Alpha-heteroatom derivatized analogues of 3-(acetylhydroxyamino)propyl phosphonic acid (FR900098) as antimalarials

Article abstract of DOI:10.1021/jm301577q

To explore the hitherto successful derivatization of the α-carbon of fosmidomycin, a series of new α-substituted analogues was prepared. This was done by introduction of a heteroatom (N or O) in α-position to the phosphonate and using the resultant OH and NH₂ groups as a handle for appending a variety of substituents by means of several functional groups such as ether, amide, urea, and 1,4-triazole. The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory potency. Both the α-azido-analogue and the α-hydroxylated analogue proved most promising, and docking experiments were performed. Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not be found.

Full text of DOI:10.1021/jm301577q

Brief Article
pubs.acs.org/jmc
Alpha-Heteroatom Derivatized Analogues of
3‑(Acetylhydroxyamino)propyl Phosphonic Acid (FR900098) as
Antimalarials
Thomas Verbrugghen,† Pierre Vandurm,‡ Jenny Pouyez,‡ Louis Maes,§ Johan Wouters,‡
and Serge Van Calenbergh*,†
†Laboratory for Medicinal Chemistry (FFW), UGent, Harelbekestraat 72, B-9000 Gent, Belgium
‡Department of Chemistry, University of Namur, FUNDP, Rue de Bruxelles 61, B-5000 Namur, Belgium
§Laboratory for Microbiology, Parasitology and Hygiene, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University
of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
S
* Supporting Information
ABSTRACT: To explore the hitherto successful derivatization of the α-carbon of fosmidomycin, a series of new α-substituted
analogues was prepared. This was done by introduction of a heteroatom (N or O) in α-position to the phosphonate and using
the resultant OH and NH2 groups as a handle for appending a variety of substituents by means of several functional groups such
as ether, amide, urea, and 1,4-triazole. The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory
potency. Both the α-azido-analogue and the α-hydroxylated analogue proved most promising, and docking experiments were
performed. Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human
erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not
be found.
Chart 1. Structures of α-Substituted Fosmidomycin
Analogues with Their IC50 Values Against P. falciparum
INTRODUCTION
■
With over 200 million clinical cases and more than half a
million fatalities per year, malaria is still one of the major
infectious diseases. As resistance against almost all currently
used antimalarial drugs is emerging or already established, there
is a high need for new therapies, preferably affecting hitherto
unexploited targets. Moreover, these drugs should be well-
tolerated because malaria is often a disease of small children
and pregnant women.1 Over the past decade, the non-
mevalonate route for isoprenoid biosynthesis has become an
attractive target for the development of antimalarials. Of
highest interest so far is the second step, the conversion of 1-
deoxy-D-xylulose-5-phosphate (DOXP) into 2-C-methyl-D-
erythritol-4-phosphate (MEP), catalyzed by DOXP-reductoiso-
merase (DXR).2 Well-known leads for the development of
DXR inhibitors are fosmidomycin (1) and its acetyl congener
FR9000983 (2) (Chart 1). Fosmidomycin has been clinically
tested as an antimalarial combination partner for clindamycin
and artesunate and found to be very safe and nontoxic.4,5
Unfortunately, repeated high doses of fosmidomycin are
required to achieve acceptable cure rates.
Significant efforts have been made to improve fosmidomy-
cin’s activity.6 The available SAR indicates that both the free
phosphonic acid group (which may be masked as a prodrug)
and an intact retrohydroxamic or hydroxamic acid functionality
are essential for DXR inhibition. Instead, the 3-carbon spacer in
1 lends itself for derivatization. Particularly, the introduction of
substituents on the α-carbon of the phosphonate has afforded
promising inhibitors, with aryl substituents as in 3 being best
explored.7,8
After α-phenyl-fosmidomycin analogues were shown to
exhibit stronger antiplasmodial activity than fosmidomycin,
many SAR studies9−11 and crystallographic12,13 studies were
dedicated to α-aryl modifications, not only to combat
Plasmodium falciparum but also in the search for DXR
inhibitors directed against Mycobacterium tuberculosis. Until
now, fosmidomycin analogues with other α-substituents are
rather scarce.
The Geffken group introduced α-alkyl, α-hydroxymethyl, and
α,α-bismethyl substituents onto prodrug forms of 1 and 2 but
noticed that, with the exception of a simple α-methyl group as
in 4, none of these substitutions were well tolerated by the
Received: October 25, 2012
Published: December 10, 2012
© 2012 American Chemical Society
376
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Journal of Medicinal Chemistry
Brief Article
DXR enzyme.8 Kurz and co-workers described the synthesis of
arylmethyl substituted prodrugs of 114 in which a methylene
linker is inserted between the α-carbon and various aryl
substituents, resulting in analogues such as 5 with reasonable to
good DXR inhibitory activities. Incorporation of a phenyl ring
in the 3-carbon spacer (as in 6),15 led to loss of potency.
Recently, we reported a series of α-halogenated analogues of 2,
which gave comparable to slightly better growth inhibition of P.
falciparum K1 in human erythrocytes.16 Accordingly, compared
to 2, α-fluorinated 2 (7) slightly increased the mean survival
time of Plasmodium berghei infected mice.
we chose a base-assisted Pudovik reaction with dibenzyl
phosphite at low temperature for it resulted in a cleaner
reaction mixture and higher yields than when using “classical”
Pudovik conditions. Using benzyl protection for both the
phosphonate and the retrohydroxamate allowed a gentle one-
step final deprotection. 13 was converted into its methyl ether
19a by a Williamson reaction with iodomethane and silver
oxide. Attempted synthesis of α-phenyl ether 19b under
standard Mitsunobu conditions in THF failed. Therefore, we
switched to more forcing conditions as described by Lepore et
al.,19 which allowed us to synthesize 19b, albeit the complex
reaction mixture called for fractionating by flash chromatog-
raphy followed by purification by preparative HPLC.
RESULTS AND DISCUSSION
■
Starting from intermediate 13, α-azidophosphonate 20 was
synthesized by means of a Mitsunobu reaction with hydrazoic
acid as the pronucleophile (Caution: HN3 is volatile, highly
toxic, and explosive!) (Scheme 2). Using “classical” Mitsunobu
In this study, we describe the synthesis and evaluation of a
series of analogues of 2, characterized by various O- or N-based
substituents in α position (Figure 1).
a
Scheme 2. Synthesis of α-(1,2,3-Triazolyl) Analogues
a
Reagents and conditions: (a) PPh3, DIAD, HN3, toluene, rt; (b) for
21a, vinyl acetate, μW (69%); for 21b, 3,3-dimethylbut-1-yne, CuSO4,
Na-ascorbate, DMF, μW (97%); for 21c, phenylacetylene, CuSO4, Na-
ascorbate, DMF, μW (95%); (c) for 11a,c, Pd/C, NH4OOCH,
MeOH, reflux; for 11b, Pd/C, H2, MeOH.
Figure 1. Target analogues and retrosynthetic strategy.
Aldehyde 14, already equipped with a protected retrohy-
droxamate moiety, served as a starting point for the synthesis of
α O-based analogues via a Pudovik reaction. Its synthesis
started with the alkylation of N-Boc-O-benzylhydroxylamine
(16) with bromobutene (15) in DMF,17 followed by a one-pot
deprotection−acetylation18 to afford terminal alkene 18.
Oxidative cleavage of the double bond with periodate and
osmate quantitatively afforded the desired aldehyde 14. For the
synthesis of benzyl protected α-hydroxylated 2:13 (Scheme 1),
conditions (2 equiv of both triphenyl phosphine and
diethylazodicarboxylate (DEAD), excess hydrazoic acid, sub-
molar concentrations in toluene), we were able to synthesize
the desired α-azide in what appeared to be pure form according
to TLC or HPLC. However, persistent ethyl signals were
1
observed in the H NMR spectrum of the product. Originally
assigned to ethyl acetate trapped in the oily product, it later
turned out that these signals arose from the α-ethylcarbonate
formed by attack of alcohol 13 on one of the carbonyl groups of
DEAD. The formation of this unwanted product, which
coelutes with α-azidophosphonate 20 both on TLC and RP-
HPLC, was avoided by switching to the more sterically
hindered diisopropylazodicarboxylate (DIAD) and mixing the
reactants in a different order (precomplexing triphenylphos-
phine and DIAD, followed by adding the hydrazoic acid
solution and finally the α-hydroxyphosphonate). The obtained
α-azidophosphonate 20 subsequently served in the synthesis of
α-1,4-triazole-substituted analogues by copper-catalyzed azide−
alkyne cycloaddition (CuAAC) with two acetylene derivatives.
To the best of our knowledge, no precedents on the CuAAC of
α-azidophosphonates are known and only thermal, non-
regiospecific, phosphonomethylazide−alkyne cycloadditions
have been performed before.20 Attempted CuAAC using
copper(II)sulfate and ascorbic acid with phenyl- or t-
butylacetylene at room temperature or with conventional
heating failed, but upon switching to microwave heating clean
products were obtained in good yields. The unsubstituted
triazole 21a was synthesized using the protocol of Hansen et
al.,21 i.e., heating azide 20 in vinyl acetate under microwave
irradiation for several hours.
Scheme 1. Synthesis of Key Intermediate 13 and α-O-Based
Analogues
a
a
Reagents and conditions: (a) NaH, DMF, rt; (b) (i) acetyl chloride,
MeOH, NaI, MeCN, 1h, rt, (ii) Et3N, DMAP; (c) NaIO4,
K2OsO4·2H2O, H2O, THF; (d) HPO(OBn)2, LiHMDS, THF, −78
°C; (e) for 19a, MeI, Ag2O, DMF, rt; for 19b, PhOH, PPh3, DIAD,
THF, ultrasound; (f) Pd/C, ammonium formate, MeOH, reflux, 20
min.
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Journal of Medicinal Chemistry
Brief Article
We considered α-azido-2 also of interest as a potential DXR
inhibitor, but for obvious reasons deprotection by reductive
debenzylation of precursor 20 was not an option. Hence, we
chose to synthesize an α-azido precursor with orthogonal
protective groups, i.e., a benzyl ether for the retrohydroxamate
and ethyl esters for the phosphonate (Scheme 3). A Pudovik
would be less economic), this method benefits from high yields
and easy purification. Conversion of amine 12 into benzamide
27a and phenylurea 27b was carried out under standard
conditions.
The use of only benzyl protecting groups allowed mild final
deprotection upon hydrogenation on palladium on carbon.
However, we noticed the importance of avoiding the use of
standard metal hydrogenation needles, as metal ions were
found to poison the reaction. Therefore, hydrogen gas was
bubbled into the reaction mixture through a glass capillary,
resulting in clean formation of 8a, 8b, and 11b. During
deprotection of analogues 21a,c, acid-mediated breakdown of
the retrohydroxamic acid moiety was observed. This problem
was solved by using catalytic transfer hydrogenation with
ammonium formate as the hydrogen donor, whereby
ammonium neutralized the formed phosphonates. Excess
ammonium formate was removed by lyophilization, yielding
11a,c as monoammonium salts.
a
Scheme 3. Synthesis of α-Azido-2 (9)
a
Reagents and conditions: (a) HPO(OEt)2, LiHMDS, THF, −78 °C;
(b) PPh3, DIAD, HN3, toluene, rt; (c) BCl3, CH2Cl2, −75 °C; (d) (i)
TMSBr, BSTFA, MeCN, (ii) aq NH4OH, MeCN.
The final compounds were tested for their inhibition of
Escherichia coli DXR activity in a spectrophotometric assay by
monitoring the reduction of NADPH in NADP+. Inhibition
constants for all analogues as well as reference 2 are shown in
Table 1.
reaction with diethyl phosphite afforded diethyl α-hydrox-
yphosphonate 22, which was converted to the α-azide 23 as
before. The retrohydroxamate moiety of 23 was first
debenzylated with boron trichloride, followed by purification
of 24 on deactivated silica gel prior to removal of the
phosphonate esters by trimethylsilyl bromide in acetonitrile and
basic workup, yielding α-azido-2 (9) as a bisammonium salt.
The synthesis of the α-N-based analogues (Scheme 4)
started from the benzyl protected α-Boc-amino-2 (26),
Table 1. Ki Values on E. coli DXR (or % Inhibition at 100
nM) and in Vitro Growth Inhibition of the P. falciparum
Strain K1
IC50 (nM)
E. coli DXR
IC50 (μM)
Pf-K1
compd
a
2
15.11
(1.42%)
(1.30%)
74.6
0.42
49.02
>64
Scheme 4. Synthesis of α-N-Based Analogues
8a
8b
9
1.98
1.82
4.00
13.02
8.96
7.76
2.75
10a
10b
10c
11a
11b
11c
52.2
(4.14%)
n.i.
(3.32%)
207.3
1129
Remarkably, potent DXR inhibition is conferred to analogues
with small substituents (azido and hydroxy) in α-position. In
light of the appreciable DXR affinity obtained with α
phenylpyridyl substituents,13 we were surprised to see that
none of the α-triazoles showed appreciable inhibitory activity.
Possibly the triazole ring is too electron rich to form strong π-
stacking with Trp211 described in this study.
Docking of both enantiomers of 9 into PfDXR suggests an
interaction between the azide group and Trp296 (Figure 1,
Supporting Information (SI)). The vicinity of an azido group
and an indole has been found in 15 structures in the Cambridge
Structure Database, suggesting they may form favorable
interactions. A similar experiment for both enantiomers of
10a resulted in poses that place the OH group in H-Bond
distance to Glu233 for the R-enantiomer and Ser306 for the S-
enantiomer (Figures 2 and 3, SI).
a
Reagents and conditions: (a) Na-p-toluenesulfinate, t-butylcarbamate,
HCOOH, THF, MeCN, H2O, rt, overnight; (b) HPO(OBn)2, NaH,
THF, rt; (c) TFA, CH2Cl2, 0 °C; (d) BzCl, DMAP, Et3N, CH2Cl2; (e)
phenylisocyanate, DMAP, Et3N, CH2Cl2; (f) Pd/C, H2, MeOH/H2O/
t-BuOH.
prepared in two steps as described by Klepacz et al.22 First,
aldehyde 14 was subjected to a three-component reaction with
t-butylcarbamate and sodium p-toluenesulfinate and the
resulting sulfone 25 was displaced with dibenzyl phosphite.
The Boc-protecting group of 26 and was removed, and amine
12 was used without further purification. Although numerous
alternatives for the synthesis of α-aminophosphonates are
known, such as a Kabachnik−Fields reaction with HMDS or
ammonium carbonate (which only gave marginal results in our
hands) or the evident Staudinger reduction of azide 20 (which
Several compounds show high potency in the low micro-
molar range when assayed against P. falciparum K1 in human
erythrocytes. Strikingly, there’s no clear correlation between the
enzyme inhibition constants and P. falciparum inhibition
concentrations. Besides other possible factors such as off-target
effect, the considerable degree of species DXR inhibitory
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Journal of Medicinal Chemistry
Brief Article
= 143.5 Hz), 173.94. 31P NMR (121 MHz, CD3OD) δ 16.45. HRMS
(ESI): calcd for C5H11N4O5P − H+, 237.0394; found [(M − H)+],
237.0423.
specificity, recently demonstrated by the Kurz group,13 may
account for this phenomenon.
3-(N-Hydroxyacetamido)-1-(benzamido)propyl-phosphonic
Acid (8a). To a solution of 27a (309 mg, 0.53 mmol) in a mixture of
MeOH−H2O−t-BuOH (10 mL) was added 10% Pd/C. Hydrogen gas
was bubbled through via a glass capillary at atmospheric pressure for
3.5 h, after which the reaction mixture was filtered and concentrated in
vacuo. The residue was taken up in t-BuOH, frozen, and lyophilized to
EXPERIMENTAL SECTION
■
1
General Methods and Materials. H, 13C, 19F, and 31P NMR
spectra were recorded in CDCl3, CD3OD, acetone-d6, DMSO-d6, or
D2O on a Varian Mercury 300 spectrometer. Chemical shifts are given
in parts per million (ppm) (δ relative to TMS for H and 13C and to
1
1
external D3PO4 for 31P). All solvents and chemicals were used as
purchased unless otherwise stated. Purity of the final compounds was
assessed by RP-LC-DAD-MS, using a Phenomenex Luna C-18 2.5 μm
particle (100 mm × 2.00 mm) column in a Waters Alliance 2695 XE
HPLC system with quaternary pump, coupled to a DAD detector and
a Waters LCT Premier XE orthogonal time-of-flight spectrometer with
API-ES source with a H2O/CH3CN gradient with 0.05% HCOOH. All
the compounds showed purity above 95%.
give the product as a white foam in quantitative yield. H NMR (300
MHz, CD3OD) δ 1.72−2.11 (m, 3 H), 2.42 (ddd, J = 14.2, 6.6, 3.2 Hz,
1 H), 3.52−3.79 (m, 1 H), 3.90 (d, J = 4.7 Hz, 1 H), 4.34 (t, J = 12.6
Hz, 1 H), 7.23−7.51 (m, 5 H), 7.61 (d, J = 7.0 Hz, 1 H). 13C NMR
(75 MHz, CD3OD) δ 21.53, 26.55, 30.04, 44.60 (d, J = 155.91 Hz),
129.90, 128.12, 130.33, 134.59, 172.20. 31P NMR (121 MHz,
CD3OD) δ 22.53. HRMS (ESI): calcd for C12H17N2O6P − H+,
315.0751; found [(M − H)+], 315.0767.
Dibenzyl 3-(N-(Benzyloxy)acetamido)-1-hydroxy-propyl-
phosphonate (13). Dibenzyl phosphite (4330 mg, 16.5 mmol) was
dissolved in THF (20 mL), the solution was cooled to −78 °C, and
LiHMDS (15 mL of a 1 M solution in THF) was added slowly. After
15 min, a solution of aldehyde 14 (3320 mg, 15 mmol) in 30 mL of
dry THF was added via syringe and the ice bath was removed. After
another 15 min of stirring, the reaction mixture had warmed up to
room temperature, at which point it was quenched by the addition of
saturated aqueous NH4Cl and extracted three times with ethyl acetate.
The combined organic phases were washed with brine, dried over
anhydrous Na2SO4, and evaporated in vacuo. The resulting crude
mixture was purified by dry column vacuum chromatography with a
gradient of ethyl acetate in toluene containing 0.1% formic acid to
ASSOCIATED CONTENT
■
S
* Supporting Information
Docking data for analogues 9 and 10a, additional experimental
1
data, and H NMR and 31P spectra for final compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: ++32 9 264.81.24. Fax: ++32 9 264.81.46 . E-mail:
Serge.vancalenbergh@ugent.be.
■
1
yield 5.22g (72%) of 13 as an off-white solid. H NMR (300 MHz,
Notes
CDCl3) δ 1.85−2.03 (m, 1 H), 2.05 (s, 3 H), 2.07−2.25 (m, 1 H),
3.56−3.72 (m, 1 H), 3.83−3.96 (m, 1 H), 4.05 (br s, 1 H), 4.57 (br s,
The authors declare no competing financial interest.
1 H), 4.71−4.85 (m, 2 H), 4.98−5.14 (m, 4 H), 7.11−7.42 (m, 15 H).
1
13C NMR (75 MHz, CDCl3) δ 20.32, 29.21, 42.09, 65.02 (d, JC−P
=
ACKNOWLEDGMENTS
■
167.0 Hz), 68.01 (d, 2JC−P = 5.8 Hz), 68.10 (d, 2JC−P = 5.8 Hz), 76.43,
127.92, 128.31, 128.50, 128.70, 128.99, 129.19, 134.12, 136.22 (d,
3JC−P = 2.2 Hz), 136.3 (d, 3JC−P = 2.2 Hz), 173.12. HRMS (ESI): calcd
We thank An Matheeussen for running the in vitro
antiplasmodial evaluation. Thomas Verbrugghen is a fellow of
the Agency for Innovation by Science and Technology (IWT)
of Flanders. Financial support by F.W.O.-Vlaanderen is
gratefully acknowledged.
for C26H30NO6P + H+, 484.1884; found [(M + H)+], 484.1852.
3-(N-Hydroxyacetamido)-1-hydroxypropyl-phosphonic
Acid, Ammonium Salt (10a). A mixture of 13 (261 mg, 0.54 mmol),
ammonium formate (520 mg, 8.10 mmol) and 10% Pd/C in MeOH
(10 mL) was heated at reflux for 20 min, followed by filtration over a
glass microfiber pad. The filter was rinsed with methanol and water,
and the filtrate was concentrated in vacuo. The resulting residue was
lyophilized from a mixture of water and t-BuOH to give the product as
an extremely hygroscopic resinous solid in quantitative yield. 1H NMR
(300 MHz, CD3OD) δ 1.67−1.98 (m, 1 H), 2.13 (s, 4 H), 3.46−3.80
(m, 2 H), 3.80−4.12 (m, 1 H). 13C NMR (75 MHz, CD3OD) δ 20.64,
30.98, 46.70 (d, J = 14.9 Hz), 67.99 (d, J = 157.8 Hz). 31P NMR (121
MHz, CD3OD) δ 19.86. HRMS (ESI): calcd for C5H12NO6P − H+,
212.0329; found [(M − H)+], 212.0351.
ABBREVIATIONS USED
■
CuAAC, copper catalyzed azide−alkyne cycloaddition; DEAD,
diethyl azodicarboxylate; DIAD, di-isopropyl azodicarboxylate;
DOXP, 1-deoxy-D-xylulose-5-phosphate; DXR, 1-deoxy-D-xylu-
lose-5-phosphate reductoisomerase; EcDXR, Escherichia coli 1-
deoxy-D-xylulose-5-phosphate reductoisomerase; HMDS, bis-
(trimethylsilyl)amine; MEP, 2-C-methyl-D-erythritol-3-phos-
phate; SAR, structure−activity relationship; TMSBr, bromo-
trimethylsilane; TLC, thin layer chromatography
3-(N-Hydroxyacetamido)-1-azidopropylphosphonic Acid,
Bisammonium Salt (9). 24 (165 mg, 0.561 mmol) was coevaporated
with toluene (3 × 10 mL), taken up in acetonitrile (5 mL), and
BSTFA (600 μL, 2.24 mmol) added. After 15 min of stirring at rt, an
ice bath was installed and TMSBr (2.5 mL, 19 mmol) was added. The
ice bath was removed after 10 min, and the reaction was stirred further
at room temperature until, after 2.5 h, 31P NMR confirmed that the
starting phosphonate was completely deprotected (shift from δ = 23−
3 ppm). All volatiles were removed in vacuo, followed by
coevaporation with toluene (3 × 10 mL). The resulting oil was
taken up in acetonitrile, concentrated ammonia was added, and the
mixture was stirred at room temperature for 30 min and evaporated to
give the crude material as a brown oil. This was dissolved in methanol,
decolorized over activated carbon, and lyophilized from water to give
the product as a hygroscopic resin in quantitative yield. 1H NMR (300
MHz, CD3OD) δ 1.63−1.87 (m, 1 H), 2.03−2.35 (m, 4 H), 3.18−
3.37 (m, 1 H), 3.45−3.69 (m, 1 H), 3.88−4.11 (m, 1 H). 13C NMR
(75 MHz, CD3OD) δ 20.57, 28.60, 46.73 (d, J = 13.0 Hz), 59.09 (d, J
REFERENCES
■
(1) World Malaria Report 2011; World Health Organization: Geneva,
Dec 2011.
(2) Wiesner, J.; Jomaa, H. Isoprenoid biosynthesis of the apicoplast
as drug target. Curr. Drug Targets 2007, 8, 3−13.
(3) Hemmi, K.; Takeno, H.; Hashimoto, M.; Kamiya, T. Studies on
Phosphonic Acid Antibiotics. 4. Synthesis and Antibacterial Activity of
Analogs of 3-(N-Acetyl-N-hydroxyamino)-propylphosphonic Acid
(FR-900098). Chem. Pharm. Bull. 1982, 30, 111−118.
(4) Borrmann, S.; Adegnika, A.; Matsiegui, P.; Issifou, S.; Schindler,
A.; Mawili-Mboumba, D.; Baranek, T.; Wiesner, J.; Jomaa, H.;
Kremsner, P. Fosmidomycin−clindamycin for Plasmodium falciparum
infections in African children. J. Infect. Dis. 2004, 189, 901−908.
(5) Borrmann, S.; Issifou, S.; Esser, G.; Adegnika, A.; Ramharter, M.;
Matsiegui, P.; Oyakhirome, S.; Mawili-Mboumba, D.; Missinou, M.;
Kun, J.; Jomaa, H.; Kremsner, P. Fosmidomycin−clindamycin for the
379
dx.doi.org/10.1021/jm301577q | J. Med. Chem. 2013, 56, 376−380

Journal of Medicinal Chemistry
Brief Article
treatment of Plasmodium falciparum malaria. J. Infect. Dis. 2004, 190,
1534−1540.
(6) Jackson, E. R.; Dowd, C. S. Inhibition of 1-Deoxy-D-Xylulose-5-
Phosphate Reductoisomerase (Dxr): A Review of the Synthesis and
Biological Evaluation of Recent Inhibitors. Curr. Top. Med. Chem.
2012, 12, 706−728.
(7) Haemers, T.; Wiesner, J.; Van Poecke, S.; Goeman, J.; Henschker,
D.; Beck, E.; Jomaa, H.; Van Calenbergh, S. Synthesis of alpha-
substituted fosmidomycin analogues as highly potent Plasmodium
falciparum growth inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 1888−
1891.
(8) Kurz, T.; Schluter, K.; Kaula, U.; Bergmann, B.; Walter, R.;
Geffken, D. Synthesis and antimalarial activity of chain substituted
pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098.
Bioorg. Med. Chem. 2006, 14, 5121−5135.
(9) Deng, L. S.; Sundriyal, S.; Rubio, V.; Shi, Z. Z.; Song, Y. C.
Coordination Chemistry Based Approach to Lipophilic Inhibitors of 1-
Deoxy-D-xylulose-5-phosphate Reductoisomerase. J. Med. Chem. 2009,
52, 6539−6542.
(10) Deng, L. S.; Diao, J. S.; Chen, P. H.; Pujari, V.; Yao, Y.; Cheng,
G.; Crick, D. C.; Prasad, B. V. V; Song, Y. C. Inhibition of 1-Deoxy-D-
Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates:
SAR, QSAR, and Crystallographic Studies. J. Med. Chem. 2011, 54,
4721−4734.
(11) Deng, L. S.; Endo, K.; Kato, M.; Cheng, G.; Yajima, S.; Song, Y.
C. Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/
Lipophilic Phosphonate Complexes. ACS Med. Chem. Lett. 2011, 2,
165−170.
(12) Andaloussi, M.; Henriksson, L. M.; Wieckowska, A.; Lindh, M.;
Bjorkelid, C.; Larsson, A. M.; Suresh, S.; Iyer, H.; Srinivasa, B. R.;
Bergfors, T.; Unge, T.; Mowbray, S. L.; Larhed, M.; Jones, T. A.;
Karlen, A. Design, Synthesis, and X-ray Crystallographic Studies of
alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of
Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoi-
somerase. J. Med. Chem. 2011, 54, 4964−4976.
(13) Behrendt, C. T.; Kunfermann, A.; Illarionova, V.; Matheeussen,
A.; Pein, M. K.; Grawert, T.; Kaiser, J.; Bacher, A.; Eisenreich, W.;
Illarionov, B.; Fischer, M.; Maes, L.; Groll, M.; Kurz, T. Reverse
fosmidomycin derivatives against the antimalarial drug target IspC
(Dxr). J. Med. Chem. 2011, 54, 6796−802.
(14) Schluter, K.; Walter, R. D.; Bergmann, B.; Kurz, T. Arylmethyl
substituted derivatives of Fosmidomycin: synthesis and antimalarial
activity. Eur. J. Med. Chem. 2006, 41, 1385−97.
(15) Kurz, T.; Schluter, K.; Pein, M.; Behrendt, C.; Bergmann, B.;
Walter, R. D. Conformationally restrained aromatic analogues of
fosmidomycin and FR900098. Arch. Pharm. 2007, 340, 339−44.
(16) Verbrugghen, T.; Cos, P.; Maes, L.; Van Calenbergh, S.
Synthesis and Evaluation of α-Halogenated Analogues of 3-
(Acetylhydroxyamino)propyl Phosphonic Acid (FR900098) as Anti-
malarials. J. Med. Chem. 2010, 53, 2342−2346.
(17) Sulsky, R.; Demers, J. P. Alkylation of N-Benzyloxyureas and
Carbamates. Tetrahedron Lett. 1989, 30, 31−34.
(18) Nazih, A.; Heissler, D. One-pot conversion of t-butyl carbamates
to amides with acyl halide−methanol mixtures. Synthesis 2002, 203−
206.
(19) Lepore, S. D.; He, Y. Use of sonication for the coupling of
sterically hindered substrates in the phenolic Mitsunobu reaction. J.
Org. Chem. 2003, 68, 8261−8263.
(20) Palacios, F.; Deretana, A. M. O.; Pagalday, J. Synthesis of
Diethyl 1,2,3-Triazolealkylphosphonates through 1,3-Dipolar Cyclo-
addition of Azides with Acetylenes. Heterocycles 1994, 38, 95−102.
(21) Hansen, S. G.; Jensen, H. H. Microwave Irradiation as an
Effective Means of Synthesizing Unsubstituted N-Linked 1,2,3-
Triazoles from Vinyl Acetate and Azides. Synlett 2009, 3275−3278.
(22) Klepacz, A.; Zwierzak, A. An expeditious one-pot synthesis of
diethyl N-Boc-1-aminoalkylphosphonates. Tetrahedron Lett. 2002, 43,
1079−1080.
380
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