The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether

Article abstract of DOI:10.1016/j.bmcl.2014.01.059

Sixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5 mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25-27 days) of malaria-infected mice.

Full text of DOI:10.1016/j.bmcl.2014.01.059

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1285–1289
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The survival times of malaria-infected mice are prolonged more by
several new two-carbon-linked artemisinin-derived dimer
carbamates than by the trioxane antimalarial drug artemether
Ryan C. Conyers a, Jennifer R. Mazzone a, Maxime A. Siegler a, Abhai K. Tripathi b,c, David J. Sullivan b,c
,
Bryan T. Mott a, Gary H. Posner a,c,
⇑
a Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, United States
b W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States
c The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Sixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical
structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only
5 mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged
the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemo-
therapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane
drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day
average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also
significantly outperformed artemether (2) in prolonging the survival times (25–27 days) of malaria-
infected mice.
Received 17 December 2013
Revised 13 January 2014
Accepted 21 January 2014
Available online 30 January 2014
Keywords:
Antimalarial chemotherapy
Trioxane dimer carbamates
Single oral dose ACT
Oral bioavailability
Ó 2014 Elsevier Ltd. All rights reserved.
Malaria remains a devastating infectious disease, especially in
tropical and sub-tropical areas of the world. Attempts at develop-
ing vaccines to protect humans from contracting malaria have
been only partially successful.1 Therefore, safe and effective che-
motherapy to cure malaria-infected patients is desperately needed.
With widespread resistance of Plasmodium falciparum malaria par-
asites to such previously reliable antimalarial drugs like chloro-
quine,2–4 antimalarial drugs with new mechanism(s) of action
are valuable for chemotherapy of malaria patients.5,6 In recent
years, a dramatic advance has been made with the use of the triox-
ane artemisinin (1) and its derivatives artemether (2) and sodium
artesunate (3, Fig. 1) as fast-acting and highly efficacious antimal-
arials.7,8 Combining such fast-acting but short lived trioxanes with
known slower-acting but longer-lived nitrogen-containing com-
pounds like mefloquine or lumefantrine is now recommended as
standard operating procedure by the World Health Organization
(WHO).9 Such artemisinin combination therapy (ACT) has led to
several combinations that are now readily available as over-the-
counter drugs. These commercial ACTs, however, typically require
multiple dosing for several days in order to achieve full cures.10–18
Compliance with such a regimen is often problematic. Therefore, a
single dose cure is becoming a major goal in modern antimalarial
chemotherapy.19–24 We have recently designed, synthesized, and
biologically evaluated a series of new C-10 carbon-linked trioxane
dimers some of which completely cure malaria-infected mice using
one single-digit oral dose of trioxane along with a non-trioxane
drug.25–29 Artemisinin-derived C-10 carbon-linked dimers having
linking units of five,26 four,27 and three28,29 carbon atoms as well
as dimers with structurally distinct linking units30–32 having
potent antimalarial activity have been reported. Recently we
described preparation of artemisinin-derived 2-carbon-linked
dimer ketone 4 (36% overall yield from artemisinin) and of its cor-
responding curative oxime derivatives 5.25 We have now discov-
ered that 2-carbon-linked dimer ketone 4 can be reduced with
very high stereocontrol predominantly into secondary alcohol dia-
stereomer 6b. The new chemical entity alcohol 6b was easily trans-
formed in one step into a series of fourteen NH-aryl carbamates 7
some of which are more efficacious than the popular monomeric
trioxane drug artemether (2) in prolonging the survival times of
malaria-infected mice (Scheme 1).
It was important to explore the utility of this new 2-carbon-
linked dimer scaffold by performing a number of functional group
transformations. The dimer ketone 4 was reduced into a pair of
diastereomeric alcohols 6a and 6b that were easily separable on
Abbreviations: SAR, structure–activity relationship; ACT, artemisinin
combination therapy; DIBALH, diisobutylaluminum hydride.
⇑
Corresponding author. Tel.: +1 410 516 4670.
E-mail address: ghp@jhu.edu (G.H. Posner).
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2014.01.059

1286
R. C. Conyers et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1285–1289
H
O
O
R1 = R2 = O
2 R1 = OCH3, R2 = H
Artemisinin
Artemether
H
1
O
3 R1 = H, R2 = OC(O)CH2CH2C(O)ONa Sodium Artesunate
O
R1 R2
Figure 1. Artemisinin and first generation derivatives.
silica gel (Scheme 2). Surprisingly, even with a bulky reducing
agent such as diisobutylaluminum hydride (DIBALH), the alcohols
6a and 6b were obtained in a 1:1 ratio. However, treatment with
commercially available enantiopure (R)-CBS-oxazaborolidine33 8a
and borane in tetrahydrofuran (BH3ÁTHF) achieved highly stereose-
lective reduction of the ketone (98% diastereomeric excess, as
determined by 1H NMR of the crude reaction mixture), allowing
direct access to diastereomer 6b. Employing the enantiomeric
(S)-CBS oxazaborolidine 8b did not afford the same selectivity,
forming both alcohol products 6a and 6b in a 62:48 ratio under
these conditions.
The more polar alcohol (by analytical TLC) was hypothesized to
be the (S)-isomer 6b based on analysis of the proton NMR signals
(Fig. 2), on the expected product from the known mechanism of
this reaction,34 and on the structural configuration by molecular
model. In the (S)-isomer, the alcohol points toward the C5 proton,
facilitating a deshielding interaction with this proton (Fig. 2III).
Furthermore, the C10 proton would be locked into a pseudo equa-
torial–axial conformation with the C17 proton (looking down the
larial activity. Reduction to the alcohol seems to contort the six-
membered glycosidic ring of the artemisinin core into a twisted
conformation. The endoperoxides are also facing in, though flexi-
bility in solution would still be expected.
The major diastereomeric alcohol 6b was converted easily in
one step using commercial aryl isocyanates into a series of four-
teen NH-aryl carbamates 7 which include phenyl, monofluoro, di-
fluoro, trifluoro, monochloro, monobromo, cyano, and nitro
derivatives (Fig. 4). Attempts at preparing NH-alkyl carbamates
using commercial alkyl isocyanates were unsuccessful.
Our recent experience showed that all of the new 2-carbon-
linked dimer oxime NH-aryl carbamates 5 had significant in vivo
antimalarial efficacy.25 Therefore, we proceeded directly with
in vivo efficacy evaluation of the new series of OC(O)NH-aryl
carbamates 7. Indeed, as expected, all of these carbamates 7 had
significant chemotherapeutic value, with some outperforming the
trioxane antimalarial drug artemether (2).
To each two-carbon-linked dimer alcohols 6a and 6b and carba-
mates 7 (0.60 mg), 113
quine hydrochloride (1.80 mg) was added and then diluted with
1087 L of deionized water for oral administration to 5-week old
lL of 7:3 Tween 80/ethanol with meflo-
C10AC17 bond), resulting in
a smaller coupling constant
(Fig. 2IV). Conversely, the alcohol would be pointed away from
the C5 proton in the (R)-isomer (Fig. 2I), and the C10–C17 protons
would be in a pseudo trans-diaxial orientation (Fig. 2II). Indeed this
trend is seen in the 1H NMR. Crystals of 6b were obtained via slow
evaporation of a mixed solvent system (1:4 mixture of dichloro-
methane and hexanes, with several drops of benzene added).
X-ray structure determination confirms the stereochemistry as de-
scribed in Figure 3. The crystal structure (Fig. 3) also revealed inter-
esting structural characteristics when compared with the ketone
precursor.25 The ketone is a rigid, cage-like structure that locked
the endoperoxide pharmacophore on the outside of the molecule,
and it was hypothesized that this would be beneficial for antima-
l
C57BL/6J male mice (from Jackson Laboratory) weighing about
20 g that were infected with Plasmodium berghei ANKA strain
(2 Â 107 parasitized erythrocytes). Each of four mice in a group
was treated orally 24 h post-infection with a single dose of
200 lL of diluted compound solution, corresponding to a dose of
5 mg/kg trioxane combined with 15 mg/kg of mefloquine hydro-
chloride. Determining blood parasitemia levels and monitoring
the duration of animal survival compared to survival time of ani-
mals receiving no drug are both widely accepted as measures of
a drug’s antimalarial efficacy. An average of 9.8% parasitemia was
observed in the control (infected but no drug treatment) group
R1 = R2 = O25
H
H
4
5
R1 = R2 = NOC(O)NHAr25
O
O
H
H
O
O
O
O
R = H, R2 = OH
1
1
6a
6b
9'
9
1 = OH, R2 = H
O 10'
O
10
R
H
H
R2
7
R1 = OC(O)NHAr, R2 = H
R1
Scheme 1. Two-carbon-linked dimer derivatives.
ART ART
ART ART
ART ART
a
+
R
S
1:1
O
OH
OH
Ph
6a
4
6b
H
N
Ph
O
b
c
62:48
1:99
B
8a - R
8b - S
o
o
8b
a) DIBALH, CH2Cl2, -78 C; 98% b)
, BH3·THF, 0 C -rt, 99% overall yield for
both diastereomers; c) , BH3·THF, 0o C - rt, 92%
8a
Scheme 2. Two-carbon-linked dimer alcohols 6.

R. C. Conyers et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1285–1289
ART ART
1287
I.
III.
HO
XHO
C17
C17
H
pseudo-
pseudo-
H
equat.-axial
protons
trans-diaxial
protons
H
H
C9
C9
H
H
O
O
C10
C10
O
O
H
H
C5
C5
More polar alcohol - 6b
Less polar alcohol - 6a
II.
IV.
H
H
ART
ART
O
O
5
5
10
10
H
H
pseudo-
pseudo-
H
HO
O
O
trans-diaxial
protons
equat.-axial
protons
OH
H
J9,10
J10,17
Compound
Structure
C5 δ
C5' δ
C10 δ
H
H
O
C5'
O
O
C5
O
O
O
6a
C10
5.37
5.30
4.73
6.19
10.93
C10'
R
H
H
OH
H
H
O
C5'
O
O
C5
O
O
O
6b
C10
5.54
5.40
4.24
6.73
3.63
C10'
H
S H
OH
Figure 2. Conformational analysis of less polar alcohol 6a (I and II) and more polar alcohol 6b (III and IV) using 1H NMR spectroscopy.
H
H
H
O
O
H
O
O
O
O
H
O
O
S
H
OH
Figure 3. Displacement ellipsoid plot (50% probability level) of two-carbon linked dimer alcohol 6b given at 110(2) K.
on day 3 post-infection. Infected mice receiving no drug died on an
average of 6.5 days post infection. The antimalarial efficacy results
of our two-carbon-linked dimer trioxanes as well as controls are
summarized in Table 1, which includes the parasitemia levels for
mice on day 3 post infection. These data show that all of our
two-carbon linked dimer derivatives 6 and 7 acted rapidly to sup-
press parasitemia. However, not all of the parasites were killed
after 3 days which leads to a difference in the efficacy for each indi-
vidual analog over the full 30 day experiment.
Important conclusions emerge from the data in Table 1. The
equipotent two-carbon linked dimer diastereomeric alcohols 6a
and 6b were more efficacious at prolonging the life of malaria-
infected mice (ꢀ25 days) compared to artemether (2) (ꢀ20 days).
Monotherapy using only mefloquine hydrochloride (15 mg/kg
single oral dose) prolonged the average survival time of malaria-
infected mice to about 20 days. Of the fourteen NH-aryl carbamates
(7) tested, three of these new chemical entities (7e, 7i, and 7j) were
more efficacious at prolonging the life of malaria-infected mice,
with average survival time of 25–27 days, compared to artemether
(2) (ꢀ20 day survival). An important characteristic of these three
efficacious compounds is the placement of a halogen (Cl or F) in
the meta-position on the phenyl ring. For example, 3-Cl-4-F-phenyl
NH-aryl carbamate 7i (average survival 25 days) is more efficacious
than the corresponding 3-methyl-4-F-phenyl NH-aryl carbamate
7d (average survival only 13.5 days). Also, 3-Cl-phenyl NH-aryl
carbamate 7j (average survival 27 days) is considerably more
efficacious than 4-Cl-phenyl NH-aryl carbamate 7k (average sur-
vival only 18 days). Having two meta-fluorines as in carbamate 7f
(average survival 22 days) offers only a small advantage over the
corresponding monofluorinated carbamate 7b (average survival
20 days). The significance of substitution at the 3-position of the
phenyl ring has previously been reported with monomeric artemis-

1288
R. C. Conyers et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1285–1289
H
H
O
O
% yield
60
% yield
64
H
H
H
H
7a
7h
Ar = Ph-4-C F3
Ar = Ph
7b Ar = Ph-3-F
7c
O
O
O
O
78
7i Ar = Ph-3-Cl-4-F 74
O
C N Ar
7j
Ar = Ph-4-F
65
Ar = Ph-3-Cl
65
99
60
95
79
O
O
6b
7d Ar = Ph-3-Me-4-F 63
7k Ar = Ph-4-Cl
7l Ar = Ph-4-Br
7e Ar = Ph-3,4-F2
7f
69
71
65
Et3N
CH2Cl2, rt
7m
Ar = Ph-3,5-F2
7g Ar = Ph-3-CF3
Ar = Ph-4-CN
O
7n Ar = Ph-4-NO2
7
O
Ar
N
H
Figure 4. Two-carbon-linked dimer carbamates 7.
Table 1
Supplementary data
In vivo antimalarial efficacy using a single oral dose of trioxane dimer (5 mg/kg)
combined with mefloquine hydrochloride (15 mg/kg) in P. berghei-infected mice
Supplementary data (crystallographic information (CCDC
981037), experimental, and tabular spectral data) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2014.01.059.
Trioxane
Survival after
infection
(days)
Avg
% parasitemia
survivala suppressionb
(days)
6a
6b
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
30, 13, 26, 30
28, 18, 27, 27
30, 13, 13, 12
30, 13, 12, 26
30, 13, 16, 16
12, 13, 13, 16
30, 30, 12, 30
26, 30, 12, 19
30, 18, 12, 12
9, 12, 9, 13
30, 26, 30, 13
28, 30, 19, 30
13, 30, 18, 12
13, 13, 12, 12
16, 12, 30, 13
30, 26, 19, 13
24.8
25
17
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
References and notes
20.3
18.8
13.5
25.5
21.8
18
10.8
24.8
26.8
18.3
12.5
17.8
22
1. The RTS, S Clinical Trials Partnership N. Engl. J. Med. 2011, 365, 1863.
2. Olliaro, P. L.; Boland, P. B. In Antimalarial Chemotherapy: Mechanisms of Action,
Resistance, and New Directions in Drug Discovery; Rosenthal, P. J., Ed.; Humana
Press: Totowa, NJ, 2001; pp 65–84.
3. Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.; Peyton, D. H.
J. Med. Chem. 2006, 49, 5623.
4. Schlitzer, M. ChemMedChem 2007, 2, 955.
5. Slack, R. D.; Jacobine, A. M.; Posner, G. H. Med. Chem. Commun. 2012, 3, 281.
6. Gibbons, P.; Verissimo, E.; Araujo, N. C.; Barton, V.; Nixon, G. L.; Amewu, R. K.;
Chadwick, J.; Stocks, P. A.; Biagini, G. A.; Srivastava, A.; Rosenthal, P. J.; Gut, J.;
Guedes, R. C.; Moreira, R.; Sharma, R.; Berry, N.; Cristiano, M. L. S.; Shone, A. L.;
Ward, S. A.; O’Neill, P. M. J. Med. Chem. 2010, 53, 8202.
7. Welcome to Coartem.com, the Novartis Malaria Initiative Website. Coartem.
http://www.coartem.com/coartem-riamet.htm.
8. MMV. Pyramax (pyronaridine-artesunate). http://www.mmv.org/research-
development/project-portfolio/pyramax%C2%AE-pyronaridine-artesunate.
9. World Health Organization: Geneva, Switzerland; Guidelines for Treatment of
Malaria, 2006.
Controls:
Infected mice (no drug)
6, 7, 7, 6
6.5
0c
Artemether (2) plus mefloquine 18, 12, 23, 28
20.3
20.3
>99.9
>99.9
Mefloquine alone
16, 11, 28, 26
a
b
c
10. Bellot, F.; Coslédan, F.; Vendier, L.; Brocard, J.; Meunier, B.; Robert, A. J. Med.
Chem. 2010, 53, 4103.
Bold entries indicate best results.
Denotes determination on day 3 after infection.
An average of 9.8% parasitemia was determined on day 3 after infection.
11. Obaldia, N., III; Kotecka, B. M.; Edstein, M. D.; Haynes, R. K.; Fugmann, B.; Kyle,
D. E.; Rieckmann, K. H. Antimicrob. Agents Chemother. 2009, 53, 3592.
12. Guo, J.; Guiguemde, A. W.; Bentura-Marciano, A.; Clark, J.; Haynes, R. K.; Chan,
W.; Wong, H.; Hunt, N. H.; Guy, R. K.; Golenser, J. Antimicrob. Agents Chemother.
2012, 56, 163.
13. Espié, E.; Lima, A.; Atua, B.; Dorba, M.; Flévaud, L.; Sompwe, E. M.; Urrutia, P. P.
P.; Guérin, P. J. Malar. J. 2012, 11, 174.
14. Yavo, W.; Faye, B.; Kuete, T.; Djohan, V.; Oga, S. A.; Kassi, R. R.; Diatta, M.; Ama,
M. V.; Tine, R.; Ndiaye, J.-L.; Evi, J.-B.; Same-Ekobo, A.; Faye, O.; Koné, M. Malar.
J. 2011, 10, 198.
15. Macedo de Oliveira, A.; Chavez, J.; Ponce de Leon, G.; Durand, S.; Arrospide, N.;
Roberts, J.; Cabezas, C.; Marquiño, W. M. J. Trop. Med. Hyg. 2011, 85, 573.
16. Sagara, I.; Diallo, A.; Kone, M.; Coulibaly, M.; Diawara, S. I.; Guindo, O.; Maiga,
H.; Niambele, M. B.; Sissoko, M.; Dicko, A.; Djimde, A.; Doumbo, O. K. Am. J.
Trop. Med. Hyg. 2008, 79, 655.
17. Rueangweerayut, R.; Phyo, A. P.; Uthaisin, C.; Poravuth, Y.; Binh, T. Q.; Tinto, H.;
Pénali, L. K.; Valecha, N.; Tien, N. T.; Abdulla, S.; Borghini-Fuhrer, I.; Duparc, S.;
Shin, C.-K.; Fleckenstein, L. N. Engl. J. Med. 2012, 366, 1298.
inin sulfur derivatives.35 The 3-Cl-phenyl NH-aryl carbamate 7j had
the highest average survival time of about 27 days. Two of the mice
were alive on day 30 with two deaths on days 19 and 28. The 3,4-
difluorophenyl NH-aryl carbamate 7e had an average survival time
of about 26 days with 3 mice alive on day 30 and one death on day
12. Compound 7i (3-Cl-4-F-phenyl NH-aryl carbamate) had an
average survival time of about 25 days, with two deaths on days
13 and 26 and two mice alive on day 30. All of the surviving mice
in this 30-day study had parasitemia levels between 8–20%.
In conclusion, we have demonstrated here that artemisinin-de-
rived 2-carbon-linked dimer secondary alcohol 6b is more effica-
cious as an antimalarial than the popular artemisinin-derived
drug artemether. Furthermore, we have established proof of prin-
ciple showing that 2-carbon-linked dimer secondary alcohol 6b is
a useful platform for generating in one step various NH-aryl carba-
mates 7. Three of these new carbamates, acting in vivo perhaps as
prodrugs,36 outperform the trioxane drug artemether in prolonging
the survival of malaria-infected mice. We are pursuing other deriv-
atives of dimer secondary alcohol 6b and will report results in due
course.
18. Kurth, F.; Bélard, S.; Basra, A.; Ramharter, M. Curr. Opin. Infect. Dis. 2011, 24,
564.
19. Charman, S. A.; Arbe-Barnes, S.; Bathurst, I. C.; Brun, R.; Campbell, M.;
Charman, W. N.; Chiu, F. C. K.; Chollet, J.; Craft, J. C.; Creek, D. J.; Dong, Y.;
Matile, H.; Maurer, M.; Morizzi, J.; Nguyen, T.; Papastogiannidis, P.; Scheurer,
C.; Shackleford, D. M.; Sriraghavan, K.; Stingelin, L.; Tang, Y.; Urwyler, H.;
Wang, X.; White, K. L.; Wittlin, S.; Zhou, L.; Vennerstrom, J. L. PNAS 2011, 108,
4400.
20. Ferrer, P.; Tripathi, A. K.; Clark, M. A.; Hand, C. C.; Rienhoff, H. Y., Jr.; Sullivan, D.
J. PLoS ONE 2012, 7, e37171. http://dx.doi.org/10.1371/journal.pone.0037171.
21. Tun, T.; Tint, H. S.; Lin, L.; Kyaw, T. T.; Myint, M. K.; Khaing, W.; Tun, Z. W. Acta
Trop. 2009, 111, 275.
22. Younis, Y.; Douelle, F.; Feng, T.-S.; González Cabrera, D.; Le Manach, C.;
Nchinda, A. T.; Duffy, S.; White, K. L.; Shackleford, D. M.; Morizzi, J.; Mannila, J.;
Katneni, K.; Bhamidipati, R.; Zabiulla, L. M.; Joseph, J. T.; Bashyam, S.;
Waterson, D.; Witty, M. J.; Hardick, D.; Wittlin, S.; Avery, V.; Charman, S. A.;
Chibale, K. J. Med. Chem. 2012, 55, 3479.
Acknowledgments
We thank the NIH (Grant R37 AI 34885 to G.H.P.), The Johns
Hopkins Malaria Research Institute, and the Bloomberg Family
Foundation for financial support.
23. Benjamin, J.; Morre, B.; Lee, S. T.; Senn, M.; Griffin, S.; Lautu, D.; Salman, S.;
Siba, P.; Mueller, I.; Davis, T. M. E. Antimicrob. Agents Chemother. 2012, 56, 2465.

R. C. Conyers et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1285–1289
1289
24. Batty, K. T.; Salman, S.; Moore, B. R.; Benjamin, J.; Lee, S. T.; Page-Sharp, M.;
Pitus, N.; Ilett, K. F.; Mueller, I.; Hombhanje, F. W.; Siba, P.; Davis, T. M. E.
Antimicrob. Agents Chemother. 2012, 56, 2472.
25. Mott, B. T.; Tripathi, A.; Siegler, M. A.; Moore, C. D.; Sullivan, D. J.; Posner, G. H.
J. Med. Chem. 2013, 56, 2630.
30. Caldarelli, S. A.; Fangour, S. E.; Wein, S.; Tran van Ba, C.; Périgaud, C.; Pellet, A.;
Vial, H. J.; Peyrottes, S. J. Med. Chem. 2013, 56, 496.
31. Amewu, R. K.; Chadwick, J.; Hussain, A.; Panda, S.; Rinki, R.; Janneh, O.; Ward, S.
A.; Miguel, C.; Burrell-Saward, H.; Vivas, L.; O’Neill, P. M. Bioorg. Med. Chem.
2013, 21, 7392.
26. Moon, D. K.; Tripathi, A.; Sullivan, D.; Siegler, M. A.; Parkin, S.; Posner, G. H.
Bioorg. Med. Chem. Lett. 2011, 21, 2773.
27. Paik, I.-H.; Xie, S.; Shapiro, T. A.; Labonte, T.; Narducci-Sarjeant, A. A.; Baege, A.
C.; Posner, G. H. J. Med. Chem. 2006, 49, 2731.
28. Rosenthal, A. S.; Chen, X.; Liu, J. O.; West, D. C.; Hergenrother, P. J.; Shapiro, T.
A.; Posner, G. H. J. Med. Chem. 2009, 52, 1198.
29. Woodard, L. E.; Chang, W.; Chen, X.; Liu, J. O.; Shapiro, T. A.; Posner, G. H. J. Med.
Chem. 2009, 52, 7458.
32. Hao, H.-D.; Wittlin, S.; Wu, Y. Chem. Eur. J. 2013, 19, 7605.
33. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551.
34. Zhu, H.; O’Leary, D. J.; Meyer, M. P. Angew. Chem., Int. Ed. 2012, 51, 11890.
35. Slack, R. D.; Mott, B. T.; Woodard, L. E.; Tripathi, A.; Sullivan, D.; Nenortas, E.;
Girdwood, S. C. T.; Shapiro, T. A.; Posner, G. H. J. Med. Chem. 2012, 55, 291.
36. Wolfe, A. L.; Duncan, K. K.; Parelkar, N. K.; Weir, S. J.; Vielhauer, G. A.; Boger, D.
L. J. Med. Chem. 2012, 55, 5878.