 1H, CH), 4.76 (s, 2H, CH2). 13C NMR: ꢀ 164.4 (C),
156.7 (C¼O), 153.3 (CH), 150.5 (C), 143.0 (C), 142.6 (CH), 119.2 (C),
43.9 (CH2). ESMS m/z 209 (M þ 1). Anal. calcd. for C7H8N6O2: C, 40.39;
H, 3.87; N, 40.37. Found: C, 40.30; H, 3.80; N, 39.90.
9-Hydroxycarbamoylmethyl-9H-purin-6-yl-ammonium
Chloride (12b)
The procedure is similar to the general procedure for 7a. The product
was obtained as a white solid in 87% yield. 1H NMR (DMSO-d6,
400 MHz): ꢀ 11.90 (bs, 3H, þNH3), 10.53 (bs, 1H, NH), 8.61 (s, 1H,
CH), 8.35 (s, 1H, CH), 4.87 (s, 2H, CH2). 13C NMR: ꢀ 163.8 (C¼O),
162.7 (C), 152.7 (C), 149.8 (C), 148.1 (CH), 144.8 (CH), 44.0 (CH2).
ESMS m/z 209 (M þ 1).
(6-Nitro-indazol-1-yl)-acetic Acid Ethyl Ester (14)
To a solution of 6-nitro-1H-indazole (13) (0.5 g, 3.06 mmol) in DMF
(2 mL) were added K2CO3 (0.95 g, 7.65 mmol) and ethyl 2-bromoacetate
(0.4 mL, 3.06 mmol) and the resulting mixture was stirred at room
temperature for 18 h. The reaction was quenched with water, and the

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1990
Muri et al.
precipitate was collected, washed with water, and dried by air. The solid
was dissolved in hot AcOEt, decolorized with charcoal, filtered through
celite, and concentrated to give 0.610 g (80%) of the ester as a yellow
solid (m.p. 98–99ꢀC). H NMR (CDCl3, 400 MHz): ꢀ 8.30 (s, 1H, CH),
1
8.13 (s, 1H, CH), 7.97 (d, J ¼ 11.7 Hz, 1H, CH), 7.80 (d, J ¼ 11.7 Hz, 1H,
CH), 5.25 (s, 2H, CH2), 4.20 (q, J ¼ 9.5 Hz, 2H, CH2), 1.24 (t, J ¼ 9.5 Hz,
3H, CH3). 13C NMR: ꢀ 167.7 (C), 147.2 (C), 139.4 (C), 135.0 (CH), 127.9
(C), 122.5 (CH), 116.2 (CH), 106.2 (CH), 62.6 (CH2), 51.0 (CH2), 14.5
(CH3). ESMS m/z 250 (M þ 1).
(6-Amino-indazol-1-yl)-acetic Acid Ethyl Ester (15)
The nitro compound 14 (0.4 g, 1.60 mmol) was dissolved in
MeOH (8 mL) and CHCl3 (3 mL) and treated with hydrogen at
40 psi in the presence of 10% Pd/C (0.1 g) for 2 h. The mixture was
filtered through celite, and the filtrate was concentrated. The residue
was purified by flash chromatography (40% AcOEt/CHCl3) to provide
1
the amine as a yellow oil (0.175 g, 50%). H NMR (CDCl3, 400 MHz):
ꢀ 7.84 (s, 1H, CH), 7.44 (d, J ¼ 8.5 Hz, 1H, CH), 6.54 (d, J ¼ 8.5 Hz,
1H, CH), 6.40 (s, 1H, CH), 4.97 (s, 2H, CH2), 4.18 (q, J ¼ 7.2 Hz, 2H,
CH2), 3.90 (bs, 2H, NH2), 1.22 (t, J ¼ 7.2 Hz, 3H, CH3). 13C NMR:
ꢀ 168.7 (C), 146.9 (C), 142.4 (C), 134.8 (CH), 122.4 (CH), 118.4 (C),
113.2 (CH), 91.8 (CH), 62.0 (CH2), 50.5 (CH2), 14.5 (CH3). ESMS m/z
220 (M þ 1).
2-(6-Amino-indazol-1-yl)-N-hydroxy-acetamide (16a)
To a solution of ester 15 (0.5 g, 2.28 mmol) in 15 mL of MeOH
was added 3 mL (28.5 mmol) of 50% H2NOH aqueous solution.
The mixture was stirred at room temperature overnight. The preci-
pitate was filtered off and recrystallized from MeOH to give the
hydroxamic acid (0.375 g, 80%) as a yellow solid (m.p. 233–234ꢀC).
1H NMR (DMSO-d6, 400 MHz): ꢀ 10.81 (bs, 1H), 9.00 (bs, 1H), 7.68
(s, 1H, CH), 7.33 (d, J ¼ 11.3 Hz, 1H, CH), 6.46 (d, J ¼ 11.3 Hz,
1H, CH), 5.30 (s, 1H, CH), 4.72 (s, 2H, CH2), 3.43 (bs, 2H, NH2).
13C NMR: ꢀ 164.9 (C¼O), 148.8 (C), 143.1 (C), 133.9 (CH), 121.8
(CH), 117.0 (C), 113.2 (CH), 91.0 (CH), 49.7 (CH2). ESMS m/z 207
(M þ 1).

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Inhibitors of Helicobacter pylori Urease
1991
1-Hydroxycarbamoylmethyl-1H-indazol-6-yl-ammonium
Chloride (16b)
The procedure is similar to the general procedure for 7a. The product
was obtained as an orange solid in 80% yield. 1H NMR (DMSO-d6,
400 MHz): ꢀ 10.37 (bs, 1H, NH), 8.17 (s, 1H, CH), 7.85 (d, J ¼ 10.7 Hz,
1H, CH), 7.63 (s, 1H, CH), 7.15 (d, J ¼ 10.7 Hz, 1H, CH), 5.01 (s, 2H, CH2).
13C NMR: ꢀ 164.4 (C¼O), 162.7 (C), 140.2 (C), 134.6 (CH), 130.9 (C), 123.3
(CH), 117.1 (CH), 105.5 (CH), 50.2 (CH2). ESMS m/z 207 (M þ 1).
3-Amino-1-methoxycarbonylmethyl-1H-pyrazole-4-carboxylic
Acid Ethyl Ester (18a)
The procedure is similar to the general procedure for 3a. The product
was purified by chromatographic column using a mixture of hexane/
AcOEt in a 20–80% gradient. The product was obtained as yellow oil
1
in 70% yield. H NMR (CDCl3, 400 MHz): ꢀ 7.67 (s, 1H, 5-H), 4.76 (bs,
2H, NH2), 4.60 (s, 2H, CH2), 4.17 (q, J ¼ 5.7 Hz, 2H, CH2), 3.66 (s, 3H,
OCH3), 1.22 (t, J ¼ 5.7 Hz, 3H, CH3). 13C NMR: ꢀ 168.3 (C¼O), 164.4
(C¼O), 157.0 (C), 134.7 (CH), 100.7 (C), 60.2 (CH2), 53.1 (CH2), 53.0
(CH3), 14.7 (CH3). ESMS m/z 228 (M þ 1).
3-(Methoxycarbonylmethyl-amino)-1H-pyrazole-4-carboxylic
Acid Ethyl Ester (18b)
The procedure is similar to the general procedure for 3a. The product
was purified by chromatographic column using a mixture of hexane/
AcOEt in a 20–80% gradient. The product was obtained as yellow oil
1
in 25% yield. H NMR (CDCl3, 400 MHz): ꢀ 7.59 (s, 1H, 5-H), 5.37 (bs,
1H, NH), 4.70 (s, 2H, CH2), 4.22 (q, J ¼ 7.0 Hz, 2H, CH2), 3.71 (s, 3H,
OCH3), 1.29 (t, J ¼ 7.0 Hz, 3H, CH3). 13C NMR: ꢀ 168.6 (C¼O), 164.8
(C¼O), 151.0 (C), 140.5 (CH), 97.0 (C), 60.0 (CH2), 53.2 (CH3), 49.5
(CH2), 14.8 (CH3). ESMS m/z 228 (M þ 1).
3-Amino-1-hydroxycarbamoylmethyl-1H-pyrazole-
4-carboxylic Acid Ethyl Ester (19a)
The procedure is similar to the general procedure for 6a. The product
was obtained as a white solid in 65% yield (m.p. 160–161ꢀC). H NMR
1

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Muri et al.
(DMSO-d6, 300 MHz): ꢀ 10.80 (bs, 1H), 9.09 (bs, 1H), 7.89 (s, 1H, 5-H),
5.32 (bs, 2H, NH2), 4.41 (s, 2H, CH2), 4.13 (q, J ¼ 7.0 Hz, 2H, CH2), 1.21
(t, J ¼ 7.0 Hz, 3H, CH3). 13C NMR: ꢀ 164.5 (C¼O), 162.7 (C¼O), 157.3
(C), 135.6 (CH), 98.7 (C), 59.1 (CH2), 52.6 (CH2), 15.2 (CH3). ESMS 229
m/z (M þ 1).
4-Ethoxycarbonyl-1-hydroxycarbamoylmethyl-1H-pyrazol-
3-yl-ammonium Chloride (19b)
The procedure is similar to the general procedure for 7a. The product
was obtained as a white solid in 85% yield. 1H NMR (DMSO-d6,
300 MHz): ꢀ 10.34 (bs, 1H, NH), 8.14 (s, 1H, 5-H), 5.55 (bs, 3H, þNH3),
4.58 (s, 2H, CH2), 4.13 (q, J ¼ 7.0 Hz, 2H, CH2), 1.20 (t, J ¼ 7.0 Hz, 3H,
CH3). 13C NMR: ꢀ 165.2 (C¼O), 164.6 (C¼O), 159.6 (C), 134.2 (CH),
101.3 (C), 59.5 (CH2), 53.6 (CH2), 15.7 (CH3). ESMS 229 m/z (M þ 1).
3-(Trityl-amino)-1H-pyrazole-4-carboxylic Acid
Ethyl Ester (20)
To a solution of amine 17 (0.2 g, 1.29 mmol) in Et3N (0.211 mL,
1.54 mmol) was added a solution of trityl chloride (0.360 g, 1.29 mmol)
in CH2Cl2 (3 mL) at ꢂ10ꢀC. The reaction mixture was allowed to warm
until room temperature in stirring overnight. The organic layer was
washed with water and brine, dried, and evaporated to give 0.372 g
(75%) of compound 20 as a white solid (m.p. 65–66ꢀC) and 0.074 g
(15%) of compound 21. 1H NMR (CDCl3, 400 MHz): 7.50 (s, 1H,
5-H), 7.32–7.27 (m, 15H, Ph), 4.29 (q, J ¼ 7.1 Hz, 2H, CH2), 1.33
(t, J ¼ 7.1 Hz, 3 H, CH3). 13C NMR: ꢀ 165.5 (C¼O), 144.7 (C), 130.5
(C), 128.9 (CH), 128.3 (CH), 128.0 (CH), 71.8 (C), 60.1 (CH2), 14.9
(CH3). ESMS 398 m/z (M þ 1).
1-Methoxycarbonylmethyl-3-(trityl-amino)-1H-pyrazole-
4-carboxylic Acid Ethyl Ester (21)
The procedure is similar to the general procedure for 3a. The product
was obtained as a white solid (m.p. 198–199ꢀC) in 55% yield. H NMR
1
(CDCl3, 300 MHz): ꢀ 7.56 (s, 1H, 5-H), 7.41–7.09 (m, 15H, Ph), 4.37
(s, 2H, CH2), 4.27 (q, J ¼ 7.1 Hz, 2H, CH2), 3.61 (s, 3H, CH3), 1.30
(t, J ¼ 7.1 Hz, 3H, CH3). 13C NMR: ꢀ 168.0 (C¼O), 165.2 (C¼O), 155.8

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Inhibitors of Helicobacter pylori Urease
1993
(C), 146.3 (C), 129.5 (CH), 127.9 (CH), 126.8 (CH), 71.8 (C), 60.2 (CH2),
53.3 (CH2), 52.9 (CH3), 14.8 (CH3). ESMS 470 m/z (M þ 1). The trityl
deprotection was carried out in 1.5% HCl solution in acetone at room
temperature for 4 h. The product 18a was obtained in 72% yield.
ACKNOWLEDGMENTS
JSW gratefully acknowledges the Chemical Computing Group
(Montreal, Quebec) for use of the MOE modeling software, and
Dr. Abby L. Parrill (University of Memphis) for help with the computer
design methods. Financial support for this project was provided in part
by grants from the Centers for Disease Control CDC U50-CCU418839
and CDC UR3-CCU418652.
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Received in the USA September 13, 2002

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