1,4-naphthoquinone cations as antiplasmodial agents: Hydroxy-, acyloxy-, and alkoxy-substituted analogues

Article abstract of DOI:10.1021/ml300242v

Cations of hydroxy-substituted 1,4-naphthoquinones were synthesized and evaluated as antiplasmodial agents against Plasmodium falciparum. The atovaquone analogues were found to be inactive as antagonists of parasite growth, which was attributed to ionization of the acidic hydroxyl moiety. Upon modification to an alkoxy substituent, the antiplasmodial activity was restored in the sub-100 nM range. Optimal inhibitors were found to possess IC₅₀ values of 17.4-49.5 nM against heteroresistant P. falciparum W2.

Full text of DOI:10.1021/ml300242v

Letter
pubs.acs.org/acsmedchemlett
1,4-Naphthoquinone Cations as Antiplasmodial Agents: Hydroxy‑,
Acyloxy‑, and Alkoxy-Substituted Analogues
Xiao Lu,† Ali Altharawi,† Jiri Gut,‡ Philip J. Rosenthal,‡ and Timothy E. Long*,†,§
†Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602, United States
‡Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco,
California 94143, United States
§Center for Drug Discovery, University of Georgia, Athens, Georgia 30602, United States
S
* Supporting Information
ABSTRACT: Cations of hydroxy-substituted 1,4-naphthoqui-
nones were synthesized and evaluated as antiplasmodial agents
against Plasmodium falciparum. The atovaquone analogues
were found to be inactive as antagonists of parasite growth,
which was attributed to ionization of the acidic hydroxyl
moiety. Upon modification to an alkoxy substituent, the
antiplasmodial activity was restored in the sub-100 nM range.
Optimal inhibitors were found to possess IC50 values of 17.4−
49.5 nM against heteroresistant P. falciparum W2.
KEYWORDS: malaria, Plasmodium, 1,4-naphthoquinones, phosphonium cations
alaria, particularly that caused by Plasmodium falciparum,
remains one of the most important infectious diseases in
The most potent of the identified antiplasmodial cations are
4- and 5-hydrocarbon analogues of vitamin K, 1a and 1b
(Figure 1). The 1,4-naphthoquinone platform from which the
M
the world.1,2 As malaria control is seriously limited by resistance
to most available drugs,3−5 it is critical that new chemo-
therapeutics are developed to replace those now limited by
drug resistance (e.g., chloroquine and antifolates) and toxicity
(e.g., primaquine, amodiaquine, and mefloquine). Antimalarials
that inhibit mitochondrial function such as atovaquone (ATV),
which is available as a component of Malarone (ATV/
proguanil), have particular clinical importance6−8 due to their
ability to eradicate both liver and blood stages of the malarial
parasite. Structural features common to ATV and related
inhibitors are lipophilic substituents,9 which aid in permeability
in the mitochondrial matrix membranes where the electron
transport complexes are embedded. As a consequence, the
physiochemical properties conferred by the hydrophobic
groups have detrimental effects on the pharmacokinetic
parameters, presenting a significant challenge in the develop-
ment of mitochondrion-acting treatments of malaria.
Figure 1. Antiplasmodial activities of naphthoquinone-based phos-
phonium cations against chloroquine-resistant P. falciparum W2.10
inhibitors were constructed is found in many known
antagonists of Plasmodium ubiquinone9,12 including ATV. The
binding site of ATV and related naphthoquinone-based
inhibitors is the cytochrome bc1 complex, which has been
demonstrated in yeast to be mediated by the C-2 hydroxyl of
the quinone ring.13 The significance of this alcohol as a H-
donor in ATV and on antiplasmodial activity gave reason to
examine 1,4-naphthoquinone cations containing a C-2
hydroxyl. Moreover, if the compounds possess potency similar
to ATV against cultured P. falciparum, this result will provide
evidence that the cations are acting on the bc1 complex. On this
basis, we set forth to evaluate phosphonium cations of 2-
hydroxy 1,4-naphthoquinone, which demonstrated unexpected
Recently, we reported a new class of 1,4-naphthoquinone-
based antiparasitic agents believed to be mitochondriotropic
antagonists of electron transport.10 The inhibitory capacity of
the compounds is thought to be conferred by a phosphonium
group that facilitates passive transport of the lipophilic cations
across plasma membranes into the energized plasmodial
mitochondria. Electrostatic attraction11 is rationalized as the
driving force for directed movement into the mitochondrion
where the antagonists localize until the membrane potential
collapses. This drug design strategy to enhance intracellular
bioavailability is the subject of current investigations for
improving the in vivo performance of antimalarials that target
the Plasmodium mitochondrion.
Received: August 15, 2012
Accepted: October 1, 2012
Published: October 1, 2012
© 2012 American Chemical Society
1029
dx.doi.org/10.1021/ml300242v | ACS Med. Chem. Lett. 2012, 3, 1029−1033

ACS Medicinal Chemistry Letters
Letter
antiplasmodial activities that led to the investigations of O-
linked acyloxy and alkoxy derivatives of quinone 1.
Table 1. Comparisons of IC50 Values for P. falciparum W2
Growth
The synthetic plan to prepare hydroxyl analogues of
naphthoquinone 1 involved first the installation of a n-
bromoalkyl side chain to which the phosphonium substituent
will subsequently be bound. The hydrocarbon linker was
attached by the Kochi−Anderson radical decarboxylation
procedure14,15 using 1,4-naphthoquinone 3 as the base material
(Scheme 1). The alkylated product 4 was then oxidized to
compd
16a
n
R
R1
IC50 (nM)
7123
8
1
8
2
4
9
9
9
9
4
Ph
Ac
H
Scheme 1. Synthesis of 2-Hydroxy 1,4-Naphthoquinone
Phosphonium Cation 9 (Table 1)
17a
Ph
Ph
Ph
Ph
n-Bu
Ph
Bn
Ph
Ph
6731
6642
5440
4075
3865
3592
3282
2175
1896
17b
H
16b
Ac
H
9a
9b
H
8a
Ac
H
9c
9d
H
8b
Ac
chloroquine
artemisinin
142.7 0.8
18.1 2.2
Scheme 2. Synthesis of 1,4-Naphthoquinone-Based
Phosphonium Cations 16 and 17 (Table 1)
epoxide 5 and treated with sulfuric acid16 to give the 2-hydroxy
naphthoquinone 6. Subsequent attempts to directly convert the
naphthoquinone to phosphonium cations 9 were unsuccessful
and resulted in the formation of complex mixtures of highly
polar products. To overcome this problem, the hydroxyl was
acetylated prior to the alkylation reaction with a tertiary
phosphine (PR3). The phosphonium salts 8 were successfully
generated at 100 °C from the acylated quinone 7 in 3:1
iPrOH:PhMe, a solvent combination that was found to
minimize thermal degradation of the products during the
sluggish reaction. In the final step, acid-catalyzed hydrolysis of
the acetyl group provided the desired 2-hydroxy naphthoqui-
none product 9 (Table 1).
For comparison, a second series of 2-hydroxy 1,4-
naphthoquinone cations were synthesized with a benzene ring
linking the phosphonium hydrocarbon chain to the platform
(Scheme 2). The analogues were prepared from phenyl-
iodonium ylide 1117 utilizing the BF3-mediated arylation
procedure developed by Spyroudis and co-workers.18 The
ylide was obtained in high yield from lawsone (10) and
(diacetoxy)iodobenzene and then coupled with 4-(bromoal-
koxy)-benzaldehydes 13 under reflux in CHCl3. Acetylation of
the C-2 hydroxyl followed by alkylation of PPh3 and O-
deprotection afforded the aryl-linked cations 17 (Table 1).
Determination of antiplasmodial activities was performed by
assessing 50% inhibitory concentrations (IC50) against
chloroquine-resistant P. falciparum (W2 strain) according to
methods previously described.19 Surprisingly, each of the 2-
hydroxy 1,4-naphthoquinone cations (9 and 17) possessed
weak activity with IC50 values between 2175 and 6731 nM
(Table 1). Similarly, the O-acetyl analogues (8 and 16)
performed poorly as antiplasmodial agents in the medium−low
micromolar range. On comparison with the uncharged controls
18 and 19 (IC50 339−392 nM), it was confirmed that the
phosphonium moiety had an adverse effect on the IC50 values.
With the unexpected results that the phosphonium modifica-
tion to the 2-hydroxy 1,4-naphthoquinones did not enhance the
activity as previously observed for cations 1, the possible
rationale behind the reduced efficacy was investigated.
The vast majority of 2-hydroxy 1,4-naphthoquinones,
including lawsone (pKa = 3.9820) and phthiocol (pKa
=
5.0821), are weak acids that undergo ionization at physiological
pH. Depending on the adjacent substituents, anion formation
may result in delocalization of the negative charge over the C-2
and C-4 oxygen atoms, which can be ascertained as a
1030
dx.doi.org/10.1021/ml300242v | ACS Med. Chem. Lett. 2012, 3, 1029−1033

ACS Medicinal Chemistry Letters
Letter
bathochromic (red) shift in the UV−vis spectrum.22 In the case
of the phosphonium cations 7 and 17, ionization was thought
to have occurred in Plasmodium growth medium (pH 7.4),
resulting in neutralization of the cationic charge of the
inhibitors (Figure 2). The loss of charge needed to facilitate
ionization of the hydroxy group and distribution of the
resulting anionic charge into the quinone. The nearly identical
emission spectra for quinone 9a at pH 7 and 10 was evidence
that the deprotonated form exists in cells and the physiological
environment. The cationic feature, which is believed to direct
the molecules to the mitochondrion, would thereby be
suppressed by the ionization, rendering the compounds
inactive. As further confirmation of the pH-dependent change
in the ionization state of hydroxy-substituted analogues, the
UV−vis absorbance spectra of the C-2 methyl analogue 1b
were compared, and little variability in pH 2−10 buffers was
observed (Figure 3b).
Figure 2. Ionization of naphthoquinone cations.
On the basis of these results, it is concluded that in order for
the naphthoquinone cations to function as growth antagonists,
an acidic moiety cannot be present in the molecule. To test this
hypothesis, the 2-methoxy analogue 21 of quinone cation 17a
(IC50 = 6731 nM) was synthesized from 2-hydroxy
naphthoquinone 14 and tested against P. falciparum W2
movement into the cell might therefore explain their lack of
antiplasmodial activity. To probe if ionization occurred, UV−
vis spectroscopy was employed to detect pH-dependent
changes in electron delocalization levels of quinone cation 9a
and its methyl analogue 1b.
On comparison of the UV−vis absorbance spectra of 9a
(IC50 = 4075 nM) in buffers ranging from pH 2 to 10, the
ionization of the 2-hydroxy residue at neutral pH was
confirmed (Figure 3a). Under acidic conditions (pH 2), the
(Scheme 3). As expected, potent activity was restored (IC50
=
Scheme 3. Synthesis of 2-Methoxy 1,4-Naphthoquinone
Phosphonium Cation 21
58.3
14.3 nM) upon removal of the acidic hydroxy
substituent on the quinone ring. With this finding, additional
O-substituted quinone cations were synthesized for evaluation
as antiplasmodial agents.
For the preparation of 3-acyloxy- and 2-alkoxy-linked
naphthoquinone cations, methyl-1,4-naphthoquinone (mena-
dione, 22, Scheme 4) was used as the initial base material.
Installation of the C-2 hydroxyl was achieved by acid-mediated
cleavage of the corresponding menadione epoxide 23.16
Acylation of phthiocol (24) with 4-bromobutanoyl and 11-
bromoundecanoyl chlorides followed by alkylation of PPh3
afforded the 3-acyloxy-linked cation derivatives 26a (n = 2) and
26b (n = 9).
Both phthiocol (24) and lawsone (10) were similarly
employed as base materials for the synthesis of 2-alkoxy
naphthoquinone cations 28 (Scheme 5). The n-bromoalkyl
chain linkers were attached to the quinone platform under THF
reflux with K2CO3, 18-crown-6, and tetrabutylammonium
Scheme 4. Synthesis of 3-Acyloxy 1,4-Naphthoquinone
Cations 26 (Table 2)
Figure 3. UV−vis absorption spectra of phosphonium cations 9a and
1b in 1-octanol and acidic−basic phosphate buffers.
quinone gave rise to quinoid transition bands centered at 280
and 335 nm for benzenoid.22 When contrasted with the spectra
obtained in neutral and basic pH buffers, the quinoid bands
were repositioned at 270 nM and as a broad emission peak at
485 nm. Similar results, albeit of lesser intensity, were observed
in 1-octanol, a medium that mimics the physiochemical
properties of biological membranes.
The quinoid absorbance at the higher λ represents an
increase in π electron delocalization.23 This was attributed to
1031
dx.doi.org/10.1021/ml300242v | ACS Med. Chem. Lett. 2012, 3, 1029−1033

ACS Medicinal Chemistry Letters
Letter
chlorine atom, the hydrocarbon linkers were attached to the C-
2 hydroxyl, and the corresponding triphenylphosphonium
bromides 36a−e (Table 2) were prepared as previously
described.
Scheme 5. Synthesis of 2-Alkoxy Naphthoquinone
Phosphonium Cations 28a−e and 31 (Table 2)
Antiplasmodial testing revealed that the 2-alkoxy analogues
28 and 36 possessed significantly higher activity than their 3-
acyloxy counterparts 26. The IC50 values of ester-linked
derivatives including quinone 31 ranged from 1230 to 4604
nM, suggesting that the lipid chains with the triphenylphos-
phonium group bound were susceptible to intracellular
hydrolysis. Conversely, the alkoxy-linked quinones (28b−e
and 36a−e), which would be stable to esterase degradation
possessed sub-50 nM IC50 values. Although few correlations
between structure and activity could be ascertained for these
analogues, compounds with shorter alkoxy linkers appeared to
be slightly more effective antagonists of parasite growth. Little
variability was also observed between analogues with different
C-3 substituents with the nominal exception of the lawsone-
derived cation 28e (IC50 = 28.5 3.0 nM).
iodide (TBAI). Supplementing the reaction with two phase-
transfer catalysts was found to enhance nucleophilicity of the C-
2 oxygen and hinder formation of K+-naphthoquinone
chelation complex.24 Alternatively, a n-bromopropyl chain was
attached to phthiocol via a glycolic spacer prior to installation
of a phosphonium group in quinone 30. In the final step, the
naphthoquinone cations 28a−e (Table 2) and 31 were
A structural feature lacking in each of the cations listed in
Table 2 is a rigid substituent attached to the quinone ring. To
compare the effect of restricted rotation of the C-3 residue on
activity, an analogue bound with a p-anisyl group was
synthesized (Scheme 7). Ylide 11 was once again employed
i
generated by the alkylation of PPh3 in 3:1 PrOH:PhMe at
100 °C.
Table 2. Comparisons of IC50 Values for P. falciparum W2
Growth
Scheme 7. Synthesis of 3-(4-Anisyl)-1,4-naphthoquinone
Phosphonium Cation 40
compd
n
R
IC50 (nM)
4604
26a
26b
31
2
9
1
8
4
1
1
4
4
4
4
1
1
Me
Me
1377
Me
1230
28a
28b
28c
28d
28e
36a
36b
36c
36d
36e
ATV
Me
119.3 11.3
42.7 1.4
41.9 4.0
40.0 0.8
28.5 3.0
49.5 7.8
49.1 6.3
47.9 6.3
46.7 4.4
42.3 0.0
0.50 0.2
Me
Me
H
H
4-ClBn
Bn
C6H11
Bn
C6H11
as the base material to construct the 2-hydroxy naphthoqui-
none 38 via the BF3-mediated arylation procedure.18 Attach-
ment of a n-propyl chain linker and installation of a
triphenylphosphonium moiety afforded the p-anisyl quinone
cation 40. Subsequent antiplasmodial testing revealed that the
incorporation of rigidity at C-3 resulted in nearly a 2-fold
increase in activity (IC50 = 17.4 4.1 nM) as compared with
analogues 28 and 36. An additional property of cation 40 that
could be contributing to the enhanced efficacy is molecular
planarity. With this finding, the correlation between planarity
and antiparasitic activity of the cationic inhibitors will be a
subject of future studies.
For further comparison, additional 2-hydroxy-3-alkyl-naph-
thoquinones prepared from the algaecide Dichlon (32) were
used to synthesize 2-alkoxy linked cation analogues 36 (Scheme
6). Derivatization of the C-3 position with cyclohexyl, benzyl,
and 4-chlorobenzyl substituents was again achieved by radical
decarboxylation.14,15 Following methanolysis of the remaining
Scheme 6. Synthesis of 1,4-Naphthoquinone-Based
Phosphonium Cations 36a−e (Table 2)
In summary, O-linked phosphonium cations of 1,4-
napthoquinones were discovered to be effective growth
inhibitors of cultured P. falciparum with IC50 values in the
nanomolar range. The activity was greatest for quinones that
did not possess an acidic functionality and were bound to the
phosphonium moiety via a short hydrocarbon chain linker.
Little variability in the IC50 values was observed for the 2-alkoxy
cation analogues 28 and 36 with a H or sp3-hybridized carbon
residue bound at the C-3 position. Alternatively, when a rigid
aromatic group was attached to the C-3 position of the
1032
dx.doi.org/10.1021/ml300242v | ACS Med. Chem. Lett. 2012, 3, 1029−1033

ACS Medicinal Chemistry Letters
Letter
Chadwick, J.; Hemingway, J.; Delves, M. J.; Sinden, R. E.; Zeeman, A.
M.; Kocken, C. H.; Berry, N. G.; O'Neill, P. M.; Ward, S. A.
Generation of quinolone antimalarials targeting the Plasmodium
falciparum mitochondrial respiratory chain for the treatment and
prophylaxis of malaria. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 8298−
8303.
(7) Vaidya, A. B. Mitochondrial and plastid functions as antimalarial
drug targets. Curr. Drug Targets Infect. Disord. 2004, 4, 11−23.
(8) Baggish, A. L.; Hill, D. R. Antiparasitic agent atovaquone.
Antimicrob. Agents Chemother. 2002, 46, 1163−1173.
quinone, a definitive increase in inhibitory activity was
observed.
Future investigations will continue to examine the effect of
rigidity and planarity on activity. In addition, analogues
possessing nitrogen-based cations will be evaluated as
antiparasitic agents. Preliminary studies have revealed that the
pyridinium (41) and imidazolium (42) derivatives of quinone
28c demonstrate weaker antiplasmodial activity than their
phosphonium counterpart (Figure 4). Although the initial
(9) Rodrigues, T.; Lopes, F.; Moreira, R. Inhibitors of the
mitochondrial electron transport chain and de novo pyrimidine
biosynthesis as antimalarials: The present status. Curr. Med. Chem.
2010, 17, 929−956.
(10) Long, T. E.; Lu, X.; Galizzi, M.; Docampo, R.; Gut, J.;
Rosenthal, P. J. Phosphonium lipocations as antiparasitic agents.
Bioorg. Med. Chem. Lett. 2012, 22, 2976−2979.
(11) Smith, R. A.; Hartley, R. C.; Cocheme, H. M.; Murphy, M. P.
Mitochondrial pharmacology. Trends Pharmacol. Sci. 2012, 33, 341−
352.
(12) Porter, T. H.; Folkers, K. Antimetabolites of coenzyme Q. Their
potential application as antimalarials. Angew. Chem., Int. Ed. Engl. 1974,
13, 559−569.
Figure 4. Antiplasmodial activity comparisons of pyridinium and
imidazolium analogues of triphenylphosphonium cation 28c against P.
falciparum W2.
(13) Kessl, J. J.; Hill, P.; Lange, B. B.; Meshnick, S. R.; Meunier, B.;
Trumpower, B. L. Molecular basis for atovaquone resistance in
Pneumocystis jirovecii modeled in the cytochrome bc(1) complex of
Saccharomyces cerevisiae. J. Biol. Chem. 2004, 279, 2817−2824.
(14) Anderson, J. M.; Kochi, J. K. Silver(I)-catalyzed oxidative
decarboxylation of acids by peroxydisulfate - Role of silver(II). J. Am.
Chem. Soc. 1970, 92, 1651−1659.
results have shown them to be several fold less active, cationic
inhibitors containing a quaternary amine may possess better
pharmaceutical properties and ultimately prove to have greater
in vivo efficacy than the phosphonium analogues.
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedures and characterization data of reported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Commandeur, C.; Chalumeau, C.; Dessolin, J.; Laguerre, M.
Study of radical decarboxylation toward functionalization of
naphthoquinones. Eur. J. Org. Chem. 2007, 3045−3052.
(16) Madej, M. G.; Nasiri, H. R.; Hilgendorff, N. S.; Schwalbe, H.;
Unden, G.; Lancaster, C. R. D. Experimental evidence for proton
motive force-dependent catalysis by the diheme-containing succinate:
Menaquinone oxidoreductase from the Gram-positive bacterium
Bacillus licheniformis. Biochemistry 2006, 45, 15049−15055.
(17) Wu, C. M.; Johnson, R. K.; Mattern, M. R.; Wong, J. C.;
Kingston, D. G. I. Synthesis of furanonaphthoquinones with
hydroxyamino side chains. J. Nat. Prod. 1999, 62, 963−968.
(18) Glinis, E.; Malamidou-Xenikaki, E.; Skouros, H.; Spyroudis, S.;
Tsanakopoulou, M. Arylation of lawsone through BF3-mediated
coupling of its phenyliodonium ylide with activated arenes and
aromatic aldehydes. Tetrahedron 2010, 66, 5786−5792.
(19) Coteron, J. M.; Catterick, D.; Castro, J.; Chaparro, M. J.; Diaz,
B.; Fernandez, E.; Ferrer, S.; Gamo, F. J.; Gordo, M.; Gut, J.; de las
Heras, L.; Legac, J.; Marco, M.; Miguel, J.; Munoz, V.; Porras, E.; de la
Rosa, J. C.; Ruiz, J. R.; Sandoval, E.; Ventosa, P.; Rosenthal, P. J.;
Fiandor, J. M. Falcipain inhibitors: Optimization studies of the 2-
pyrimidinecarbonitrile lead series. J. Med. Chem. 2010, 53, 6129−6152.
(20) Zaugg, H. E.; Rapala, R. T.; Leffler, M. T. Naphthoquinone
antimalarials. 14. 2-Hydroxy-3-aryl-1,4-naphthoquinones. J. Am. Chem.
Soc. 1948, 70, 3224−3228.
(21) Ball, E. B. Studies on oxidation-reduction. XXI. Phthiocol, the
pigment of the human tubercle bacillus. J. Biol. Chem. 1934, 106, 515−
524.
(22) Singh, I.; Ogata, R. T.; Moore, R. E.; Chang, C. W. J.; Scheuer,
P. J. Electronic spectra of substituted naphthoquinones. Tetrahedron
1968, 24, 6053−6073.
(23) Juster, N. J. Color and chemical constitution. J. Chem. Educ.
1962, 39, 596−601.
(24) Lu, X.; Althawari, A.; Hansen, E. N.; Long, T. E. Phase-transfer
catalysts in the O-alkylation of 2-hydroxynapthoquinones. Synthesis,
2012, 44, in press.
■
S
AUTHOR INFORMATION
Corresponding Author
*Tel: +1-706-542-8597. Fax: +1-706-542-5358. E-mail: tlong@
rx.uga.edu.
■
Funding
Financial support was generously provided by the R. C. Wilson
Pharmacy Fund from the College of Pharmacy at The
University of Georgia to T.E.L., the National Institutes of
Health to P.J.R., and the Doris Duke Charitable Foundation,
with which P.J.R. is a Distinguished Clinical Scientist.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Greenwood, B. M.; Bojang, K.; Whitty, C. J.; Targett, G. A.
Malaria. Lancet 2005, 365, 1487−98.
(2) Snow, R. W.; Guerra, C. A.; Noor, A. M.; Myint, H. Y.; Hay, S. I.
The global distribution of clinical episodes of Plasmodium falciparum
malaria. Nature 2005, 434, 214−7.
(3) The malERA Consultative Group on Drugs. A research agenda
for malaria eradication: Drugs. PLoS Med. 2011, 8, e1000402.
(4) Fidock, D. A. Drug discovery: Priming the antimalarial pipeline.
Nature 2010, 465, 297−298.
(5) Greenwood, B. Anti-malarial drugs and the prevention of malaria
in the population of malaria endemic areas. Malar. J. 2010, 9 (Suppl.
3), S2.
(6) Biagini, G. A.; Fisher, N.; Shone, A. E.; Mubaraki, M. A.;
Srivastava, A.; Hill, A.; Antoine, T.; Warman, A. J.; Davies, J.;
Pidathala, C.; Amewu, R. K.; Leung, S. C.; Sharma, R.; Gibbons, P.;
Hong, D. W.; Pacorel, B.; Lawrenson, A. S.; Charoensutthivarakul, S.;
Taylor, L.; Berger, O.; Mbekeani, A.; Stocks, P. A.; Nixon, G. L.;
1033
dx.doi.org/10.1021/ml300242v | ACS Med. Chem. Lett. 2012, 3, 1029−1033