Coordination chemistry based approach to lipophilic inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase

Article abstract of DOI:10.1021/jm9012592

1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC₅₀ of 1.4 μM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20-100 μM (or 3.7-19 μg/mL).

Full text of DOI:10.1021/jm9012592

J. Med. Chem. 2009, 52, 6539–6542 6539
DOI: 10.1021/jm9012592
DXR inhibitors (Chart 1) have been reported, but they possess
moderate inhibitory activity (IC50 of ∼4and7μM). In addition,
a high-throughput screening of 32 000 compounds only yielded
30 hits with IC50 < 20 μM. However, the structures of these hits
were not disclosed and these compounds therefore cannot be
confirmed and further developed. Here, we report the discovery
of novel, lipophilic DXR inhibitors with good antibacterial
activity, using a coordination chemistry and structure based
approach.
Coordination Chemistry Based Approach to
Lipophilic Inhibitors of 1-Deoxy-D-xylulose-
5-phosphate Reductoisomerase
Lisheng Deng,† Sandeep Sundriyal,† Valentina Rubio,§
Zheng-zheng Shi,§ and Yongcheng Song*,†
†Department of Pharmacology, Baylor College of Medicine,
Houston, Texas 77030, and §Department of Radiology,
The Methodist Hospital Research Institute, 6565 Fannin Street,
Houston, Texas 77030
DXR is a Mg2þ-dependent enzyme, catalyzing the isomer-
ization and reduction of 1-deoxy-D-xylulose-5-phosphate
(DXP) to 2-C-methyl-D-erythritol-4-phosphate with NADPH
as a hydride donor. The crystal structure of the DXR-1
complex9 shows that the hydroxamate group of 1 chelates
the central Mg2þ ion, which is anchored to the protein by
coordination to the side chains of the residues Asp149, Glu151,
and 230 (see Supporting Information Figure S1). The substrate
DXP binds to DXR in a similar manner (see Supporting
Information Figure S1).10 These results suggested that coordi-
Received August 21, 2009
Abstract: 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR)
in the non-mevalonate pathway found in most bacteria is a validated
anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is
active against Gram-negative bacteria. A coordination chemistry and
structure based approach was used to discover a novel, lipophilic DXR
inhibitor with an IC50 of 1.4 μM. It exhibited a broad spectrum of
activity against Gram-negative and -positive bacteria with minimal
inhibition concentrations of 20-100 μM (or 3.7-19 μg/mL).
nation chemistry could be used to design a strong Mg2þ
chelating group as a viable approach to DXR inhibition.
-
Mg2þ is a hard metal ion because of its small ionic radius,
high electronegativity, and low polarizability. It therefore
only forms stable complexes with dioxygen based, hard
ligands, such as catechol and hydroxamate. In addition,
the stability constant (k1) of the Mg2þ-catechol complex was
Despite great success in the development of antibiotics,
bacterial infections are still the number 1 cause of human
mortality in the world, killing ∼6 million people each year.
Furthermore, drug resistant bacteria have reached epidemic
levels during the past few decades.1 Even in developed coun-
tries, bacterial infections have now become a serious threat to
public health, mainly because of rising drug resistance. On the
other hand, production of new antibiotics by the pharmaceu-
tical industry has decreased considerably since 1980.2 There is
therefore a pressing need to find new drugs to combat
bacterial infections that are resistant to current therapies.
1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXRa)
in the non-mevalonate isoprene biosynthesis pathway
(Figure 1) is an attractive target for developing novel anti-
infective drugs,3 since humans do not have the enzyme or its
homologues. The non-mevalonate pathway is used by the vast
majority of bacteria and apicomplexan protozoa (e.g., malaria
parasites) to make essential isopentenyl diphosphate and
dimethylallyl diphosphate, which are two common precursors
for biosynthesis of all isoprenoids/terpenoids. Fosmidomycin
(1, Chart 1), a naturally occurring antibiotic,4 has been found
to be a very potent DXR inhibitor.5 It has also shown
antimalarial activity in preclinical studies and recent clinical
trials.6 However, 1 has limited cellular uptake for many
bacteria7 and a short half-life (∼1.5 h) in plasma because of
its high hydrophilicity.
found to be 1.7 ꢀ 105,11 which is ∼3ꢀ as stable as the Mg2þ
-
hydroxamic acid complex (k1 = 5.2 ꢀ 104),12 suggesting
catechol compounds, such as 2-4 in Chart 2, that mimic the
structure of 1, could be DXR inhibitors. Indeed, 2 was found
to be an inhibitor of E. coli DXR with an IC50 of 24.8 μM.
Although 3 had only 25.7% inhibitory activity at 100 μM
against the enzyme, 4 was found to be a good DXR inhibitor
with an IC50 of 4.5 μM. A docking study using Glide
13
€
(in Schrodinger 2008) showed that it could have a similar
binding mode as 1, with catechol chelating the Mg2þ and the
phosphonate located very close to that of 1, as shown in
Figure 2A. In line with the result, the analogous compound 5,
having a carboxylate group with less electrostatic interactions
(compared to a phosphonate), exhibited only weak inhibition
against the enzyme.
When 4 was tested against the growth of four bacteria that
use the non-mevalonate pathway, i.e., E. coli, Pseudomonas
aeruginosa, Bacillus anthracis, and Micrococcus luteus, it
exhibited, however, only weak antibacterial activity, with
minimal inhibition concentrations (MIC, the lowest concen-
tration of an agent that can inhibit visible bacterial growth
upon 24 h of incubation at 37 °C) being g1000 μM, as shown
in Table 1. The polar, negatively charged phosphonate group
(at physiological pH) might limit the cell membrane perme-
ability of 4, resulting in high MIC values.
To design more lipophilic inhibitors that could have better
cell permeability, we further looked into the DXR structure
and found, beside the 1/DXP and NADPH binding sites,
a mostly hydrophobic pocket that can be exploited (see
Supporting Information Figure S2). Compounds 6 and 7
(Chart 3), which contain a catechol as a Mg2þ chelator and
a simple lipophilic group (i.e., phenyl or benzyl) that could
occupy the hydrophobic pocket, as suggested by our dock-
ing studies (Figure 2B), were designed and synthesized.
Much interest has therefore been generated to develop
potent DXR inhibitors. However, it has turned out to be a
great challenge.8 Except FR900098 (Chart 1), other derivatives/
analogues of 1 with a lipophilic group invariably have
considerably reduced DXR inhibitory activity and exhibit no
antibacterial activity. Two structurally distinct, bisphosphonate
*To whom correspondence should be addressed. Phone: (713) 798-
7415. Fax: (713) 798-3145. E-mail: ysong@bcm.edu.
a Abbreviations: DXR, 1-deoxy-D-xylulose-5-phosphate reductoi-
somerase; DXP, 1-deoxy-D-xylulose-5-phosphate; MIC, minimal inhi-
bition concentration.
r
2009 American Chemical Society
Published on Web 10/19/2009
pubs.acs.org/jmc

6540 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Deng et al.
Table 1. MICs (μM) against Four Bacteria
Gram-negative bacteria
Gram-positive bacteria
compd
E. coli
P. aeruginosa
B. anthracis
M. luteus
4
6
7
8
1
>1000
500
1000
100
10
1000
200
200
50
1000
200
200
20
>1000
200
200
100
20
100
0.1
5
>1000
1
20
ampicillin
kanamycin
5
10
500
200
Chart 3. Structures of 6-18 and Their IC50 Values (or %
Inhibition at 100 μM) against E. coli DXR in Parentheses
Figure 1. Non-mevalonate and mevalonate isoprene biosynthesis
pathways.
Compound 8 exhibited good activity against all four bac-
terial species, with MICs of 20-100 μM (or 3.7-19 μg/mL)
(Table 1). Three known antibiotics, i.e., 1, ampicillin, and
kanamycin, were included in the test as positive controls.
Consistent withprevious results,4 1 had potent activity against
Gram-negative bacteria but displayed weak or no activity
against Gram-positive bacteria because of limited cellular
uptake.7 In addition, although 1 (IC50 = 80 nM) is ∼16ꢀ
more activethan 8 against the E. coli DXR(enzyme), 8 ismore
active against the growth of Gram-positive bacteria. This
could be due to (1) increased lipophilicity and/or bioavail-
ability of 8, (2) improved activity of 8 against DXRs from
other bacteria, or both. It is also remarkable that 8 exhibited
impressive antibacterialactivity(MIC=50μMor9.4μg/mL)
against a clinical isolate of P. aeruginosa. The bacterium
P. aeruginosaisa major hospital-acquired pathogen notorious
for its significant intrinsic and acquired antibiotic resis-
tance. This clinical strain is highly resistant to two common
antibiotics, ampicillin and kanamycin (MICs of 500 and
200 μM, Table 1). However, it had a similar susceptibility
to our novel DXR inhibitor 8. In addition, 8 exhibited
negligible effects against the growth of two noncancerous
human cell lines, Beas2B (lung epithelial) and WI-38
(fibroblast), with IC50 of >300 μM. All these features make
8 a promising lead compound for further antibacterial drug
development.
Figure 2. (A) Docking structure of 4 (ball and stick model) in
DXR, with superimposed crystal structure of 1. (B) Docking
structure of 6 in DXR, showing its phenyl group in a hydrophobic
pocket. Mg2þ is shown as a pink sphere.
Chart 1. Structures of DXR Inhibitors
Chart 2. Structures of 1-5 and Their IC50 Values (or %
Inhibition at 100 μM) against E. coli DXR in Parentheses
Both compounds were found to be modest DXR inhibitors
with IC50 of 44.7 and 22.4 μM. However, compared to 4, they
exhibited better antibacterial activity (Table 1) with MICs of
200-1000 μM (or 37-190 μg/mL). Compounds 8-15, each
of which has a different dioxygen containing ligand and
a phenyl/benzyl group, were made in an effort to identify
a better Mg2þ chelating group for DXR inhibition. Although
9-15 had no or weak activity, 8 containing a 1-hydroxypyr-
idin-2-one group as a Mg2þ chelator was found to be a potent
DXR inhibitor with an IC50 of 1.4 μM.
Next, 16-18 (Chart 3) were prepared to test if both -OH
groups (or tautomeric carbonyl) in 8 and 6 are involved in
chelating the Mg2þ. Compared to 8, compounds 16 and 17
exhibited >50ꢀ weaker inhibition against DXR. In addition,
the lack of activity of 18 also shows that -NH2, a softer
ligand, even with an adjacent, hard -OH, is not able to bind
the Mg2þ strongly. This preliminary mechanistic study, to-
gether with the docking results (Figure 2), supports that both
oxygen atoms in 8 and 6 chelate the central metal ion, which is
key to DXR inhibition.

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21 6541
Scheme 2a
Scheme 1a
aReagents and conditions: (i) LiAlH4, THF; (ii) MsCl, NEt3, then
NaI; (iii) P(OEt)3, 120 °C; (iv) BBr3, CH2Cl2; (v) TMSBr, CH3CN;
(vi) NaBH4; (vii) MsCl, NEt3; (viii) NaH, triethyl phosphonoacetate,
THF; (ix) H2, 5% Pd/C; (x) NaOH, MeOH.
aReagents and conditions: (i) Pd(PPh3)4, K2CO3, THF, reflux; (ii)
BBr3, CH2Cl2; (iii) AcOH/H2O2, 70 °C; (iv) AcCl, reflux, then MeOH;
(v) H2, 5% Pd/C; (vi) NH3, EtOH.
Moreover, it is noteworthy that the hydroxamate group
seems to be considered as the ligand of choice for many
metalloenzymes and it has been widely used to design their
inhibitors. However, hydroxamate compounds, which under-
go a variety of rapid metabolic degradations in vivo (e.g.,
hydrolysis, glucuronidation, and sulfation), generally have
poor pharmacokinetic and/or toxicological profiles.14 Using
coordination chemistry to design a wide range of ligands
targeting the central metal ion is therefore of particular
importance with respect to drug discovery and development.
However, this approach has not been widely explored.15
Finally, we describe the synthesis of 2-18.16 Compounds
2-5 can be readily prepared according to Scheme 1. Di-
methoxyphenylacetic acid 19 was reduced to the correspond-
ing alcohol with LiAlH4, which was converted to iodide 20 by
treatment with methanesulfonyl chloride followed by NaI.
Arbuzov reaction using 20 and triethyl phosphite afforded
21, which was then deprotected by successive treatments
with boron tribromide and bromotrimethylsilane to give 2
or 4. Compound 3 was prepared similarly. A Horner-
Wadsworth-Emmons reaction using 3,4-dimethoxybenzal-
dehyde and sodium salt of triethyl phosphonoacetate, fol-
lowed by hydrogenation and deprotections, gave 5.
Most compounds in Chart 3 were synthesized with Suzuki
coupling as the key step (Scheme 2). Suzuki coupling using an
appropriate bromide and a boronic acid gave, after a simple
deprotection (if necessary), 6, 7, 11, 13, 16, and 18. Compound
8 was made from the intermediate 16a, with an AcOH/H2O2
mediated oxidation and subsequent demethylation. Treat-
ment of the intermediate 11a with ammonia in ethanol
afforded, after hydrogenation, compound 12.
Compounds 9, 10, 14, 15, and 17 were made according to
Scheme 3. Benzyl cyanide was reacted with hydroxylamine and
the resulting phenylacetylamidoxime treated with dimethyl
acetylenedicarboxylate to give 23. It was then hydrolyzed and
decarboxylated to afford 9. O-Benzylhydroxylamine was alky-
lated with 2-bromoacetaldehyde diethyl acetal, followed by
treatment with benzyl isocyanate, to produce urea 24. It was
cyclized in the presence of 98% formic acid to give, after
hydrogenation, 10. Urea 25, obtained from O-benzylhydrox-
ylamine and potassium cyanate, was reacted with methyl
3-dimethoxypropionate and NaH, affording 26, which was selec-
tively alkylated and hydrogenated to give 14. Syntheses of 15
and 17 were readily achieved according to standard protocols.
Scheme 3a
aReagents and conditions: (i) NH2OH, MeOH, reflux; (ii) dimethyl
acetylenedicarboxylate, 70 °C for 1 h, then 150 °C for 3 h; (iii) NaOH,
MeOH; (iv) 6 N HCl, reflux; (v) BnONH2, NEt3, DMF, 90 °C; (vi)
BnNCO; (vii) HCO2H; (viii) H2, 5% Pd/C; (ix) KNCO, 10% AcOH/
H2O; (x) NaH, (OMe)2CHCH2CO2Me, DMSO, 70 °C; (xi) BnBr,
K2CO3; (xii) BnONH2, EDC, NEt3; (xiii) AcOH/H2O2, 70 °C.
In summary, this work is of interest for a number of
reasons. First, although DXR has been identified as a vali-
dated anti-infective drug target for over a decade, there has
been a great challenge in finding potent, druglike DXR
inhibitors. We used coordination chemistry and structure
based design to obtain, for the first time, a strong, lipophilic
DXR inhibitor 8, which has a distinct structure from 1.
Second, 8 exhibited a broad spectrum of antibacterial activity,
including a multidrug resistant clinical isolate of P. aerugino-
sa, a major nosocomial pathogen. It is also noncytotoxic to
human cells. This compound should represent a novel drug
lead for further development. Third, the hydroxamate group
has been widely applied to design metalloenzyme inhibitors.
However, other nonhydrolyzable, aromatic metal-chelating
groups have been mostly overlooked.15 This work shows that
coordination chemistry should be considered in designing
novel, potentially more metabolically stable inhibitors of
metalloproteins, given the generally poor pharmacokinetics
of hydroxamate compounds.

6542 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Deng et al.
Acknowledgment. This work was supported by a start-up
fund to Y.S. from Baylor College of Medicine. We thank Dr.
Eric Oldfield for providing DXR, Dr. Adam Kuspa for
providing the bacteria, and Waleed Nasser for technical
assistance.
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Supporting Information Available: Figures S1 and S2 and
Experimental Section. This material is available free of charge
via the Internet at http://pubs.acs.org.
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