Modifications around the hydroxamic acid chelating group of fosmidomycin, an inhibitor of the metalloenzyme 1-deoxyxylulose 5-phosphate reductoisomerase (DXR)

Article abstract of DOI:10.1016/j.bmcl.2012.09.021

Fosmidomycin derivatives in which the hydroxamic acid group has been replaced by several bidentate chelators as potential hydroxamic alternatives were prepared and tested against the DXR from Escherichia coli. These results illustrate the predominant role

Full text of DOI:10.1016/j.bmcl.2012.09.021

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6563–6567
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Modifications around the hydroxamic acid chelating group of fosmidomycin,
an inhibitor of the metalloenzyme 1-deoxyxylulose 5-phosphate
reductoisomerase (DXR)
⇑
⇑
Catherine Zinglé, Lionel Kuntz, Denis Tritsch, Catherine Grosdemange-Billiard , Michel Rohmer
Université de Strasbourg/CNRS, Strasbourg, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal 67081, Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2012
Revised 4 September 2012
Accepted 6 September 2012
Available online 15 September 2012
Fosmidomycin derivatives in which the hydroxamic acid group has been replaced by several bidentate
chelators as potential hydroxamic alternatives were prepared and tested against the DXR from Escherichia
coli. These results illustrate the predominant role of the hydroxamate functional group as the most effec-
tive metal binding group in DXR inhibitors.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Metalloenzyme
1-Deoxy-
D-xylulose 5-phosphate reducto-
isomerase
Metal chelating group inhibitors
Fosmidomycin derivatives
Metalloenzymes are a family of enzymes that contains in the
active site one or more metal ions, which are essential for their bio-
logical function. Metals are involved in structure stabilization of
the enzymes and/or in catalysis. They participate in numerous en-
zyme reactions including hydrolysis,1 oxido-reduction,2 isomeriza-
tion3 and electron transfer reactions.4 Since these enzymes are
mostly implied in essential metabolic pathways, their inhibition
affects the growth of living organisms.5 Inhibitors of metalloen-
zymes typically contain simultaneously a group that binds to the
catalytic metal ion and a moiety that mimics the substrate to
which the chelating group is attached, providing the specificity of
the binding.6
Phosphonate antibiotics such as fosmidomycin 3 or FR-900098
4 are naturally occurring potent inhibitors of the DXR (Scheme 2)
and present strong antibacterial and antimalarial activity.9,10 Due
to their moderate oral bioavailability and their fast clearance these
compounds cannot be used as drugs.11 In addition, many patho-
gens, such as Mycobacterium tuberculosis, are completely resistant
to fosmidomycin and its analogues.12 The crystal structure of the
Escherichia coli DXR-fosmidomycin complex was resolved at 2.5 Å
and revealed two binding sites in the catalytic domains: a specific
positively charged pocket anchors by hydrogen bonds the nega-
tively charged phosphonate and a chelating site for the binding
of the divalent metal cation by the two oxygen atoms of the
hydroxamate group.13 Based on the elucidation of crystal struc-
tures of DXR, several modifications of fosmidomycin and of its ana-
logue FR 900098 were carried out to expand the library of potential
DXR inhibitors and, most importantly, numerous analogues have
been synthesized to improve the pharmaceutical properties. The
modifications concern essentially the three-carbon spacer between
the hydroxamate and the phosphonate groups.14–16 Most of them
are, however, much less efficient than fosmidomycin. We replaced
the phosphonate group by bioisosteric groups (sulfonate, carboxyl-
ate) but the results were also disappointing, these compounds
being only weak inhibitors of the DXR.17
Among this family, the 1-deoxy-
to-isomerase (DXR), the second enzyme of the 2-C-methyl-
ritol 4-phosphate (MEP) pathway catalyzes the Mg2+ triggered
rearrangement of 1-deoxy- -xylulose 5-phosphate 1 (DXP) into a
non-isolable aldehyde and its concomitant NADPH-dependent
reduction into 2-C-methyl- -erythritol 4-phosphate 2 (Scheme 1).
D-xylulose 5-phosphate reduc-
D-eryth-
D
D
DXR is an attractive target for the development of new antimicro-
bials and herbicides.7 Indeed the MEP pathway is present in most
eubacteria, in green algae, in the chloroplasts of phototrophic
organisms and in some unicellular eukaryotes, but is absent in ani-
mals and fungi.8
Hydroxamates are monoanionic bidentate chelating groups that
bind Mg2+ with two oxygen donor atoms and form hydrogen
bound within the DXR active site. Most hydroxamic acids have
poor oral bioavailability and have binding affinities for metals such
as zinc(II), copper(II), iron(III) and nickel(II).18,19 To overcome some
⇑
Corresponding authors. Tel.: +33 368 851 349; fax: +33 368 851 345 (C.G.-B.);
tel.: +33 36 885 1345; fax: +33 36 885 1346 (M.R.).
E-mail addresses: grosdemange@unistra.fr (C. Grosdemange-Billiard), mirohmer
@unistra.fr (M. Rohmer).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.021

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C. Zinglé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6563–6567
Mg2+
OH
HO
OH OH
HO
O
NADPH
O
H
OP(O)(OH)2
OP(O)(OH)2
OP(O)(OH)2
OH
OH
2
1
Scheme 1. Reaction catalyzed by the DXR.
of these limitations, variations of the chelating group have also
been investigated based on the replacement of the hydroxamate
by an hydroxyurea, a benzoxazolone, a benzoxazolethione, an oxa-
loylpyridone, and catechols.20 In this context, we have previously
reported the synthesis of two phosphonohydroxamates 5 and 6
(Scheme 2) that present a reverse hydroxamate moiety with re-
spect to that of fosmidomycin. They show a biological activity
comparable to that of fosmidomycin, particularly the N-methyl-
ated compound 6, which is also efficient on a fosmidomycin-resis-
tant E coli. strain.21 The goal of our studies was to discover an
effective alternative to the hydroxamate metal binding group.
We investigated accordingly the replacement of the hydroxamate
group by other bidentate chelators such as a catechol,20c,22 a hydra-
zide,23 or a dithiocarbamate group.24 The modification of the
spacer length was also included in this study, and the hydroxamic
acid functionality was modified by alkylating the hydroxamate
oxygen. All compounds were tested on the DXR of E. coli for poten-
tial inhibition.
benzaldehyde.22 As its higher homologue 2-(2,3-dimethoxy-
phenyl)acetaldehyde is not commercially available, compound 7b
was prepared according to Scheme 3. The reduction of 2,3-dimeth-
oxycinnamic acid 12 with NaBH4 in the presence of LiCl, followed
by hydrogenation, gave alcohol 14. This compound was converted
to bromide 15 by treatment with phosphorus tribromide. Nucleo-
philic substitution with bromide 15 with the NaH generated anion
of dibenzyl phosphite gave the corresponding phosphonate 16. The
simultaneous deprotection of the methoxy and the benzyl groups
was performed in one step with boron tribromide and afforded
compound 7b.
The syntheses of the sodium salt of dithiocarbamates 9a and 9b
and their S-methylated derivatives 8a and 8b are shown in
Scheme 4. Treatment of the commercially available diethyl 2,2-
diethoxyethylphosphonate 17a and its C3 homologue diethyl 2,2-
diethoxypropylphosphonate 17b with a solution of 2 M HCl gave
respectively aldehydes 18a and 18b. Reductive amination of the
aldehydes with NaBH3CN and methylamine hydrochloride affor-
ded the amines 19a and 19b, which were converted into dithiocar-
bamates 9a and 9b by treatment with carbon disulfide in presence
The catechol phosphonate 7a was synthesized as previously
described by J.W. Frost, starting from commercial 2,3-dimethoxy-
OH
O
(HO)2(O)P
N
R
(HO)2(O)P
OH
N
R
O
3
4
R = H fosmidomycine
R = Me FR-900098
5 R = H
6 R = Me
O
P
O
S
S
OH
(HO)2(O)P
HO
P(O)(OH)2
HO
N
S Na
N
H
S
n
n
n
Na
7a
8a
9a
n = 1
9b n = 2
n = 1
n = 1
7b n = 2
8b n = 2
O
O
(HO)2(O)P
NH2
(HO)2(O)P
O
N
H
N
R
10
11
R = H
12 R = Me
Scheme 2. Structures of fosmidomycin 3, FR-900098 4, reverse phosphonohydroxamates 5 and 6 and target compounds 7–12.
OMe
O
OMe
OMe
ii
i
MeO
MeO
MeO
OH
OH
OH
64%
98%
13
12
14
OMe
OMe
OH
v
iii
37%
iv
13%
MeO
MeO
HO
Br
P(O)(OBn)2
P(O)(OH)2
92%
16
15
7b
Scheme 3. Synthetic route to compound 7b. (i) NaBH4, LiCl, THF/EtOH, 0 °C; (ii) H2, 10% Pd/C, MeOH; (iii) PBr3, Et2O reflux; (iv) NaH, THF, HP(O)(OBn)2, 0 °C; (v) BBr3, CH2Cl2/
H2O.

C. Zinglé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6563–6567
6565
O
OEt
OEt
O
P
O
S
ii
iii
i
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
H
N
H
HO
N
S
Na
n
n
n
n
18a
n = 1 99%
19a
19b
9a n = 1 72%
9b
17a n = 1
17b n = 2
n = 1 99%
n = 2 96%
Na
18b n = 2 96%
n = 2 78%
iv
S
S
v
(HO)2(O)P
(EtO)2(O)P
N
n
S
N
S
n
20a n= 1 62%
20b n= 2 73%
8a n = 1 78%
8b n = 2 84%
Scheme 4. Synthetic route towards dithiocarbamates 8a and 8b, 9a and 9b. (i) HCl 2 M aq; (ii) NH2Me.HCl, NaBH3CN, MeOH, 0 °C; (iii) CS2, NaOH 3 M, THF; (iv) CS2, Et3N, THF,
0 °C then MeI; (v) HCl 6 M aq, reflux, 2 days.
i
ii
Br
COOEt
(BnO)2(O)P
COOEt
(BnO)2(O)P
COOH
86%
74%
21
59%
22
v
iii
84%
O
O
O
(BnO)2(O)P
O
(BnO)2(O)P
NH2
N
R
N
H
24 R = H
25 R = Me
vi
56%
23
vii
iv
99%
O
(HO)2(O)P
NH2
(HO)2(O)P
O
N
H
N
R
10
11
12
R = H 91%
R = Me 76%
Scheme 5. Synthetic route to hydrazide 10 and O-methylated hydroxamates 11 and 12. (i) (BnO)2P(O)H, NaH, THF; (ii) LiOH, THF/H2O, rt; (iii) H2N–NH2, EtOH; (iv) H2, Pd/C,
EtOH; (v) NH2OMe.HCl, AlMe3, THF, À40 °C; (vi) NaH, THF, MeI; (vii) H2, Pd/C, MeOH.
of 3 M NaOH, a treatment that also released the free phosphonate
group from the ethyl diester. The S-methylated analogues were ob-
tained by addition of carbon disulfide on the amines 19a and 19b
in presence of triethylamine followed by in situ addition of methyl
iodide. Deprotection of the ethyl groups in acidic conditions affor-
ded the desired compounds 8a and 8b. The 1H NMR spectra of 20
and 8 display two peaks at ca. 3.20 and 3.40 ppm for the N-methyl
protons corresponding, respectively, to the Z and E conformers in a
ca. 60/40 ratio. In fact, it has been shown that the N-substituted
dithiocarbamates are present as an equilibrium mixture of the Z
and E conformations due to the restricted rotation around the
dithiocarbamate C–N bond.25
The synthesis of hydrazide 10 is described in Scheme 5. The
first step was the introduction of the phosphonate group. Depro-
tonation of dibenzyl phosphite with sodium hydride in THF affor-
ded the corresponding anion, which upon reaction with the
commercially available ethyl 4-bromobutanoate gave the corre-
sponding phosphonate 21. Hydrolysis of the ethyl ester 21 with
lithium hydroxide afforded the carboxylic acid 22, which was
converted into the hydrazides 23 by treatment with hydrazine.
The benzyl groups were removed by catalytic hydrogenolysis in
the presence of palladium over activated charcoal at room
temperature and atmospheric pressure to provide the desired
hydrazide 10.
Treatment of the ester 21 with methoxyamine hydrochloride in
the presence of trimethylaluminium afforded the O-methyl
hydroxamate 24.26
The N-methylation of the O-methyl hydroxamate 24 was
accomplished by using methyl iodide in the presence of NaH to
provide the expected compound 25. The benzyl groups of 24 and
25 were removed by catalytic hydrogenolysis with palladium over
charcoal under atmospheric pressure and at room temperature.
The yields were quantitative, and no further purification of the
O-methylated hydroxamates 11 and 12 was required.
The ability of the synthetic compounds 7–12 to inhibit the His-
tagged recombinant E. coli DXR was investigated. The rate of con-
version of DXP into MEP by the enzyme was determined by mon-
itoring the NADPH consumption at 340 nm with an UV–visible
spectrophotometer.21 Since fosmidomycin and probably most of
its derivatives are slow tight-binding inhibitors of the DXR,27 the
IC50 values of the inhibitors were determined with and without
pre-incubation (2 min at 37 °C) of the compounds 7–12 with the
enzyme and NADPH before the reaction was started by addition
of DXP. The results are summarized in Table 1.
Compared to fosmidomycin 3 and its reverse hydroxamate ana-
logue 6, all synthesized compounds were found to be either no or
weak inhibitors (millimolar IC50 values) of the E. coli DXR (Table 1).
Except for compound 11, the pre-incubation of the enzyme with
the different compounds did not improve notably the inhibition
potency (maximum 1.8 fold) while, in the case of fosmidomycin
The O-methylhydroxamate derivatives 11 and 12 were pre-
pared from phosphonate 21 as previously described (Scheme 5).

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C. Zinglé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6563–6567
Table 1
the corresponding hydroxamate 6 (2300 fold), was more efficient
and showed a slow tight-binding behavior as compared to the
other tested chelators. Indeed its IC50 decreased about ten-fold,
as observed with compounds 3 and 6, when the inhibitor is pre-
incubated for 2 min with the enzyme before starting the enzymatic
reaction. In contrast, the interactions of the O,N-dimethylated com-
pound 12 with DXR was less effective than all N-methyl hydroxa-
mate previously described, which were more effective inhibitors
than the non-methylated compounds.21 This is probably due to
the presence of the bulky O-methyl group, which prevents the
binding by steric hindrance.
In summary, fosmidomycin derivatives in which the hydroxa-
mic acid group has been replaced by several bidentate chelators
as potential hydroxamic alternative were prepared and tested
against the DXR of E. coli. Even if divalent Mg2+ is a hard ion and
prefers hard ligands with oxygen being the most preferred coordi-
nating atom followed by nitrogen, the replacement of the hydroxa-
mic group by hydrazine, catechol and O-methylated hydroxamate
moieties resulted in an increase of the IC50 value. These results
showed that the attempts to replace the hydroxamate group by
other chelating groups are ineffective and illustrate the predomi-
nant role of the hydroxamate functional group as the most effec-
tive metal binding group in DXR inhibitors.
Inhibition of recombinant His tagged E. coli DXR by fosmidomycin 3 and reverse N-
methylated phosphonohydroxamate 6 and chelating analogues 7–12
Compd
IC50
pre-incubation
(
l
M)a without
IC50 (l
M)a with
pre-incubation (2 min)
3
6
0.25
0.5
0.032
0.048
1200
nib
7a
7b
8a
8b
9a
9b
10
11
12
2000
nib
2800
nib
2700
nib
nib
nib
nib
nib
1800
11500
6900
1000
930
3800
a
Mean from at least 2 different assays. Errors were <5%.
ni = no inhibition at 1000 lM.
b
and compound 6, the enhancement was about 8 and 10 fold
respectively. Compounds 7b and 8b having a hydrocarbon spacer
with an additional methylene group showed a dramatic decrease
of the affinity of DXR with regard to the compounds 7a and 8a hav-
ing a three methylene carbon chain like fosmidomycin.17
As previously reported by Deng et al. catechol 7a is a weak
inhibitor, with regard of fosmidomycin, of the E. coli DXR. This
compound does not fit well in the active site. Either the interac-
tions between the catechol group and the cation or those between
the phosphonate group and the enzyme do not take place. Interest-
ingly they noted a slightly better inhibition (fivefold) with a cate-
chol having the phosphonate chain in beta position of one the
hydroxyl groups.28 This catechol has been also reported to be the
best Mycobacterium tuberculosis DXR inhibitor with an IC50 value
in the micromolar range, in a series of five compounds in which
the hydroxamic acid moiety has been replaced by metal binding
heterocycles.20c In those cases, the catechol group adopts a better
positioning in the active site leading to a tighter binding between
the enzyme and the inhibitor. Compound 7b did not inhibit the en-
zyme. We expected, however, that the additional methylene group
would increase the flexibility of the spacer and lead to a better fit-
ting of compound 7b into the active site. The absence of inhibition
with this compound may be explained by a steric hindrance pre-
venting the formation of the enzyme/inhibitor complex and/or by
the rigidity of the active site preventing its accommodation to lar-
ger molecule.
The high inhibition potency of fosmidomycin was due to the
ideal fitting of the molecule in the active site of DXR. The phospho-
nate group binds in the phosphate recognition site of DXP, the sub-
strate of the enzyme, and the hydroxamate group chelates
optimally to the catalytic Mg2+ cation. The two functional groups
responsible for the inhibitor binding are linked by a three methy-
lene spacer. Fosmidomycin is a slow-binding inhibitor; its binding
to the enzyme is followed by a conformational change leading to a
more stable complex.21,27 A preincubation of DXR with compounds
3 or 6 leads to an about 10 fold improvement of the IC50 values. It is
not known if the effective coordination results from the conforma-
tional change or if it takes place immediately after binding of the
inhibitor. If we assume that the phosphonate group of the different
potential inhibitors binds as fosmidomycin in the phosphate bind-
ing pocket, the low inhibitory potency of these molecules could re-
sult from the lack of formation of a strong coordination complex
between the tested chelating groups and the cation. The absence
of a strong binding could be explained by the fact that the chelat-
ing groups are not ideally placed with regard to the catalytic ion.
This is probably the case for catechol derivatives, a group known
to chelate Mg2+ ions as efficiently as a hydroxamate.20c Indeed
the inhibitory potency depends on the positions of the hydroxyl
groups: the compound with hydroxyls in positions 3,4 are more
efficient than the compound with hydroxyls in positions 2,3.28
Concerning the dithiocarbamate derivatives, the problem can also
come from the chelating capacity of the reactive group with regard
to the Mg2+ ion. The latter is a hard ion, which prefers hard ligands
and generally binds oxygen ligands in an octahedral coordination.
Nitrogen or sulfur tends to coordinate to soft and more polarizable
ions like zinc.31
Chelating agents such as dithiocarbamate are well-known me-
tal complexing compounds due to the presence of the anionic
CS2 moiety, which can coordinate mono- or bidentate cations.29
À
In our case, the replacement of the hydroxamate with a S-methyl-
ated dithiocarbamate does not improve the IC50 value. The relative
failure of the S-methylated dithiocarbamate 8a and 8b derivatives
to inhibit the DXR can be due to the soft base character of the sul-
fur atoms, which have a weak affinity for hard cations such as
Mg2+. Moreover dithiocarbamates compounds are known be unsta-
ble, and their rates of decomposition depend on the substituent on
the nitrogen, pH and temperature.30 In our enzyme assay condi-
tions (pH = 7.5), the sodium salt of dithiocarbamates 9a and 9b
decomposed releasing off carbon disulfide. Consequently, their
inhibition capacity could not be determined.
Replacing the hydroxamate chelating group with a hydrazide
group as in molecule 10 showed no improvement of the inhibition.
The IC50 value was similar to that obtained with 7a. The reason is
probably that the hydrazide group is protonated at the pH of the
enzymatic assays (pH 7.5), reducing the chelating potency of the
N–H with the Mg2+ ion.
Our results illustrate the predominant role of the hydroxamate
group as the most effective bidentate metal binding group in DXR
inhibitors.
Acknowledgements
The authors are indebted to B. Vincent, D. Sauer, M. Coppé and
Dr. L. Allouche for running the NMR experiments and H. Nierengar-
ten and M. Lebreton, for measuring the mass of the compounds. C.
Zinglé was a recipient of a grant from the ‘Ministère de la Recher-
che’. This work was supported by a grant from the ‘‘Agence Natio-
nale de la Recherche’’ (Grant Nb ANR-06-BLAN-0291-01).
With O-methylated hydroxamate 11 and its O,N-dimethylated
derivative 12, the inhibition, although less effective than that of

C. Zinglé et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6563–6567
6567
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Supplementary data
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