Novel 4-aminoquinolines active against chloroquine-resistant and sensitive P. falciparum strains that also inhibit botulinum serotype A

Article abstract of DOI:10.1021/jm800737y

We report on the initial result of the coupling of 4-amino-7- chloroquinoline with steroidal and adamantane constituents to provide small molecules with excellent in vitro antimalarial activities (IC₉₀ (W2) down to 6.74 nM). The same entities also inhibit the botulinum neurotoxin serotype A light chain metalloprotease at low micromolar levels (7-31 μM). Interestingly, structural features imparting increased antimalarial activity also provide increased metalloprotease inhibition, thus allowing for simultaneous compound optimizations against distinct targets.

Full text of DOI:10.1021/jm800737y

4388
J. Med. Chem. 2008, 51, 4388–4391
ized heme, possibly through membrane disruption. The develop-
ment of widespread drug-resistance to chloroquine (CQ), the
standard antimalarial drug, has resulted in severe health issues
for countries in malaria endemic regions.2 Therefore, significant
focus has been placed on the syntheses of peroxide antimalarials3
as well as the development other molecules that attack heme
polymerization.4 Currently, those of greatest interest, due to their
low toxicity, are new 4,7-ACQs,5 4-pyridones,6 combinations
of 4,7-ACQs with drug-reversals,7 ferrocenes,8 and bisquino-
lines.9 A promising drug candidate possessing the 4,7-ACQ
moiety appears to be AQ-13, a des-methyl chloroquine deriva-
tive.10
Novel 4-Aminoquinolines Active against
Chloroquine-Resistant and Sensitive P.
falciparum Strains that also Inhibit
Botulinum Serotype A
,†
Bogdan A. Solaja,* Dejan Opsenica,‡ Kirsten S. Smith,§
ˇ
Wilbur K. Milhous,§,| Natasˇa Terzic´,† Igor Opsenica,†
James C. Burnett, Jon Nuss,# Rick Gussio,3 and
Sina Bavari‡,#
Faculty of Chemistry, UniVersity of Belgrade, Belgrade, Serbia,
Institute of Chemistry, Technology, and Metallurgy, Belgrade,
Serbia, DiVision of Experimental Therapeutics, Walter Reed Army
Institute of Research, Washington, D.C. 20307-5100,
SAIC-Frederick, Inc., Target Structure-Based Drug DiscoVery
Group, Frederick, Frederick, Inc., National Cancer Institute at
Frederick, P.O. Box B, FVC 310, Frederick, Maryland 21702,
DeVelopmental Therapeutics Program, National Cancer Institute at
Frederick, P.O. Box B, FVC 310, Frederick, Maryland 21702, U.S.
Army Medical Research Institute of Infectious Diseases, Fort
Detrick, 1425 Porter Street, Frederick, Maryland 21702
Antimalarial agents possessing the 4,7-ACQ have previously
been shown to inhibit the metalloprotease activity of the
botulinum neurotoxin serotype a light chain (BoNT/A LC),11,12
a potential biothreat agent. This serotype, along with botulinum
neurotoxin serotypes B-G, are responsible for the characteristic
neuroparalysis associated with the disease state botulism.13
Structurally, BoNTs consist of a heavy chain (HC) and a light
chain (LC), which are connected by a disulfide bridge. The HC
binds to neurons and transports the LC into the cell cytosol.
The LC is a zinc metalloprotease that cleaves components of
the soluble NSF-ethylmaleimide-sensitive factor attachment
protein receptor complex (which mediates the exocytosis of
acetylcholine into neuromuscular junctions). Of the seven known
serotypes (i.e., A-G), A and E cleave SNAP-25 [synaptosomal-
associated protein (25 KDa)] (19), B, D, F, and G cleave vesicle-
associated membrane protein (20-23), and serotype C cleaves
both SNAP-25 and syntaxin 1. BoNT/A possesses a lethal dose
of 1-5 ng kg-1 for humans.13 For perspective, this lethality is
106 times greater than cobra toxin and ca. 1011 times greater
than cyanide. Currently, the only available treatment for botulism
(i.e., once BoNTs have innervated) is critical care mechanical
ventilation. However, as BoNTs remain active for several
weeks,13 this avenue of treatment is not practical for widespread
application, hence the need to identify and develop small
molecule inhibitors of the enzyme’s metalloprotease.
ReceiVed June 17, 2008
Abstract: We report on the initial result of the coupling of 4-amino-
7-chloroquinoline with steroidal and adamantane constituents to provide
small molecules with excellent in vitro antimalarial activities (IC90 (W2)
down to 6.74 nM). The same entities also inhibit the botulinum
neurotoxin serotype A light chain metalloprotease at low micromolar
levels (7-31 µM). Interestingly, structural features imparting increased
antimalarial activity also provide increased metalloprotease inhibition,
thus allowing for simultaneous compound optimizations against distinct
targets.
Malaria parasites contain acidic food vacuoles (FV)a that are
responsible for hemoglobin hydrolysis, and it is these vacuoles
that appear to be the site of action for a number of existing
antimalarials. The heme, obtained via hemoglobin degradation
in the FV, is transformed into insoluble hemozoin pigment,
while the globin is hydrolyzed into individual amino acids.
Antimalarial drugs appear to kill the parasite either by producing
toxic free radicals in the FV or by blocking the formation of
hemozoin from heme molecules once they are liberated from
hemoglobin, as in the case of 4-amino-7-chloroquinolines (4,7-
ACQs)1 The antiparasitic effects of compounds possessing the
4,7-ACQ are presumably caused by the toxicity of nonpolimer-
Recently, we reported the synthesis of 4,7-ACQ’s possessing
a steroidal, cholic acid carrier, and their inhibitory activity
against the BoNT serotype A light chain (BoNT/A LC)
metalloprotease.12 Here, we show that the same compounds are
also potent antimalarial agents. Moreover, we report the
syntheses and the antimalarial and BoNT/A LC inhibitory
potencies of novel 4,7-ACQ-adamantane derivatives and de-
scribe how the structure activity data for both sets of compounds
follow very similar trends for both targets.
The syntheses of the compounds represented in Charts 1 and
2 are described in detail in the Supporting Information and in
ref 12 The quintessential feature of our synthetic approach is
the simple and efficient preparation of the target compounds
using readily available and inexpensive starting materials. The
chiral centers in the steroidal components are not prone to
racemization, so products were obtained as single enantiomers.
In an alternative approach, the achiral aminoquinolines were
prepared.14
ˇ
* To whom correspondence should be addressed. For B.S.: phone, +381-
11-263-86-06; fax, +381-11-263-60-61; E-mail, bsolaja@chem.bg.ac.yu;
address, Faculty of Chemistry, University of Belgrade, Studentski trg 16,
P.O. Box 158, 11001 Belgrade, Serbia. For S.B.: phone, 00-1-301-619-
4246; fax, 00-1-301-619-2348; E-mail, sina.bavari@us.army.mil.
†
Faculty of Chemistry, University of Belgrade.
Institute of Chemistry, Technology and Metallurgy
Walter Reed Army Institute of Research.
Current address: College of Public Health, University of South Florida,
‡
§
|
13201 Bruce B. Downs Boulevard, MDC 56 Tampa, FL 33612.
SAIC-Frederick, National Cancer Institute at Frederick.
#
U.S. Army Medical Research Institute of Infectious Diseases.
Developmental Therapeutics Program, National Cancer Institute at
In vitro antimalarial activity is given in Table 1. General
observations regarding antimalarial activity include:15 (1)
compounds with an amide functionality linking the 4,7-ACQ
moiety to the steroid, or to adamantane, are inactive (the
exception is 5, which is less active than MFQ against W2 but
has comparable activity to MFQ against D6 and the multidrug
3
Frederick.
a Abbreviations: FV, food vacuole; CQ, chloroquine; MFQ, mefloquine;
ART, artemisinin; SI, the selectivity index (SI) is defined as the ratio of
the IC90 for the resistant versus sensitive strain; BoNT, botulinum
neurotoxin; BoNT/A, BoNT serotype A; LC, light chain; 4,7-ACQ, 4-amino-
7-chloroquinoline.
10.1021/jm800737y CCC: $40.75
2008 American Chemical Society
Published on Web 07/19/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4389
Chart 1
Chart 2
resistant TM91C235 strain), (2) 4,7-ACQs with two ionizable
nitrogens, i.e., 6, 8, and 9, are more potent against all three
strains than monoamino analogues 4, 1 (2), and 10, respectively
(Table 1), (3) the most active compounds are the epimeric
steroidal 4,7-ACQs 7 and 8 and adamantane derivatives 20, 21.
In particular, steroid containing 7 and 8 are more active than
ART against all tested strains, while ethanediamino derivative
20 is as active as ART against the highly resistant W2 strain
and more active than ART against the CQ susceptible D6 and
the multidrug resistant TM91C235 strains. The propanediamino
congener 21 is 2-3 times more active than CQ against the D6
strain, as active as ART against the TM91C235 strain, and
slightly less active against W2 strain.
Analyzing the selectivity index (SI), it is evident that most
of compounds are more active against the D6 strain than against
the CQ resistant strain. However, several features merit further
elaboration. SIs for the two adamantane derivatives, 20 and its
homologue 21, are almost identical in each instance, revealing
that the two compounds themselves are equally potent against
both drug resistant strains. In addition, both compounds have
very similar activity to ART against both strains. Another group
of compounds that merits additional analysis are steroidal
derivatives 6, 7, and 8. 6 is two times less active against the
D6 and W2 strains than CQ and ART, respectively, but is 1.5-4
times more active than CQ and MFQ against the TM91C235
strain. A significant feature is that this compound has an SIW2/
D6 of 0.95.16 In addition to their superior activity against all
three strains, compared to CQ, MFQ, and ART, epimeric
aminoquinolines 7 and 8 are also more active against the W2
strain than against the D6 strain (SIW2/D6 0.65 and 0.91,
respectively). The observed in vitro antiprotozoal behavior of
7 and 8 is very similar to ART, an unusual characteristic for an
aminoquinoline that does not possess additional functionalities,
such as hydroxybenzene or ferrocene. The side products of the
reductive amination (Supporting Information), compounds 23
and 24, were several times less active against all strains,
presumably due to their two voluminous adamantyl components.
All compounds shown in Charts 1 and 2 were examined for
BoNT/A LC metalloprotease inhibitory activity using a previ-
ously described HPLC-based assay.17 Compounds in Chart 1
were examined previously.12 For Chart 2 compounds, diami-
noethyl derivatives 20 and 17 and diaminopropyl derivatives
21 and 18 were found to inhibit the enzyme. IC50 values for
these compounds, as well as those examined previously,12 are
shown in Table 2. Interesting structural features resulting in
increase/decrease antimalarial activity also follow similar trends
for BoNT/A LC inhibition, specifically: (1) compounds incor-
porating an amide in the linker between the 4,7-ACQ and either
the steroidal or adamantane components were inactive, (2) 4,7-
ACQs with two ionizable nitrogens, i.e., 6, 7, 8, 17, etc., are
the most potent inhibitors of the BoNT/A LC, while those
possessing a single ionizable nitrogen demonstrate poor11 to no
activity, (3) inhibitors possessing the cholic acid moiety, i.e.,
6, 7, and 8, are more potent than inhibitors possessing the
adamantine motif, most likely due to greater steric occupancy
of the enzyme’s substrate binding cleft, and (4) 23 and 24, which
each possess a second adamantane group, were also inactive
against the BoNT/A LC, most likely due to their increased steric
bulk.

4390 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15
Letters
Table 1. In Vitro Antimalarial Activities of Aminoquinoline Compounds against P. falciparum Strains
D6a (nM)
TM91C235b (nM)
W2c (nM)
compd
IC50
IC90
IC50
IC90
IC50
IC90
SId
1
2
3
4
5
6
7
8
10.65
68.18
3022.31
15.75
19.01
16.87
6.17
20.71
98.17
6915.40
30.71
21.13
34.21
10.43
12.35
22.78
99.26
157.33
293.60
347.38
464.76
370.46
631.71
13.65
23.27
24.75
8.23
30.05
99.46
3506.06
37.04
28.79
27.74
11.01
12.83
32.18
50.52
238.10
201.00
602.18
438.69
524.68
765.01
17.76
42.11
67.23
8.73
68.60
366.71
6058.39
70.49
34.78
77.92
24.97
24.39
75.95
72.84
382.92
464.34
776.84
685.39
787.15
984.39
24.43
171.09
168.39
14.93
107.72
208.98
7191.35
139.61
48.85
11.38
3.38
563.15
1851.51
3.31/27.20
3.74/18.86
1176.50
70.57
32.50
6.74
11.18
2.30/38.31
1.65/3.34
2.28/0.95
2.39/0.65
1.97/0.91
3.33/1.08
0.73/1.48
9.47
5.74
9
14.07
33.05
78.50
105.87
267.28
201.68
213.69
511.34
8.59
17.83
111.03
253.81
337.19
517.72
484.51
877.99
884.29
15.66
33.66
159.71
8.40
12.10
130.95
78.15
83.21
392.09
4.96
24.60
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CQe
MFQe
ARTf
147.21
396.84
852.69
660.39
724.44
1358.80
1408.66
30.96
1.79/2.27
7.35/2.41
6.80/12.55
1.81/1.85
3.15/3.13
8.51/8.85
3.22/1.62
2.19/1.69
14.84/32.35
3.78/0.52
1.36/0.90
11.43
21.92
4.26
56.09
310.82
15.22
3.83
6.41
7.39
20.20
20.05
15.19
51.85
52.22
12.44
11.25
9.0
18.94
69.97
78.31
16.38
28.06
12.80
75.34
100.71
109.43
124.24
33.46
13.04
161.25
225.20
171.29
243.15
106.04
17.40
167.69
113.35
132.30
529.86
14.70
6.7
11.5
a P. falciparum African D6 clone. b P. falciparum multidrug resistant TM91C235 strain (Thailand). c P. falciparum Indochina W2 clone. d The selectivity
index (SI) is defined as the ratio of the IC90 for the resistant versus sensitive strain, TM91C235/D6 and W2/D6, respectively. e Control compounds. Average
of seven replicates. f Average of greater than eight replicates.
Table 2. In Vitro Inhibitory Activity of Aminoquinolines against
BoNT/A LC
multidrug resistant TM91C235, than chloroquine. Of particular
importance is the finding that steroidal aminoquinolines 7 and
8 are more active against the W2 strain than artemisinin, with
SIs (W2/D6) of 0.65 and 0.91, respectively. A compelling aspect
of this study is that the most active 4,7-ACQ derivatives
examined in the antimalarial screens are also the most potent
inhibitors of BoNT/A LC metalloprotease activity and follow
similar structure activity trends for both. This is extraordinary
given that fact that the two distinct targets share completely
different mechanisms of action. Hence, 4,7-ACQ derivatives
provide an efficient synthetic paradigm for simultaneously
developing novel small molecules that can be used to treat either
malaria infection or BoNT/A poisoning.
compd
inhibition IC50 (µM)
6a
10.00 ((0.80)
17.00 ((1.7)
7.00 ((1.0)
31.98 ((3.2)
18.92 ((2.8)
50.10 ((2.8)
11.81 ((1.6)
7a
8a
21b
20b
18b
17b
a Results taken from ref 12. b IC50 values were calculated from plots of
concentration versus inhibition (see Experimental Section, Supporting
Information, for details), and are the averages of five determinations.
Interestingly, inhibitors 20 and 17, possessing ionizable
nitrogen positions separated by an ethenyl spacer, are 1.7 and
4.2 fold more potent than their respective analogues, 21 and
18, which both possess a corresponding propenyl spacer.
Moreover, the longer corresponding pentenyl spacer found in
19 and 22 completely obviates activity. This agrees with results
from our previous study,12 which showed that N1-(7-chloro-
quinolin-4-yl)-ethane-1,2-diamine inhibited the BoNT/A LC
with 1.5 fold more potency than N1-(7-chloroquinolin-4-yl)-
propane-1,3-diamine. Finally, 23 and 24, which each possess a
second adamantane group, were also inactive against the
BoNT/A LC, most likely due to their increased steric bulk.
In conclusion, we have synthesized novel 4,7-ACQ deriva-
tives that target both heme polymerization in malaria and
BoNT/A LC zinc metalloprotease activity. The screening of
these compounds against three P. falciparum strains indicated
that our N1-[(7-chloro-4-quinolinyl)-1,2-ethanediamine and 1,3-
propanediamines coupled with steroid and adamantyl carriers
are good-to-excellent inhibitors of CQ-susceptible and CQ-
resistant P. falciparum strains. Out of 14 ionizable diamines,
five compounds (7, 8, 17, 20, 21) are more active than CQ (IC90
) 12.8-6.4 nM). In addition, 12 compounds are more active
against highly CQ-resistant W2, and 13 are more active against
Acknowledgment. This work has been partially supported
by the Ministry of Science of Serbia (grant no. 142022) and
the Serbian Academy of Sciences and Arts. Botulinum studies
were funded by the U.S. Army Medical Research and Material
Command Research plan no. 02-4-3U-057 and IAA no. Y3-
CM-100505 (MRMC and NCI). The contents have been
reviewed by the Walter Reed Army Institute of Research. There
is no objection to its presentation or publication. The opinions
or assertions contained herein are the private views of the author
and are not to be construed as official or as reflecting true views
of the Department of the Army, the Department of Defense, or
the National Institutes of Health. For J.C.B. and R.G., this
project has been funded in whole or in part with federal funds
from the National Cancer Institute, National Institutes of Health,
under contract N01-CO-12400. The content of this publication
does not necessarily reflect the views or policies of the
Department of Health and Human Services nor does mention
of trade names, commercial products, or organizations imply
endorsement by the U.S. Government. For J.C.B. and R.G., this
research was supported (in part) by the Developmental Thera-

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4391
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Supporting Information Available: Full experimental section.
This material is free of charge via the Internet at http://pubs.acs.org.
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