Overcoming drug resistance to heme-targeted antimalarials by systematic side chain variation of 7-chloro-4-aminoquinolines

Article abstract of DOI:10.1021/jm800106u

Systematic variation of the branching and basicity of the side chain of chloroquine yielded a series of new 7-chloro-4-aminoquinoline derivatives exhibiting high in vitro activity against four different strains of P. falciparum. Many of the compounds test

Full text of DOI:10.1021/jm800106u

J. Med. Chem. 2008, 51, 1995–1998
1995
Overcoming Drug Resistance to
Heme-Targeted Antimalarials by Systematic
Side Chain Variation of
7-Chloro-4-aminoquinolines
Kimberly Yearick,† Kekeli Ekoue-Kovi,† Daniel P. Iwaniuk,†
Jayakumar K. Natarajan,†,‡ John Alumasa,†
Angel C. de Dios,†,§ Paul D. Roepe,*,†,‡,§ and
Christian Wolf*,†,§
Department of Chemistry, Department of Biochemistry and Cellular
and Molecular Biology, and Center for Infectious Diseases,
Georgetown UniVersity, 37th and O Streets, Washington, D.C.
Figure 1. Structures of antimalarial aminoquinolines.
responsible for killing the parasite.5–9 It is widely accepted that
the 4-aminoquinoline pharmacophore plays a crucial role in the
complexation to FPIX resulting in inhibition of hemozoin
formation and parasite growth,10 while the presence of a basic
amino group in the side chain is generally considered essential
for trapping high concentrations of the drug in the acidic food
vacuole of the parasite.11
ReceiVed February 1, 2008
Abstract: Systematic variation of the branching and basicity of the
side chain of chloroquine yielded a series of new 7-chloro-4-
aminoquinoline derivatives exhibiting high in vitro activity against four
different strains of P. falciparum. Many of the compounds tested
showed excellent potency against chloroquine sensitive and resistant
strains. In particular 4b, 5a, 5b, 5d, 17a, and 17b were found to be
significantly more potent than chloroquine against the resistant strains
Dd2 and FCB.
To date, numerous isolates of P. falciparum have developed
resistance against a majority of currently employed antimalarial
drugs. In order to address the ever-increasing health impact of
malaria, promising chloroquine resistant (CQR) reversal agents12,13
and new therapeutics14 including artemisinin and other endo-
peroxides have been introduced.15–20 However, the latter are
less affordable in the most plagued tropical and subtropical
regions and resistance to endoperoxide-derived antimalarials has
already been reported.21 Arguably, quinine, chloroquine, and
mefloquine are among the most successful antimalarial drugs
ever used, and additional lead compounds with improved activity
against CQR strains have been discovered via synthetic modi-
fications of these structures.22–24 Importantly, 4-aminoquinolines
carrying an aliphatic side chain are often well tolerated and
afford excellent activity-toxicity profiles.25 The evident need
for safe, effective, and inexpensive antimalarials that are equally
active against multiple species of Plasmodia, e.g., P. falciparum
and P. ViVax, has therefore directed increasing efforts to the
design of new CQ analogues.
Since modifications of the 7-chloroquinoline ring, i.e.,
incorporation of other electron-withdrawing or electron-donating
substituents such as amino and methoxy groups into the various
positions in the quinoline ring, have generally proved detrimental
to the antimalarial activity,26,27 a systematic variation of the
side chain structure and basicity seems to be more promising.
Although few comprehensive and methodical modifications of
the CQ side chain have been reported to date, it has been
established that both shortening and lengthening of the separa-
tion of the two aliphatic amino groups to 2–3 or 10–12 carbon
atoms and the incorporation of a phenol moiety can lead to
increased activity against CQR strains.28–31 Several studies
revealed that introduction of a branched dialkylamino motif at
the side chain terminus of CQ, e.g., replacement of the ethyl
by isopropyl or tert-butyl groups, can furnish metabolically more
stable antimalarials with enhanced lifetime and retained activity
against drug resistant strains of P. falciparum.32,33
Malaria remains the world’s most widespread and devastating
infectious disease, with approximately 300 million annual cases
and more than 2 million casualties. Among the protozoan
parasites of the genus Plasmodium causing malaria in humans,
Plasmodium falciparum is the most lethal species. Since the
discovery of the antimalarial potency of quinine and other
cinchona alkaloids, many agents exhibiting a 4-substituted
quinoline pharmacophore have been introduced. In particular,
chloroquine (CQa), mefloquine, sontoquine, and amodiaquine
have proved to be among the most effective antimalarial drugs
(Figure 1).1–3 Aminoquinolines are known to form a complex
with ferriprotoporphyrin IX (FPIX), which is generated in the
food vacuole of the intraerythrocytic malaria parasite as a result
of proteolysis of host hemoglobin (Hb), which serves as a major
source of amino acids during the protozoan life stages within
the infected red blood cell. Free FPIX is cytotoxic to Plasmo-
dium, which therefore has developed a strategy to limit the
amount of free FPIX, converting it into insoluble crystalline
hemozoin.4 The drug-FPIX interactions inhibit conversion of
hematin to hemozoin and hence its detoxification via crystal-
lization, and the accumulation of significant concentrations of
toxic FPIX-aminoquinoline adducts is believed to be ultimately
* To whom correspondence should be addressed. For P.D.R.: phone,
202-687-7300; fax, 202-687-6209; e-mail, roepep@georgetown.edu. For
C.W.:
phone,
202-687-3468;
fax,
202-687-6209;
e-mail,
cw27@georgetown.edu.
†
Department of Chemistry.
‡
Department of Biochemistry and Cellular and Molecular Biology.
Center for Infectious Diseases.
Abbreviations: CQ, chloroquine; CQR, chloroquine resistant; CQS,
§
a
chloroquine sensitive; Dd2, chloroquine resistant strain; FCB, chloroquine
resistant strain; HB3 chloroquine sensitive strain; GCO3, chloroquine
sensitive strain; FPIX, ferriprotoporphyrin IX; Hb, hemoglobin; P. falci-
parum, Plasmodium falciparum; IC50, 50% inhibitory drug concentration;
EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Py-
bop, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate;
CDMT, 2-chloro-4,6-dimethoxy-1,3,5-triazine.
We envisioned that incorporation of an increasing number
of basic amino groups along with systematic structural variations
(length and branching) of the aliphatic side chain attached to
the potent 4-amino-7-chloroquinoline pharmacophore would
10.1021/jm800106u CCC: $40.75
2008 American Chemical Society
Published on Web 03/18/2008

1996 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Letters
hydrochloride (EDC) furnished amides 3, which were reduced
with borane-dimethyl sulfide to the corresponding series of
secondary amines 4. Finally, tertiary amines 5 were prepared
by treatment of precursors 4 with sodium borohydride in glacial
acetic acid.
The symmetrically branched amines 6 and 7 were synthesized
from 4-ketopimelic acid, 8, and 5-oxoazelaic acid, 9 (Scheme
2). Screening of different coupling conditions revealed that
Pybop and CDMT allow efficient amide formation with diethyl-
amine and diisopropylamine, respectively. The corresponding
R,ω-diamides 10 and 11 were thus obtained in 62–99% yield.
Reductive amination of the ketone group using ammonium
acetate and sodium cyanoborohydride and subsequent reduction
of the terminal amides with lithium aluminum hydride gave
triamines 14 and 15 in good yields. These amines were then
employed in a carefully optimized nucleophilic aromatic
substitution procedure using excess of 1 at high temperatures
in a closed vessel to produce chloroquinolines 6 and 7. The
1,3- and 1,4-diaminocyclohexane-derived chloroquinolines 16a,
16b, 17a, and 17b were prepared from 4,7-dichloroquinoline
and a mixture of the cis- and trans-isomers of diaminocyclo-
hexanes 18 and 19. The nucleophilic halide displacements were
followed by treatment of intermediates 20 and 21 with either
NaBH4 and acetic acid or acetone and NaBH(OAc)3 (Scheme
3).
The antiplasmodial activity of tribasic compounds 4a-e,
5a-e, 6a,b, and 7a,b and the dibasic 1,3- and 1,4-diamino-
cyclohexane-derived chloroquinoline analogues 16a, 16b, 17a,
and 17b was measured versus two CQS (HB3 and GCO3) and
two CQR (Dd2 and FCB) strains using a standardized,
inexpensive assay based on SYBR Green I intercalation that
hasrecentlybeenadoptedandvalidatedbyseverallaboratories.34–36
The IC50 values were calculated from experiments carried out
in triplicate and compared to CQ (Table 1). Many of the
aminoquinolines prepared for this study showed antimalarial
activity versus HB3 and GCO3 similar to that of CQ, and we
Figure 2. Structures of tribasic and dibasic 4-amino-7-chloroquinolines.
provide new candidates that overcome antimalarial drug resist-
ance. The introduction of a highly branched tether between the
two amino functions in CQ and the replacement of the
metabolically unstable terminal diethylamino group by an
isopropyl analogue were expected to enhance the lifetime of
CQ analogues exhibiting retained activity against CQR strains.
Herein, we report the synthesis and evaluation of the antimalarial
activity of novel 4-amino-7-chloroquinolines carrying a branched
or a linear side chain with two or three amino functions (Figure
2).
Our synthetic approach toward these heme-targeted anti-
malarials involved inexpensive materials and high-yielding steps
in most cases. Amination of 4,7-dichloroquinoline, 1, with
commercially available R,ω-diaminoalkanes gave N-(7-chloro-
4-quinolyl)-1,n-diaminoalkanes 2 in 83-91% yield (Scheme 1).
Coupling of 2 with N,N-diethylamino-3-propionic acid in the
presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Scheme 1. Synthesis of 4-Amino-7-chloroquinolines 4a-e and 5a-e
Scheme 2. Synthesis of Symmetrically Branched 4-Amino-7-chloroquinolines 6a,b and 7a,b

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7 1997
Scheme 3. Synthesis of 1,3- and 1,4-Diaminocyclohexane-Derived Chloroquinolines 16a,b and 17a,b
Table 1. Antiplasmodial Activity
strain/experimental IC50 (nM)
similar to that of CQ, and more importantly, they retain their
potency against CQR strains. Comparison of the antimalarial
activity of 5a and 5b with the results obtained for the tribasic
aminoquinolines 4a and 4b suggests that the presence of a
tertiary central amino group in this series is crucial for the
activity against Dd2, GCO3, and FCB but not for HB3.
Similarly, the potency of 5a and 5b versus Dd2, GCO3, and
FCB diminishes when the chain length is increased. The
impressive SI values of all compounds tested demonstrate that
systematic variations of both the CQ side chain structure and
basicity provide new venues to overcome antimalarial drug
resistance. This can be combined with the introduction of a third
basic amino function, which should further favor accumulation
of the drug within the acidic food vacuole of the parasite.
However, the relatively high IC50 values of 6a, 6b, 7a, and 7b
reveal that the basicity and structure of the side chain cannot
be optimized independently.
a
compd
HB3
Dd2
SIb
GCO3
FCB
SIb
CQ
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
7a
13.5
29.2
27.3
72.5
46.0
82.8
27.3
21.2
24.1
15.7
62.9
187
140
129
56.3
170
103
269
10.4
4.43
16.0
118
64.8
139
68.7
129
37.7
27.6
87.4
55.2
175
96.6
42.4
517
1512
40.6
32.0
26.1
19.5
170
146
73.7
189
97.3
216
52.7
49.1
156
10.6
1.24
2.06
2.34
2.25
3.25
1.14
1.33
3.52
2.76
4.36
0.68
2.26
1.23
1.94
3.04
2.03
2.74
2.42
1.14
1.36
1.42
1.67
1.40
1.78
1.78
1.21
1.50
1.92
2.45
2.05
1.47
2.78
1.80
4.21
3.89
31.2
28.1
84.6
43.4
274
128
99.8
882
2550
80.0
66.8
263
186
44.1
716
104
1060
2225
113
57.6
110
7b
16a
17a
16b
17b
1314
26.3
25.5
27.8
31.3
51.8
76.1
75.7
In conclusion, we have prepared a series of new heme-
targeted antimalarials by systematically varying the structure
and basicity of the side chain attached to the 7-chloro-4-
aminoquinoline pharmacophore of CQ. All 18 compounds tested
show potent antiplasmodial activity against 4 different strains
in vitro and can be synthesized from readily available, inex-
pensive starting materials through a few high-yielding steps.
Comparison with CQ revealed that 4b, 5a, 5b, 5d, 16a, 16b,
17a, and 17b afford clearly superior activity against the CQ
resistant strain Dd2, and 4b, 5a, 5b, 5d, 17a, and 17b proved
significantly more potent against FCB. In particular, the tribasic
4-aminoquinolines 5a and 5b carrying a short linear side chain
with two additional aliphatic tertiary amino functions are highly
potent antimalarials and equally effective against both CQS and
CQR strains. This study reveals that methodical variation of
the side chain of chloroquine provides a promising entry toward
affordable heme-targeted antimalarials that overcome the ever-
increasing problem with worldwide drug resistance.
66.0
a The experimental IC50 values are averages of two separate determina-
tions each conducted in triplicate. b The selectivity index (SI) is the ratio
of the IC50 for the resistant versus the sensitive strain (Dd2/HB3, 4th column;
FCB/GCO3, 7th column).
were pleased to find that several compounds were significantly
more potent against the resistant strains Dd2 and FCB than CQ.
Among the 18 compounds evaluated, 8 gave IC50 values
between 28.1 and 80.0 nM for Dd2 (CQ IC50 ) 140 nM) and
6 showed IC50 values ranging from 49.1 to 73.7 nM for FCB
(CQ IC50 ) 170 nM). Interestingly, the antimalarial activity of
the linear tribasic aminoquinolines 4a-e and 5a-e proved to
be generally superior over that of the tribasic compounds 6a,
6b, 7a, and 7b carrying a symmetrically branched side chain.
Impressive antimalarial activity was also observed with the
highly branched dibasic CQ analogues 16a, 16b, 17a, and 17b,
but these compounds possess an inherently higher selectivity
index (SI, the ratio of the IC50 for a resistant versus a sensitive
strain) than the linear tribasic aminoquinolines. Noteworthy,
diastereomeric mixtures of 16a and 17a have previously been
prepared by Drake et al. and Jensen later reported higher
antimalarial activity against certain CQS and CQR strains
relative to chloroquine.37–39 The selectivity index provides a
quantitative measure of the antimalarial activity against CQR
strains relative to that against sensitive strains and thus indicates
promising drug discovery leads. The selectivity index of CQ is
about 10, whereas all compounds tested have SI values between
0.68 and 4.43. In this regard, it is important that 5a and 5b
combine high antimalarial activity against HB3 and GCO3 with
very low SI values between 1.14 and 1.78. These new heme-
targeted antiplasmodials thus show activity versus CQS strains
Acknowledgment. We thank the NIH (Grant RO1AI060792)
for financial support.
Supporting Information Available: Synthetic procedures of all
compounds tested and synthetic precursors, product characterization,
1H and 13C NMR spectra, and HPLC chromatograms obtained by
two orthogonal methods. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) De, D.; Byers, L. D.; Krogstad, D. J. Antimalarials: synthesis of
4-aminoquinolines that circumvent drug resistance in malaria parasites.
J. Hetercycl. Chem. 1997, 34, 315–320.

1998 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Letters
(2) O’Neill, P. M.; Bray, P. G.; Hawley, S. R.; Ward, S. A.; Park, B. K.
4-Aminoquinolinesspast, present, and future: a chemical perspective.
Pharmacol. Ther. 1998, 77, 29–58.
(3) Dominguez, J. N. Chemotherapeutic agents against malaria: What next
after chloroquine? Curr. Top. Med. Chem. 2002, 2, 1173–1185.
(4) Pagola, S.; Stephens, P. W.; Bohle, D. S.; Kosar, A. D.; Madsen, S. K.
The structure of malaria pigment ꢀ-haematin. Nature 2000, 404, 307–
310.
in-vitro artemether and point mutations of the SERCA-type PfATPase
6. Lancet 2005, 366, 1960–1963.
(22) Delarue, S.; Girault, S.; Maes, L.; Debreu-Fontaine, M. A.; Labaeid,
M.; Grellier, P.; Sergheraert, C. Synthesis and in vitro and in vivo
antimalarial activity of new 4-anilinoquinolines. J. Med. Chem. 2001,
44, 2827–2833.
(23) O’Neill, P. M.; Willock, D. J.; Hawley, S. R.; Bray, P. G.; Storr, R. C.;
Ward, S. A.; Park, B. K. Synthesis, antimalarial activity, and molecular
modeling of tebuquine analogues. J. Med. Chem. 1997, 40, 437–448.
(24) Madrid, P. B.; Liou, A. P.; DeRisi, J. L.; Guy, R. K. Incorporation of
an intramolecular hydrogen-bonding motif in the side chain of
4-aminoquinolines enhances activity against drug-resistant P. falci-
parum. J. Med. Chem. 2006, 49, 4535–4543.
(25) Riccio, E. S.; Lee, P. S.; Winegar, R. A.; Krogstad, D. J.; De, D.;
Mirsalis, J. C. Genetic toxicology testing of the antimalarial drugs
chloroquine and a new analog, AQ-13. EnViron. Mol. Mutagen. 2001,
38, 69–79.
(26) Egan, T, J.; Hunter, R.; Kaschula, C. H.; Marques, H. M.; Misplon,
A.; Walden, J. C. Structure-function relationships in aminoquinolines:
effect of amino and chloro groups on quinoline-hematin complex
formation, inhibition of ꢀ-hematin formation, and antiplasmodial
activity. J. Med. Chem. 2000, 43, 283–291.
(27) Kaschula, C. H.; Egan, T. J.; Hunter, R.; Basilico, N.; Parapani, S.;
Tarameli, D.; Pasini, E.; Monti, D. Structure-activity relationships
in 4-aminoquinoline antiplasmodials. The role of the group at the
7-position. J. Med. Chem. 2002, 45, 3531–3539.
(28) Ridley, R. G.; Hofheinz, H.; Matile, H.; Jacquet, C.; Dorn, A.;
Masciadri, R.; Jolidon, S.; Richter, W. F.; Guenzi, A.; Girometta,
M. A.; Urwyler, H.; Huber, W.; Thiathong, S.; Peters, W. 4-Amino-
quinoline analogues of CQ with shortened side chains retain activity
against CQ-resistant Plasmodium falciparum. Antimicrob. Agents
Chemother. 1996, 40, 1846–1854.
(29) De, D.; Krogstad, F. M.; Byers, L. D.; Krogstad, D. J. Structure-activity
relationships for antiplasmodial activity among 7-substituted 4-amino-
quinolines. J. Med. Chem. 1998, 41, 4918–4926.
(30) Madrid, P. B.; Liou, A. P.; DeRisi, J. L.; Guy, K. Incorporation of an
intramolecular hydrogen bonding motif in the side chain of 4-amino-
quinolines enhances activity against drug-resistant P. falciparum.
J. Med. Chem. 2006, 49, 4535–4543.
(31) Hawley, S. R.; Bray, P. G.; Park, B. K.; Ward, S. A. Amodiaquine
accumulation in plasmodium falciparum as a possible explanation for
its superior antimalarial activity over chloroquine. Mol. Biochem.
Parasitol. 1996, 80, 15–25.
(32) Stocks, P. A.; Raynes, K. J.; Bray, P. G.; Park, B. K.; O’Neill, P. M.;
Ward, S. A. Novel short chain chloroquine analogues retain activity
against chloroquine resistant K1 Plasmodium falciparum. J. Med.
Chem. 2002, 45, 4975–4983.
(33) Madrid, P. B.; Wilson, N. T.; DeRisi, J. L.; Guy, R. K. Parallel
synthesis and antimalarial screening of a 4-aminoquinoline library.
J. Comb. Chem. 2004, 6, 437–442.
(34) Bennett, T. N.; Paguio, M.; Gligorijevic, B.; Seudieu, C.; Kosar, A. D.;
Davidson, E.; Roepe, P. D. Novel, rapid, and inexpensive cell-based
quantification of antimalarial drug efficacy. Antimicrob. Agents
Chemother. 2004, 48, 1807–1810.
(35) Smilkstein, M.; Sriwilaijaroen, N.; Kelly, J. X.; Wilairat, P.; Riscoe,
M. Simple and inexpensive fluorescence-based technique for high-
throughput antimalarial drug screening. Antimicrob. Agents Chemother.
2004, 48, 1803–1806.
(36) Johnson, J. D.; Dennull, R. A.; Gerena, L.; Lopez-Sanchez, M.; Roncal,
N. E.; Waters, N. C. Assessment and continued validation of the
malaria SYBR green I-based fluorescence assay for use in malaria
drug screening. Antimicrob. Agents Chemother. 2007, 51, 1926–1933.
(37) Drake, N. L.; Creech, H. J.; Garman, J. A.; Haywood, S. T.; Peck,
R. M.; van Hook, J. O.; Walton, E. Synthetic antimalrials. The
preparation of certain 4-aminoquinolines. J. Am. Chem. Soc. 1946,
68, 1208–1213.
(38) Geary, T. G.; Divo, A. A.; Jensen, J. B. Activity of quinoline-
containing antimalarials against chloroquine-sensitive and -resistant
strains of Plasmodium falciparum in Vitro. Trans. R. Soc. Trop. Med.
Hyg. 1987, 81, 499–503.
(5) Ridley, R. G. Medical need, scientific opportunity and the drive for
antimalarial drugs. Nature 2002, 415, 686–693.
(6) Leed, A.; DuBay, K.; Ursos, L. M.; Sears, D.; de Dios, A. C.; Roepe,
P. D. Solution structures of antimalarial drug-heme complexes.
Biochemistry 2002, 41, 10245–10255.
(7) Chong, C. R.; Sullivan, D. J., Jr. Inhibition of heme crystal growth
by antimalarials and other compounds: implications for drug discovery.
Biochem. Pharmacol. 2003, 66, 2201–2212.
(8) de Dios, A. C.; Casabianca, L. B.; Kosar, A.; Roepe, P. D. Structure
of the amodiaquine-FPIX µ-oxo dimer solution complex at atomic
resolution. Inorg. Chem. 2004, 43, 8078–8084.
(9) de Dios, A. C.; Tycko, R.; Ursos, L. M. B.; Roepe, P. D. NMR studies
of chloroquine-ferriprotoporphyrin IX complex. J. Phys. Chem. A
2003, 107, 5821–5825.
(10) Cheruku, S. R.; Maiti, S.; Dorn, A.; Scorneaux, B.; Bhattacharjee,
A. K.; Ellis, W. Y.; Vennerstrom, J. L. Carbon isosteres of the
4-aminopyridine substructure of chloroquine: effects on pKa, hematin
binding, inhibition of hermozoin formation, and parasite growth.
J. Med. Chem. 2003, 46, 3166–3169.
(11) Egan, T. J.; Hunter, R.; Kaschula, C. H.; Marques, H. M.; Misplon,
A.; Walden, J. Structure-function relationships in aminoquinolines:
effect of amino and chloro groups on quinoline-hematin complex
formation, inhibition of ꢀ-hematin formation, and antiplasmodial
activity. J. Med. Chem. 2000, 43, 283–291.
(12) Martin, S. K.; Oduola, A. M.; Milhous, W. K. Reversal of chloroquine
resistance in Plasmodium falciparum by verapamil. Science 1987, 235,
899–901.
(13) Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.;
Peyton, D. H. A chloroquine-like molecule designed to reverse
resistance in Plasmodium falciparum. J. Med. Chem. 2006, 49, 5623–
5625.
(14) Weisman, J. L.; Liou, A. P.; Shelat, A. A.; Cohen, F. E.; Guy, R. K.;
DeRisi, J. L. Searching for new antimalarial therapeutics amongst
known drugs. Chem. Biol. Drug Des. 2006, 67, 409–416.
(15) Tang, Y.; Dong, Y.; Wittlin, S.; Charman, S. A.; Chollet, J.; Chiu,
F. C.; Charman, W. N.; Matile, H.; Urwyler, H.; Dorn, A.; Bajpai, S.;
Wang, X.; Padmanilayam, M.; Karle, J. M.; Brun, R.; Vennerstrom,
J. L. Weak base dispiro-1,2,4-trioxolanes: potent antimalarial ozonides.
Bioorg. Med. Chem. Lett. 2007, 17, 1260–1265.
(16) Dong, Y.; Tang, Y.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.;
Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C.; Scorneaux,
B.; Bajpai, S.; Alexander, S. A.; Wang, X.; Padmanilayam, M.;
Cheruku, S. R.; Brun, R.; Vennerstrom, J. L. Effect of functional group
polarity on the antimalarial activity of spiro and dispiro-1,2,4-
trioxolanes. Bioorg. Med. Chem. 2006, 14, 6368–6382.
(17) Posner, G. H.; Paik, I. H.; Chang, W.; Borstnik, K.; Sinishtaj, S.;
Rosenthal, A. S.; Shapiro, T. A. Malaria-infected mice are cured by
a single dose of novel artemisinin derivatives. J. Med. Chem. 2007,
50, 2516–2519.
(18) Paik, I. H.; Xie, S.; Shapiro, T. A.; Labonte, T.; Narducci Sarjeant,
A. A.; Baege, A. C.; Posner, G. H. Second generation, orally active,
antimalarial, artemisinin-derived trioxane dimers with high stability,
efficacy, and anticancer activity. J. Med. Chem. 2006, 49, 2731–2734.
(19) Vennerstrom, L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu,
F. C.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.;
McIntosh, K.; Padmanilayam, M.; Santo Tomas, J.; Scheurer, C.;
Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N.
Identification of an antimalarial synthetic trioxolane drug development
candidate. Nature 2004, 430 (7002), 900–904.
(20) O’Neill, P. M.; Posner, G. H. A medicinal chemistry perspective on
artmeisinin and related endoperoxides. J. Med. Chem. 2004, 47, 2945–
2964.
(21) Jambou, R.; Legrand, E.; Niang, M.; Khim, N.; Lim, P.; Volney, B.;
Ekala, M. T.; Bouchier, C.; Esterre, P.; Fandeur, T.; Mercereau-
Puijalon, O. Resistance of Plasmodium falciparum field isolates to
(39) Geary, T. G.; Jensen, J. B. Lack of cross-resistance to 4-aminoquino-
lines in chloroquine-resistant Plasmodium falciparum in Vitro. J.
Parasitol. 1983, 69, 97–105.
JM800106U