Phosphonium lipocations as antiparasitic agents

Article abstract of DOI:10.1016/j.bmcl.2012.02.045

Phosphonium lipocations were synthesized and evaluated for inhibition of the development of Plasmodium falciparum and Trypanosoma cruzi, etiological agents of malaria and Chagas disease, respectively. Optimal phthalimides and 1,4-naphthoquinone-based lipocations were active in vitro at mid-high nM concentrations against P. falciparum and low μM concentrations against T. cruzi.

Full text of DOI:10.1016/j.bmcl.2012.02.045

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2976–2979
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Phosphonium lipocations as antiparasitic agents
Timothy E. Long a, , Xiao Lu a, Melina Galizzi b, Roberto Docampo b, Jiri Gut c, Philip J. Rosenthal c
⇑
a Department of Pharmaceutical and Biomedical Sciences and Center for Drug Discovery, University of Georgia, Athens, GA 30602, USA
b Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
c Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Phosphonium lipocations were synthesized and evaluated for inhibition of the development of
Plasmodium falciparum and Trypanosoma cruzi, etiological agents of malaria and Chagas disease, respec-
tively. Optimal phthalimides and 1,4-naphthoquinone-based lipocations were active in vitro at mid-high
Received 9 January 2012
Revised 9 February 2012
Accepted 13 February 2012
Available online 23 February 2012
nM concentrations against P. falciparum and low
lM concentrations against T. cruzi.
Published by Elsevier Ltd.
Keywords:
Malaria
Chagas
Antiparasitic drugs
Plasmodium
Trypanosoma
Malaria and American trypanosomiasis (Chagas disease) are
vector-borne infections that cause hundreds of millions of illnesses
and nearly a million deaths in the tropics each year.1 With malaria,
clinical illness results when erythrocytes become infected with
Plasmodium parasites. Effective antimalarial therapies must elimi-
nate erythrocytic parasites while inflicting minimal host toxicity.
Older antimalarial therapies such as chloroquine are seriously lim-
ited by drug resistance.2 Newer agents include the artemisinins
and the ubiquinone (CoQ) antagonist atovaquone (ATV). Artemisi-
nins are rapidly active components of new combination regimens
now widely used to treat malaria,3 although resistance to artemis-
inins may be emerging.4 ATV is co-formulated with proguanil
(Malarone) for the treatment and prevention of malaria because
of synergistic interaction of the two components and high recru-
descence rates after monotherapy.5 ATV acts on the mitochondrion
and demonstrates low toxicity due in part to evolutionary dissim-
ilarities between plasmodial and mammalian mitochondria. How-
ever, for pharmaceuticals that require internalization by
mitochondria, subcellular and therapeutic efficacy can be limited
by the physiochemical properties of a compound.
for the management of Parkinson’s disease, hepatitis C, and fatty li-
ver disease. As a positively-charged analog of the dietary antioxi-
dant idebenone (Catena/Sovrima, Fig. 1), the enhanced therapeutic
efficacy of mitoquinone is conferred by attachment of a triphenyl-
phosphonium group to the decyl side chain. This modification
guides the lipocation into energized mitochondria by electrostatic
O
O
OH
MeO
MeO
H
n
O
O
Cl
ubiquinone
(CoQ)
atovaquone
(ATV)
OMs
PPh3
O
O
Phosphonium cations are used extensively as molecular probes
for studying mitochondrial function6 and have demonstrated utility
as mediators of antioxidant,7 antimicrobial,8 and antineoplastic9
transport into mitochondria. Mitoquinone7a (MitoQ, Fig. 1), a syn-
thetic analog of ubiquinone, is the most clinically advanced phos-
phonium cation, and it has progressed to phase II trials in the U.S.
OH
MeO
MeO
MeO
MeO
( )
9
( )
9
O
O
idebenone
(Catena/Sovrima)
mitoquinone
(MitoQ mesylate)
⇑
Figure 1. Chemical structures of ubiquinone analogs atovaquone, idebenone, and
mitoquinone.
Corresponding author. Tel.: +1 706 542 8597; fax: +1 706 542 5358.
E-mail address: tlong@rx.uga.edu (T.E. Long).
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2012.02.045

T. E. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2976–2979
2977
O
O
Methods A-C
Br(CH2)nCH2Br
2a-j
NH
N ( )
n
Cs2CO3, MeCN
80 oC, 9-15 h
n = 3, 5, 9
Br
O
O
1a-c
Method A: PR3, μW, 0.5 h; B: P(2-PhMe)3, 110 oC, 16-40 h; C: PMe3, 2-PrOH:PhMe,
90 oC, 48-72 h.
Scheme 1. Synthesis of phthalimide-based phosphonium lipocations 2 (Table 1).
attraction and leads to increased drug concentrations in the mito-
chondrial matrix.7d
phthalimide 3 and triphenylphosphonium cations 4 in the study.
Conversely, substituents on the phosphonium moiety and the lipid
chain length (n) had a moderate impact on activity. The P-substitu-
ent could be either alkyl (e.g., R = cyclohexyl, 2i) or aromatic (e.g.,
R = Ph, 2g), with only a moderate effect on the IC50 values. The tri-
methyl derivative 2a was an exception having much weaker activ-
ity compared to analogs of equal chain length (i.e., 2d–j). A similar
detrimental effect was observed for compounds possessing shorter
chain lengths, with the 4- and 6-carbon chain analogs, 2b and c
respectively, demonstrating 4–15-fold reduced activity compared
to the 10-carbon chain lipocation 2g.
A structural feature common to mitoquinone and other CoQ
mimics (e.g., ATV) is a lipophilic side chain, which increases per-
meability in the inner phospholipid bilayers of mitochondria,
where electron transport complexes are embedded. We hypothe-
sized that if a phosphonium moiety were bound to the lipid substi-
tuent in antagonists of the Plasmodium and Trypanosoma electron
transport chains, higher drug concentrations would be achieved
inside the mitochondrion and lead to increased antiparasitic ef-
fects. In this initial report, we examine the effects on antiparasitic
activity of phosphonium group attachment to structural analogs of
CoQ containing phthalimide and 1,4-naphthoquinone platforms.
The first series of molecules chosen for evaluation were derived
from phthalimide, which has structural similarities to CoQ, and served
as a simple platform to conduct an SAR study on the lipocation chain
component. N-alkylphthalimides 1a–c(Scheme 1) were prepared from
dibromoalkanes of various chain lengths and then coupled with a ter-
tiary phosphine under microwave10 or conventional heating condi-
tions (methods A–C) to afford the phosphonium lipocations.
Minimum inhibitory concentrations (IC50) were determined for
the phthalimide-based lipocations 2a–j against the chloroquine-
resistant Plasmodium falciparum strain W2, using methods as pre-
Although investigation of the phthalimide-based lipocations
was beneficial in confirming activity and examining SAR, it was
apparent that the phthalimide group was not serving as an antag-
onist of CoQ, as supported by similarities in the IC50 values of phos-
phonium salts 2f–j and 4a. Attention was turned to lipocations
containing the 1,4-naphthoquinone platform which is found in
ATV and many other known inhibitors of the Plasmodium cyto-
chrome bc1 complex.12 The analogs were synthesized from qui-
nones 5 using three different approaches to install the lipocation
chain (Scheme 2). The first method was by nucleophilic addition13
of straight-chain amino alcohols to 1,4-naphthoquinone (R1 = H),
followed by mesylation of the corresponding alcohol, and genera-
tion of the phosphonium salts under microwave irradiation. The
second approach introduced the cation by chloroalkylation14 of
naphthoquinone 5 (R1 = Me) with formaldehyde and subsequent
conversion to triphenylphosphonium salt 9f. The final method
was by alkylation of naphthoquinones 5 (R1 = H, Me) via radical
decarboxylation.15 The resulting bromides were then converted
to the lipocations by methods A–C (Scheme 1), which often re-
sulted in substantial amounts of reduced products (i.e., 1,4-naph-
thalenediols) being formed. When this occurred, re-oxidation to
the quinone was accomplished with nitric oxide generated in situ
viously described.11 The IC50s ranged from 134.0 nM to >3.5
lM
(Table 1), compared to 66.9 nM for chloroquine (CQ). Analysis of
structure–activity relationships revealed that antiplasmodial ef-
fects were conferred by the phosphonium moiety, and the pres-
ence or absence of the phthalimide group had minimal influence
on activity. This conclusion was established by inclusion of
Table 1
Comparisons of IC50s for P. falciparum growth
16
from NaNO2 and subsequent counterion exchange to the mesy-
O
O
late salt form to ensure chemical conformity of the product.
Susceptibility testing of the naphthoquinone-based lipocations
against W2-strain P. falciparum revealed an SAR profile similar to
that of the phthalimide series (Table 2). Antiplasmodial activity
was conferred by the installation of a phosphonium-containing
hydrocarbon chain, and a variety of P-substituents could be uti-
lized without significant deviations in the IC50 values (i.e., 9i–m).
The activities for many of the 10-carbon chain analogs were once
again comparable to the lipocation control 4a (IC50 141.6 nM), sug-
gesting that the inhibitory effects were due not to a specific mech-
anism (e.g., cytochrome bc1 inhibition), but rather to a nonspecific
action such as disruption of plasma membrane integrity. The two
apparent exceptions were lipocations 9n (IC50 48.3 nM) and 9o17
(IC50 18.7 nM), which displayed 3–7-fold greater activity than con-
trol 4a. The 5- and 4-carbon chain analogs were also more active
than their 10-carbon chain counterpart 9k (IC50 143.4 nM), a rever-
sal in the SAR profile observed with the phthalimide series. In addi-
tion, a comparison of analog 9o to its 4-carbon chain control 4b
( )
N
N ( )
( )
n
8
n
PR3
PPh3
O
O
3
4a
(n = 8) 141.6 3.5 nM
2a-j
(Table 1)
>10,000 nM
4b (n = 2) 3,500 nM
Compd
n
R
IC50 (nM)
LogDa
MWb
2a
2b
2c
2d
2e
2f
2g
2h
2i
9
3
5
9
9
9
9
9
9
9
Me
Ph
Ph
4-PhF
Bn
n-Bu
Ph
2-PhMe
C6H11
4-PhOMe
>10,000
3500
À0.08
362.5
464.5
492.6
602.6
590.8
488.7
548.7
590.8
566.8
638.7
0.01
1021 93.2
345.6 15.3
288.5 35.2
194.2 3.8
172.7 4.0
143.4 7.0
140.6 0.7
134.0 1.7
1.14
2.13
1.37
3.68
1.67
À0.75
4.50
2j
3.19
CQ
66.9 2.3
319.9
a
Measured by 1-octanol–water partition at pH 7.4.
Molecular weights of lipocations 2 minus the counterion.
and phthalimide 2b (IC50s 3.5
lM) established that the naphtho-
b
quinone platform had a role in achieving sub-50 nM activities.

2978
T. E. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2976–2979
O
1. H2N(CH2)nOH
H
N
OMs
( )
n
PR3
EtOH, r.t.
7a-f
2. MsCl, Et3N
μW, high abs.
150 oC, 0.5 h
H
DCM, 0 oC - r.t.
O
R1 = H; n = 2, 10
6a,b
O
O
H
PPh3
37% CH2O
Cl
Me
9f
μW, high abs.
150 oC, 0.5 h
AcOH, HCl
R1
R1 = Me
O
O
8
5
O
HO2C(CH2)nBr
0.5 eq. AgNO3
( )
Methods A-C
Br
9a-e
9g-o
n
R1
aq. (NH4)8S2O8
MeCN, 60 oC
O
R
1 = H, Me; n = 4, 5, 10
10a-d
Scheme 2. Synthesis of 1,4-naphthoquinone-based phosphonium lipocations 7 and 9 (Table 2).
Table 2
Table 3
Comparisons of IC50s for P. falciparum growth
Comparisons of IC50s for T. cruzi growth and Vero cell toxicity
O
O
O
O
Compd
n
R
T. cruzi IC50
(
l
M)
Vero cell toxicitya
(lM)
H
N
PR3
X
H
( )
n
( )
n
( )
8
25
12.5
6.25
PR3
R1
R1
11
12
9n
9i
9h
9a
9o
9l
17.3 7.1
9.3 1.3
5.4 0.1
4.0 3.6
3.7 1.8
3.0 1.3
2.7 1.0
2.4 0.7
1.6 0.5
1.6 0.5
2.1 0.4
À
À
+
À
À
À
+
À
À
À
À
À
À
À
À
+
O
O
5
Ph
n-Bu
Bn
Bn
Ph
C6H11
Ph
Ph
7a-f
(Table 2)
9a-o
(Table 2)
11
12
>10,000 nM
>10,000 nM
(X=NH)
(X=CH2)
10
10
10
4
10
10
10
+
+
+
À
À
+
À
À
+
Compd
n
R
R1
IC50 (nM)
LogDa
MWb
7a
7b
7c
7d
7e
7f
2
10
10
10
10
10
Ph
4-PhF
Bn
4-PhOMe
Ph
H
H
H
H
H
H
519.9 61.2
292.0 53.2
214.6 0.5
134.2 10.5
113.9 7.6
94.4 35.2
À1.08
462.5
628.7
616.8
664.8
574.7
592.9
7e
+
+
+
1.67
2.80
4.37
3.60
3.41
9k
+
+
BNZb
À
À
À
a
+, cytotoxicity observed; À, cytotoxicity not evident.
b
C6H11
Benznidazole.
9a
9b
9c
9d
10
10
10
5
Bn
4-PhF
Ph
H
H
H
H
1303.5 13.4
846.3 0.7
259.2 18.7
156.6 6.5
5.32
1.66
4.08
1.00
601.8
613.7
559.7
489.6
amastigotes.19 The IC50s for inhibition of parasite development
ranged from 1.6 to 5.4 M and variable degrees of Vero cell toxicity
was observed (Table 3). For comparison, benznidazole was used as
l
Ph
9e
9f
9g
9h
9i
9j
9k
9l
5
1
Me
Ph
Me
Bn
n-Bu
2-PhMe
Ph
C6H11
4-PhOMe
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
955.6 2.5
543.4 79.2
404.2 16.7
212.0 27.2
155.8 9.0
143.4 7.0
143.4 6.3
134.3 1.8
130.9 6.6
48.3 1.5
0.21
1.89
1.95
6.64
5.10
3.58
3.97
3.64
3.52
2.15
1.91
317.4
447.5
373.5
615.8
513.8
615.8
573.7
591.9
663.8
503.6
489.6
a positive control (IC50 2.1
trations indicated.
lM) and was non-toxic at the concen-
10
10
10
10
10
10
10
5
As with P. falciparum, the lipocation analogs were more effective
antitrypanosomal agents than their uncharged naphthoquinone
counterparts 11 and 12. Chain length and P-substituent type ap-
peared to have little effect on the activity but, were influential on
Vero cell cytotoxicity and may have resulted in the increased effi-
9m
9n
9o
cacy observed for lipocations 7e and 9k (IC50s 1.6
potent compound not displaying toxicity at 25 M was the 4-car-
bon chain analog 9o (IC50 2.7 M) which also possessed the highest
lM). The most
4
Ph
18.7 0.3
l
ARTc
ATV
7.31 0.14
0.28 0.19
262.3
366.3
l
antiplasmodial activity at 18.7 nm. Additional testing of lipocation
9o further revealed therapeutic index values {TI = [IC50(Vero)]/
[IC50(parasite)]} of 19.5 and 2818 for T. cruzi and P. falciparum,
respectively.
a
b
c
Measured by 1-octanol–water partition at pH 7.4.
Molecular weights of lipocations 7 and 9 minus the counterion.
Artemisinin.
With these findings, a question to be addressed is whether
pharmacological activity is conferred by charge-mediated accumu-
lation of the lipocations inside the mitochondrion. As with mito-
chondrial-targeted modulators of similar design,7,20 we belive
subcellular internalization of the antagonists is governed by their
physiochemical properties. It is hypothesized that the lipid
character of the cations combined with electrostatic forces facili-
tates non-carrier-mediated transport through the cytoplasmic
The naphthoquinone-derived lipocations were additionally
evaluated as growth inhibitors against Trypanosoma cruzi, the etio-
logical agent of Chagas disease. Like P. falciparum, T. cruzi has a
complex life cycle which includes infective, non-replicating blood-
stream trypomastigote forms and intracellular amastigotes that in-
fect cardiac and other cells, leading to disease.18 The compounds
were assessed for efficacy against Vero cell-infected T. cruzi

T. E. Long et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2976–2979
2979
P.J.R. and the Doris Duke Charitable Foundation, with which P.J.R.
is a Distinguished Clinical Scientist. Special thanks is also given
to Dr. Jim Franklin for many insightful discussions and Dr. Dennis
Phillips for mass spectroscopy analyses.
extracellular
environment
host cell
cytoplasm
O
ψm
?
( )
PPh3
4
References and notes
ψp
Me
ψp
1. (a) Greenwood, B. M.; Bojand, K.; Whitty, C. J. M.; Targett, G. A. Lancet 2005,
365, 1487; (b) Snow, R. W.; Guerra, C. A.; Noor, A. M.; Myint, H. Y.; Hay, S. I.
Nature 2005, 434, 214; (c) Rassi, A., Jr.; Rassi, A.; Marin-Neto, J. A. Lancet 2010,
375, 1388; (d) Urbina, J.; Docampo, R. Trends Parasitol. 2003, 19, 495.
2. Petersen, I.; Eastman, R.; Lanzer, M. FEBS Lett. 2011, 585, 1551.
3. White, N. J. Science 2008, 320, 330.
4. Dondorp, A. M.; Nosten, F.; Yi, P.; Das, D.; Phyo, A. P.; Tarning, J.; Lwin, K. M.;
Ariey, F.; Hanpithakpong, W.; Lee, S. J.; Ringwald, P.; Silamut, K.; Imwong, M.;
Chotivanich, K.; Lim, P.; Herdman, T.; An, S. S.; Yeung, S.; Singhasivanon, P.;
Day, N. P.; Lindegardh, N.; Socheat, D.; White, N. J. N. Engl. J. Med. 2009, 361,
455.
5. Canfield, C. J.; Pudney, M.; Gutteridge, W. E. Exp. Parasitol. 1995, 80, 373.
6. (a) Murphy, M. P. Biophys. Acta, Bioenerg. 2008, 1777, 1028; (b) Ross, M. F.; Da
Ros, T.; Blaikie, F. H.; Prime, T. A.; Porteous, C. M.; Severina, I. I.; Skulachev, V. P.;
Kjaergaard, H. G.; Smith, R. A. J.; Murphy, M. P. Biochem. J. 2006, 400, 199; (c)
Ross, M. F.; Kelso, G. F.; Blaikie, F. H.; James, A. M.; Cochemé, H. M.; Filipovska,
A.; Da Ros, T.; Hurd, T. R.; Smith, R. A. J.; Murphy, M. P. Biochemistry (Moscow)
2005, 70, 222; (d) Ono, A.; Miyauchi, S.; Demura, M.; Asakura, T.; Kamo, N.
Biochemistry 1994, 33, 4312.
7. (a) Smith, R. A. J.; Murphy, M. P. Ann. N.Y. Acad. Sci. 2010, 1201, 96; (b) Murphy,
M. P. Biochim. Biophys. Acta 2008, 1777, 1028; (c) Murphy, M. P.; Smith, R. A. J.
Annu. Rev. Pharmcol. Toxicol. 2007, 47, 629; (d) James, M. A.; Cochemé, H. M.;
Smith, R. J.; Murphy, M. P. J. Biol. Chem. 2005, 280, 21295; (e) Asin-Cayuela, J.;
Manas, A. B.; James, A. M.; Smith, R. A. J.; Murphy, M. P. FEBS Lett. 2004, 571, 9;
(f) Kelso, G. F.; Porteous, C. M.; Coulter, C. V.; Hughes, G.; Porteous, W. K.;
Ledgerwood, E. C.; Smith, R. A. J.; Murphy, M. P. J. Biol. Chem. 2001, 276, 4588.
8. (a) Luque-Ortega, J. R.; Reuther, P.; Rivas, L.; Dardonville, C. J. Med. Chem. 2010,
53, 1788; (b) Kanazawa, A.; Ikeda, T.; Endo, T. Antimicrob. Agents Chemother.
1994, 38, 945; (c) Kanazawa, A.; Ikeda, T.; Endo, T. J. Appl. Bacteriol. 1995, 78,
55; (d) McAllister, P. R.; Dotson, M. J.; Grim, S. O.; Hillman, G. R. J. Med. Chem.
1980, 23, 862; (e) Levi-Schaffer, F.; Tarrab-Hazdai, R.; Meshulam, H.; Arnon, R.
Int. J. Immunopharmacol. 1984, 6, 619; (f) Kinnamon, K. E.; Steck, E. A.; Rane, D.
S. J. Med. Chem. 1979, 22, 452; (g) Hanson, W. L.; Chapman, W. L., Jr.; Kinnamon,
K. E. Int. J. Parasitol. 1977, 7, 443; (h) Kinnamon, K. E.; Steck, E. A.; Hanson, W. L.;
Chapman, W. L., Jr. J. Med. Chem. 1977, 20, 741.
O
parasite
9o
host cell
cytoplasmic
membrane
Figure 2. The antiparasitic effects of phosphonium lipocation 9o is believed to be
due to electrostatic forces that increase subcellular (mitochondrial) concentrations
of the inhibitor.
membranes of the host cell and parasite. The charge distribution
across the molecules presumably confers sufficient lipid character
to enable passage through phospholipid bilayers with electrostatic
forces guiding the cationic inhibitors towards points of increasing
negative charge in a parasitized cell (Fig. 2)
In the case of plasmodia, the inward cytoplasmic membrane po-
tential (Dwp) of erythrocytes and P. falciparum are reportedly
6À35 mV21 and À95 2 mV,22 respectively, which offers a rational
basis for a
Dw-directed route into the parasite. Further, with the
absence of mitochondria in uninfected erythrocytes, the Plasmo-
dium mitochondrion would be the site of highest negative charge
in an infected erythrocyte, and thereby be the primary location
where the lipocations would be expected to accumulate. Con-
versely, mammalian cells usually possess hundreds of mitochon-
dria also capable of taking up the lipocations, which may have
led to the reduced efficacy observed against Vero cell-infected T.
cruzi. Although host mitochondria will cause a decrease of lipoca-
tion concentrations in the parasite, T. cruzi amastigotes have only
a single mitochondrion.23 Lower drug concentrations would there-
9. (a) Millard, M.; Pathania, D.; Shabaik, Y.; Taheri, L.; Deng, J.; Neamati, N. PLoS
One 2010, 5, e13131; Delikatny, E. J.; Cooper, W. A.; Brammah, S.; Sathasivam,
N.; Rideout, D. C. Cancer Res. 2002, 62, 1394; (c) Cooper, W. A.; Bartier, W. A.;
Rideout, D. C.; Delikatny, E. J. Magn. Reson. Med. 2001, 45, 1001; (d) Manetta, A.;
Gamboa, G.; Nasseri, A.; Podnos, Y. D.; Emma, D.; Dorion, G.; Rawlings, L.;
Carpenter, P. M.; Bustamante, A.; Patel, J.; Rideout, D. Gynecol. Oncol. 1996, 60,
203; (e) Rideout, D.; Bustamante, A.; Patel, J. Int. J. Cancer 1994, 57, 247; (f)
Dubois, R. J.; Lin, C. C.; Beisler, J. A. J. Med. Chem. 1978, 21, 303.
fore likely be required to collapse the Dwm and confer lethal effects
on the trypanosome compared to host cells.
In summary, phosphonium lipocations were found to be effica-
cious inhibitors of the development of cultured P. falciparum and T.
cruzi. Preliminary SAR profiles were established for lipocations de-
rived from phthalimide and 1,4-naphthoquinone platforms. In
both series, antiparasitic activity was greater for compounds con-
taining a phosphonium group. The P-substituent could be either
aromatic or alkyl without significant deviations in the IC50s, while
a lipid chain of 4-carbons appeared to be the optimal length for
1,4-naphthoquinone-based inhibitors. Current research efforts are
focused on evaluating the antiparasitic activity of lipocations con-
taining various platform types of known electron transport antag-
onists. The goal will be to identify compounds that are equipotent
to other mitochondrion-acting agents (e.g., ATV) and demonstrate
minimal cytotoxicity. Ideally, the lipocations will also have good
distribution in tissues most susceptible to damage by the infection
(erythrocytes for malaria parasites and cardiac and intestinal myo-
cytes for T. cruzi) and cost-effective, orally active agents to merit
their development as antiparasitic drugs.
10. (a) Kiddle, J. J. Tetrahedron Lett. 2000, 41, 1339; (b) Cvengros, J.; Toma, S.;
Marque, S.; Loupy, A. Can. J. Chem. 2004, 82, 1365.
11. 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. J. Med. Chem. 2010, 53, 6129–6152.
12. (a) Rodrigues, T.; Lopes, F.; Moreira, R. Curr. Med. Chem. 2010, 17, 929; (b)
Porter, T. H.; Folkers, K. Angew. Chem., Int. Ed. 1974, 13, 559.
13. Bittner, S.; Gorohovsky, S.; Paz-Tal, O.; Becker, J. Y. Amino Acids 2002, 22, 71.
14. Lipshutz, B. H.; Kim, S.-K.; Mollard, P.; Stevens, K. L. Tetrahedron 1998, 54, 1241.
15. Commandeur, C.; Chalumeau, C.; Dessolin, J.; Laguerre, M. Eur. J. Org. Chem.
2007, 3045.
16. Bozell, J. J.; Hoberg, J. O.; Dimmel, D. R. Tetrahedron Lett. 1998, 39, 2261.
17. (4-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)butyl)triphenyl-
phosphonium methanesulfonate (9o): orange oil; TLC (SiO2) Rf 0.27 (9:1 DCM/
MeOH); 1H NMR (500 MHz, CDCl3) d 8.04–8.02 (m, 1H), 7.97–7.96 (m, 1H),
7.81–7.68 (m, 17H), 3.69–3.63 (m, 2H), 2.68–2.66 (m, 5H), 2.17 (s, 3H), 1.86–
1.80 (m, 2H), 1.76–1.69 (m, 2H); 13C NMR (125 MHz, CDCl3) d 185.1, 184.9,
146.0, 144.4, 135.09, 135.06, 133.64, 133.56, 133.5, 133.4, 132.1, 131.9, 130.6,
130.5, 126.3, 126.2, 118.6, 117.9; 31P NMR (202 MHz, CDCl3) d 24.9; ESI-HRMS
calcd for C33H30O2P [M+] 489.1977, found 489.1982.
18. Docampo, R. Curr. Pharm. Des. 2001, 7, 1157.
19. Demoro, B.; Caruso, F.; Rossi, M.; Benítez, D.; Gonzalez, M.; Cerecetto, H.;
Parajón-Costa, B.; Castiglioni, J.; Galizzi, M.; Docampo, R.; Otero, L.; Gambino,
D. J. Inorg. Biochem. 2010, 104, 1252.
Acknowledgments
20. Frantz, M. C.; Wipf, P. Environ. Mol. Mutagen. 2010, 51, 462.
21. Mikkelsen, R. B.; Tanabe, K.; Wallach, D. H. F. J. Cell. Biol. 1982, 93, 685.
22. Allen, R. J.; Kirk, K. J. Biol. Chem. 2004, 279, 11264.
Financial support was generously provided by endowed funds
from the College of Pharmacy at The University of Georgia to
T.E.L, the National Institutes of Health to R.D. (AI082542) and
23. Fidalgo, L. M.; Gille, L. Pharm. Res. 2011, 28, 2758.