Synthesis of tetrazole analogues of phosphonohydroxamic acids: An attempt to improve the inhibitory activity against the DXR

Article abstract of DOI:10.1016/j.bmcl.2013.01.080

This work is focused on the design of new antimicrobial drugs and on the development of lipophilic inhibitors of the DXR, the second enzyme of the MEP pathway for the biosynthesis of isoprene units in most bacteria, by replacing the phosphonate group of fosmidomycin derivatives by a tetrazoyl moiety capable of multiple hydrogen bonding. The N- and C-substituted tetrazole analogues of phosphonohydroxamate inhibitors were synthesized and tested on the DXR of Escherichia coli. This work points out the hypothesis that the phosphonate/phosphate recognition site might be too rigid to accommodate other functional groups.

Full text of DOI:10.1016/j.bmcl.2013.01.080

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1643–1647
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of tetrazole analogues of phosphonohydroxamic acids:
An attempt to improve the inhibitory activity against the DXR
⇑
⇑
Anh Thu Nguyen-Trung, 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:
This work is focused on the design of new antimicrobial drugs and on the development of lipophilic
inhibitors of the DXR, the second enzyme of the MEP pathway for the biosynthesis of isoprene units in
most bacteria, by replacing the phosphonate group of fosmidomycin derivatives by a tetrazoyl moiety
capable of multiple hydrogen bonding. The N- and C-substituted tetrazole analogues of phosphonohydr-
oxamate inhibitors were synthesized and tested on the DXR of Escherichia coli. This work points out the
hypothesis that the phosphonate/phosphate recognition site might be too rigid to accommodate other
functional groups.
Received 12 December 2012
Revised 15 January 2013
Accepted 17 January 2013
Available online 29 January 2013
Keywords:
Tetrazole analogues of fosmidomycin
Inhibitors of 1-deoxy-D-xylulose 5-
Ó 2013 Elsevier Ltd. All rights reserved.
phosphate reducto-isomerase
Isoprenoid biosynthesis via the MEP
pathway
Tetrazoles represent an important class of heterocycles, which
exhibit a wide range of application in synthetic and medicinal
chemistry. They have the particularity to be resistant to biological
degradation and therefore they are used as isosteric substituents of
various functional groups in the development of pharmaceutical
products.1 5-Substituted-1H-tetrazoles have been widely reported
as non-classical isosteres for carboxylic acids.2,3 Indeed, 5-subtitut-
ed-1H-tetrazoles have pKa values that are similar to those of the
corresponding carboxylic acids (4.5–4.9 vs 4.2–4.4) and are ionized
at physiological pH. However, it has been shown that anionic tet-
razoles are ten times more lipophilic than carboxylic acids.4 This
increased lipophilicity allows these compounds an easier crossing
of the cell plasma membrane. In medicinal chemistry, 1,5-disubsti-
tuted tetrazoles have attracted much attention, as these deriva-
tives mimic cis amide bonds and were therefore used as
peptidomimetics.2b In contrast, few examples of 1-substituted tet-
razoles (for instance b-lactam antibiotics5,6) as well 2-substituted
tetrazoles have been mentioned in the literature, probably due to
the difficulty to obtain such compounds.7 Even if the replacement
of a phosphate8 or phosphonate9,10 by a tetrazoyl group in inhibi-
tor analogs requiring a negative charge moiety enhances the cell
permeability and is effective, it is impossible to predict in advance
the biological activity of such a replacement.
Part of our work on the design of new antimicrobials is based on
the inhibition of the MEP pathway leading to isopentenyl diphos-
phate (IPP) and dimethylallyl diphosphate (DMAPP), the two
essential precursors of all isoprenoids.11 This metabolic route is
present in most bacteria, including pathogenic bacteria such as
Mycobacterium tuberculosis, and in the protozoan Plasmodium
parasite responsible for malaria, but is absent in mammals.12 We
focused our attention on the development of lipophilic inhibitors
of the deoxyxylulose 5-phosphate reductoisomerase (DXR), the
second enzyme of the MEP pathway. Efficient inhibitors known
today are phosphonohydroxamic acids such as fosmidomycin 1,
FR-900098 2 and compound 413,14 (Scheme 1). Fosmidomycin
has an antibacterial activity against many Gram-negative bacteria
and an antimalarial activity in clinical trials.15,16 Since, fosmidomy-
cin 1 is highly hydrophilic, it has a short half lifetime in plasma and
a poor oral availability. Moreover, the fosmidomycin 1 is not active
on mycobacteria such as Mycobacterium tuberculosis due to the lack
of cellular uptake.17 In an attempt to find more lipophilic inhibitors
of DXR and consequently to improve their pharmacological proper-
ties, putative inhibitors have been synthesized. Their structures are
R
N
R
HO
N
O
P(O)(OH)2
P(O)(OH)2
O
OH
⇑
Fosmidomycin
FR900098
1
2
3
4
R = H
R = CH3
Corresponding authors. Tel.: +33 368 851 349; fax: +33 368 851 345 (C.G.-B.);
tel.: +33 368 851 346; fax: +33 368 851 345 (M.R.).
E-mail addresses: grosdemange@unistra.fr (C. Grosdemange-Billiard), miroh-
mer@unistra.fr (M. Rohmer).
Scheme 1. Inhibitors of the deoxyxylulose reducto-isomerase.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.080

1644
A. T. Nguyen-Trung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1643–1647
R
N
R
N
R
N
N
N
HO
HO
( )n
HO
( )n
( )n
N
N
N
N
O
N
O
N
N
O
N
HN
N
N1: a
N2: b
R = H n =2: 13 R = CH3 n =0: 11
12
5a,b
6a,b
R = H n =0:
n =1: 7a,b
9a,b
R= CH3 n =0:
n =1: 8a,b
10a,b
n =1:
n =2: 14
n =2:
n =2:
Scheme 2. N-substituted and C-substituted tetrazole analogues of phosphonohydroxamates 3 and 4.
widely based on that of fosmidomycin 1 and phosphonohydroxa-
mates 3 and 4 by replacing the hydroxamic acid as well as the
phosphonic acid moieties by other chelating groups or phospho-
nate isosteres capable of hydrogen bonding, without conclusive re-
sults.18–20 In addition, coordination chemistry was used to find
lipophilic inhibitors of DXR. These modifications yielded com-
pounds presenting at best an activity close to that of fosmidomycin
and in most case reduced inhibitory activity.20,21
the substitution over the elimination, we used the commercial
3-bromopropionic acid as starting material allowing the formation
of a crude mixture of the two regioisomers 15, which was directly
used in the next step (Scheme 3).
To introduce the hydroxamate moiety two methods were used.
The first one was an addition/elimination reaction using O-benzyl-
hydroxylamine hydrochloride, which was treated with LiHMDS in
large excess to afford the corresponding anion, which reacted with
ethyl esters 16a,b and 17a,b to give 19a,b and 20a,b as a mixture of
two Z/E conformers in a, respectively 70/30 ratio. To prepare the
shorter tetrazole derivatives 18a,b, we used an amidation coupling
reagent. The crude mixture 15 was treated with O-benzyl-hydrox-
ylamine in the presence of 1-(3-dimethyl-aminopropyl)-3-ethyl-
carbodiimide hydrochloride (EDCI) in THF to afford the
hydroxamates 18a and 18b as a mixture of two Z/E conformers
(70/30). The 1H NMR spectra of 18a–20a and 18b–20b show two
signals for the –CH2CONROBn protons: one major signal in the
ca. 2.1–2.8 ppm region corresponding to the protons of the Z con-
former and a second deshielded signal at ca. 2.3–3.1 ppm corre-
sponding to the protons of the E conformer. It has been shown
that the N-substituted and N- and O-substituted hydroxamic acids
are present as an equilibrium mixture of Z and E conformations due
to the restricted rotation around the C–N bond.24
The N-methylation of the hydroxamates 18–20 was accom-
plished by using methyl iodide in the presence of DBU to provide
the expected compounds 21–23 present as the sole E conformer
as expected.25 Finally, the benzyl group of 18–23 was removed
by catalytic hydrogenolysis with palladium over charcoal under
atmospheric pressure at room temperature in quantitative yield
requiring no further purification of the hydroxamate tetrazoles 7
and 9 that were obtained as a mixture of the two Z and E conform-
ers in favor of the Z conformer, whereas hydroxamate tetrazoles 5,
6 and 8 appear as the sole E conformer. The 1H NMR spectrum in
D2O of the N-methylated hydroxamate tetrazole 10 with a longer
spacer surprisingly showed three sets of signals for the N-methyl
protons suggesting that the two isomers 10a and 10b are present
as a mixture of three conformers. The two singlets at 3.22 and
3.36 ppm correspond, respectively to the E and Z conformers as re-
ported in the literature18 and the third deshielded singlet at
2.70 ppm might be assigned two a cyclic conformer resulting from
an intramolecular hydrogen bond between the proton of the
hydroxamate (OH) and one of the lone electron pairs on one of
the nitrogen atoms of the tetrazole.
As the affinity of tetrazole analogues for their biomolecular tar-
gets is, however, not predictable, and as the properties of a tetra-
zole group (increased the lipophilicity, hydrogen bonding
capability and metabolic resistance), are quite interesting, we syn-
thesized tetrazolic derivatives of phosphonohydroxamates 3 and 4
and determined their inhibitory potential on the DXR (Scheme 2).
Two series of derivatives were aimed: on the one hand the
hydroxamate chelating group was attached via a linker on the
N-1 nitrogen atom (compounds noted a, 5a–10a) or the N-2 nitro-
gen atom (compounds noted b, 5b–10b) and, on the other hand on
the C-5 carbon atom (11–14). The physicochemical properties of
N- and C-substituted derivatives are quite different. The main
difference concerns essentially the charge of the tetrazolic moiety.
When the tetrazolic ring is substituted on the C-5 atom, it is
negatively charged, while, when the tetrazole group is substituted
on one of the N atoms, it is neutral. As the active site of the DXR is
surrounded by a flexible loop, which closes after substrate or
inhibitor binding, it is difficult to predict the optimal length of
the linker. Consequently, we synthesized tetrazole analogues with
spacers of different lengths. These compounds were all tested
in vitro on the DXR isolated from Escherichia coli.
Synthesis of the N-1 and N-2 substituted tetrazole derivatives
5a,b–10a,b
The synthetic route used for the preparation of N-1 (noted a)
and N-2 (noted b) substituted tetrazole derivatives 5a,b–10a,b is
outlined in Scheme 3. The keys steps are the alkylation of commer-
cial tetrazole at the first step allowing the formation of the corre-
sponding N-1 and N-2 substituted tetrazoles in one step followed
by the synthesis of the hydroxamate chelator. Nucleophilic substi-
tution of commercially available ethyl 4-bromobutyrate and its C5
homologue ethyl 5-bromovalerate with tetrazole in presence of
K2CO3 at reflux in dry acetone gave, respectively alkylated tetra-
zoles 16 and 17 as a mixture of two regioisomers in a ca. 1/2 ratio
in favor of the N-2 alkylated tetrazole as predicted by ab initio
molecular orbital calculations (Scheme 3).22 Separation by flash
chromatography afforded N-1 (16a, 17a) and N-2 (16b, 17b) regioi-
somers as pure compounds. They were identified by 1H and 13C
NMR according to the literature. Signals of the C-5 tetrazolic car-
bon and H-5 proton for the N-2-substituted isomer appear at lower
field than those of the corresponding N-1-substituted isomer (ca.
153 vs 148 ppm in 13C NMR and 8.9 vs 8.5 ppm in 1H NMR).23
Alkylation of the tetrazole with the commercial ethyl 3-bromopro-
pionate in the previous described conditions led predominantly to
ethyl propenoate, a product of the elimination reaction. To favor
Synthesis of the C-substituted tetrazole derivatives 11–14
The synthesis of C-substituted tetrazole derivatives 11–14 is de-
scribed in Scheme 4. The key step is the formation of the tetrazole
cycle by a 1,3-dipolar cycloaddition between a cyanide and an
azide ion. The first step was the introduction of a cyano group.
Nucleophilic substitution of the commercial ethyl 4-bromobuty-
rate and ethyl 5-bromovalerate with sodium cyanide in presence
of a catalytic amount of tetrabutylammonium iodide at reflux in
an ethanol/DMF (3/2) solution afforded the corresponding nitrile

A. T. Nguyen-Trung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1643–1647
1645
N
N
O
N
N
O
N
N
O
N
Br
i
OR
OEt
OEt
n
n
N
n
1: 2
n = 0
R = H
n=1: 16a 32%
16b
n=1:
65%
n = 1, 2 R= Et
17a
n=2:
35%
n=2: 17b 63%
iii
ii
N
N
N
N
O
N
O
n
N
v
O
iv
N
N
N
OBn
OBn
OH
N
N
N
N
N
n
n
H
n=0
15
n=0: 21a 40% 21b: 34%
n=1: 22a 35% 22b: 42%
n=0: 18a 13% 18b: 31%
19a
19b
: 68%
n=1:
67%
23a
23b
: 47%
n=2: 20a 58% 20b: 64%
n=0:
43%
vi
vi
N
N
N
O
N
O
N
N
OH
OH
N
N
N
N
n
n
H
6a,b
n=0:
5a,b
7a,b
n=0:
n=1:
100%
100%
8a,b
n=1:
n=2: 10a,b
n=2: 9a,b
Scheme 3. Synthesis of the N-1 and N-2 substituted tetrazole derivatives 5a,b–10a,b. Reagents and conditions: (i) tetrazole, K2CO3, acetone, reflux, 10 h; (ii) LiHMDS,
NH2OBnꢀHCl, THF, ꢁ78 °C; (iii) 0.45 M tetrazole in CH3CN, Et3N, rt, 24 h; (iv) EDCI, NH2OBnꢀHCl, THF, rt; (v) MeI, DBU, THF, rt; (vi) H2, Pd/C, MeOH.
O
O
n
O
i
ii
NC
OBn
Br
NC
N
OR'
OR'
n
n
H
n=0: 27 67%
28
n = 0: 24 54% R = H
n = 1: 25 78% R = Et
n=0
n =1,2 R' = Et
R' = H
n=1:
74%
26
n=2: 29 61%
n = 2:
82% R = Et
n =2, iv
OBn
iii
N
N
N
O
N
O
O
N
N
v
iv
OH
NC
OBn
N
N
N
R
N
R
N
n
n
n
H
H
n = 0: 33 20% R = Me
34
n = 2: 35 18% R = H
n = 2: 36 20% R = Me
n=0: 30 32%
31
38%
n = 0: 11 R = Me
12
n = 2: 13 R = H
n = 2: 14 R = Me
:
n = 1
15% R = Me
n=1:
n=2: 32 42%
n = 1:
R = Me
100%
Scheme 4. Synthesis of the C-substituted tetrazole derivatives 11–14. Reagents and conditions: (i) NaCN, Bu4NI cat, EtOH/DMF (3:2), reflux, 10 h; (ii) n = 0, EDCI, DMAP,
NH2OBnꢀHCl, THF, rt, n = 1,2, LiHMDS, NH2OBnꢀHCl, THF, ꢁ78 °C; (iii) MeI, DBU, THF, rt; (iv) NaN3, ZnBr2, H2O/iPrOH (2/1), reflux; (v) H2, Pd/C, MeOH.
ester derivatives 25 and 26 in 78% and 62% yield, respectively. In
these conditions, the commercial ethyl 3-bromopropanoate gave
predominantly the elimination product, whereas 3-bromopropion-
ic acid led to the shorter C2 nitrile acid 24 in good yield. As previ-
ously described, the hydroxamate derivatives 27–29 were obtained
from the nitrile acid 24 and from the nitrile esters 25 and 26 as a
mixture of Z/E conformers with a predominant Z conformer
(Scheme 4). The N-methylation of 27–29 was achieved by using
the same conditions as described above affording the N-methyl-
ated derivatives 30–32 in moderate yields as a sole E conformer.
Few methods of preparation of a tetrazole cycle by a 1,3-dipolar
cycloaddition between an unactivated alkyl nitrile and an azide
salt have been described. All tested methods26 afforded non-iden-
tified byproducts except the reaction described by Demko and
Sharpless.27 This method was performed in presence of zinc bro-
mide by refluxing in a water/isopropanol (2/1) mixture. In these
conditions, the N-methylated hydroxamate tetrazole derivatives
33–34, 36 were obtained as a sole E conformer whereas the N–H
tetrazole derivatives 35 gave a mixture of Z/E conformers in a
90/10 ratio.
Finally, the benzyl group was removed by catalytic hydrogen-
olysis in the presence of palladium over activated charcoal at
room temperature and atmospheric pressure to provide the
desired C-substituted tetrazoles 11–14 as the sole E conformer
except for the tetrazole 13, which is present as a mixture of
three conformers. In fact, the 1H NMR spectrum of 13 in D2O
showed three sets of triplets for the CH2CONHOH protons at d
2.08, 2.16, and 2.18 ppm corresponding, respectively to the Z
and E conformers accompanied with a third conformer. Variable
temperature 1H NMR experiments performed at different tem-
peratures (25, 40, 50 and 65 °C) indicated a coalescence of the
two signals corresponding to the CH2CONHOH protons of the E
conformer and the additional one. Since the N-methylated
hydroxamate tetrazole 14 is present as a sole E conformer, a
putative cyclic conformer, resulting from an intramolecular
hydrogen bond between the proton (N–H) of the hydroxamate

1646
A. T. Nguyen-Trung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1643–1647
and the lone electron pair on one of the nitrogens of the tetra-
zole, is a likely structure.
being by far the most efficient among the other C-substituted tet-
razoles 11, 13 and 14, seemed to be the most suitable for an opti-
mal binding. As previously reported for other fosmidomycin
analogues,14 the N-methylation of the hydroxamate group
improves the inhibitory potency of the compounds. Here also the
tetrazole derivative 14 with an N-methylated hydroxamate group
is more active than compound 13 whose hydroxamate group is
not methylated (Table 1 and 4.9 vs 44 mM).
Compared to the C-substituted tetrazoles, the N-substituted tet-
razoles were expected to have different binding potentials. The
ability to generate hydrogen bonds is maintained but the H-donor
or the nitrogen acceptor atoms should be differently positioned
with the possibility to bind to other amino acids present in the ac-
tive site. The aromatic character of the heterocycle could even al-
low binding with aromatic amino acids of the active site via pp
Biological activity of the C- and N-substituted tetrazole
derivatives
All tetrazole compounds were tested on the recombinant His-
tagged DXR of E. coli.14 Suspecting that they are, like fosmidomy-
cin, slow binding inhibitors, they were pre-incubated with DXR
during 2 min in the presence of NADPH. The residual activity was
measured after initiating the enzymatic reaction by addition of
DXP. The results are given in Table 1. Compared to fosmidomycin
or compound 4, all the tested compounds are poor inhibitors of
DXR.
The tridimensional structure of the ternary complex (DXR–
NADPH–fosmidomycin) allowed solving the binding mode of fosm-
idomycin to DXR. Concerning the phosphonate group, the inhibitor
essentially binds to the enzyme via H-bonds with amino acids of
the active site.28 The importance of the negative charge of the
phosphonate in the binding is under debate as the replacement
of the phosphonate by non-charged20,21 or other negatively
charged groups (carboxylate or sulfonate)18 led to a dramatic de-
crease of the inhibitory potency. The C-substituted tetrazoles
which are negatively charged at physiological pH have found com-
mon usage as an non-classical isostere replacement of the carbox-
ylic acid moiety in the development of biologically active
substances.1,2 The fosmidomycin analogues with a tetrazolate
group 12 was about 30 times less efficient than its carboxylate
stacking interactions or with basic amino acids via cation–p inter-
actions.29,30 One of the main differences between N- and C-substi-
tuted tetrazoles is that the former are not charged. The inhibitory
effect of the N-substituted derivatives 5–10 is listed in Table 1.
None of them showed a significant inhibition potential. Moreover,
the N-substituted compounds being much less soluble in the incu-
bation buffer than the C-substituted, testing at higher concentra-
tion than these indicated in Table 1 was not possible. At the
highest tested concentration the inhibition did not exceed 15% of
the control. The N-substituted derivatives 5–10 were not recog-
nized by the DXR and probably none of the foreseen interactions
between the potential inhibitors and the enzyme take place. No an-
swer about the requirement of a negatively charged group in fosm-
idomycin-like inhibitors to be recognized by DXR could be given.
Despite the inefficiency of the tetrazole compounds to inhibit
DXR, the ability to inhibit bacterial growth (Escherichia coli) was
checked by the disc diffusion method but none was able to inhibit
bacterial growth when 400 nmol of compounds were spotted on
the paper discs.
derivative (800 vs 25 l
M).19 The replacement of a carboxylate by
a tetrazole ring thus does not improve in that case the inhibitory
potential. The difference of inhibitory potency between the fosmi-
domycin analogues with a tetrazole group and a carboxylate may
result essentially from structural differences between the hetero-
cycle and the carboxylic group. The tetrazole group has a rigid pla-
0
To our knowledge, the different attempts performed by us and
others to improve the inhibitory activity of fosmidomycin and its
analogues, by replacement of the phosphonate group were not
conclusive. One of the reasons might be due to the rigidity of the
phosphonate/phosphate recognition site preventing a necessary
accommodation of the pocket to the different analogues bearing
other functional groups than a phosphonate/phosphate. Moreover,
the conformational change of the enzyme, observed after the bind-
ing of the inhibitor, strengthens the interactions between the
inhibitor and the enzyme. This proposal is reinforced by the fact
that the length of the carbon linker between the hydroxamate
and the phosphonate groups is an essential aspect in the inhibition
potency of fosmidomycin analogues.
nar structure and its H-bond environment is extended by ca. 1.2 ÅA
by comparison with carboxylate analogues.29 While the tetrazole
ring has several possibilities to form H-bonds with amino acids
of the active site, it seems evident that such interactions do not
take place. Recently, Andaloussi et al. replaced the phosphonate
of FR900098 2 by diverse groups including a tetrazole, but none
has a significant inhibitory power.20
As the chain length of the linker between the two functional
groups is primordial for inhibitory activity,18 we synthesized ana-
logues with variable chain lengths from two to four methylene
groups. With a linker of three methylene groups, compound 12,
Table 1
Concerning the binding of the tetrazole derivatives, at least one
of the two binding sites is probably not thoroughly occupied by
one of the potential binding groups. The attaching chronology of
the two groups involved in the interactions with the enzyme
should help to determine which site is not filled.
Inhibition of recombinant His tagged E. coli DXR by
fosmidomycin 1, phosphonohydroxamate 4, N-sub-
stituted tetrazoles 5–10 and C-substituted tetrazoles
11–14
Compounds
Inhibition (IC50)
Fosmidomycin 1
4
32 nM14
48 nM14
>0.6 mMa
>1.0 mM
>0.6 mMa
>0.6 mMa
>0.6 mMa
>0.6 mMa
47 mMb
0.8 mM
Supplementary data
5a/5b
6a/6b
7a/7b
8a/8b
9a/9b
10a/10b
11
12
13
14
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.01.080.
References and notes
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4.9 mM
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Compounds, slightly soluble in water, were first
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b
Value obtained by extrapolation.

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