Case study of small molecules as antimalarials: 2-amino-1-phenylethanol (APE) derivatives

Article abstract of DOI:10.1021/ml500015r

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 ?M are able to show in vivo activity.

Full text of DOI:10.1021/ml500015r

Letter
pubs.acs.org/acsmedchemlett
Case Study of Small Molecules As Antimalarials: 2‑Amino-1-
phenylethanol (APE) Derivatives
†
†
†
†
‡
́
María J. Chaparro, Jaume Vidal, Inigo Angulo-Barturen, Jose M. Bueno, Jeremy Burrows,
́
̃
Nicholas Cammack,† Pablo Castaneda,† Gonzalo Colmenarejo,§ Jose M. Coteron,† Laura de las Heras,†
́
́
̃
Esther Fernandez,† Santiago Ferrer,† Raquel Gabarro,† Francisco J. Gamo,† Mercedes García,†
́
́
María B. Jimenez-Díaz,† María J. Lafuente,† María L. Leon,† María S. Martínez,† Douglas Minick,∥
́
́
†
†
†
†
†
‡
́
Sara Prats, Margarita Puente, Lourdes Rueda, Elena Sandoval, Angel Santos-Villarejo, Michael Witty,
and Felix Calderon*,†
́
́
†Tres Cantos, Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain
‡Medicines for Malaria Venture (MMV), 20 route de Pre-
Bois, 1215 Geneva 15, Switzerland
́
§Centro de Investigacion
́ ́
Basica, GlaxoSmithKline, Santiago Grisolía, 28760 Tres Cantos, Madrid, Spain
∥GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, Durham, North Carolina 27709, United States
S
* Supporting Information
ABSTRACT: Antiparasitic oral drugs have been associated to lipophilic molecules
due to their intrinsic permeability. However, these kind of molecules are associated
to numerous adverse effects, which have been extensively studied. Within the Tres
Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and
simple hits that even presenting antiplasmodial activities in the range of 0.4−0.5
μM are able to show in vivo activity.
KEYWORDS: Aminoalcoholes, malaria, tres cantos antimalarial set, TCAMS, mefloquine
linical resistance against artemisins has already been
reported. Artemisinins are the mainstay of Artemisinin
compounds were marketed without phase III trials due to the
C
special historical conditions in which they were developed.
In early 2000s, three randomized controlled trials in healthy
populations confirmed that aminoalcohols can cause physio-
Combination Therapies (ACTs), which currently are the first
line of antimalarial treatment recommended by WHO to treat P.
falciparum malaria. As a consequence, there is an urgent need to
develop novel antimalarial drugs as potential replacements for
artemisinins.1 Aiming at disease eradication, it would be
enormously advantageous that the new drugs were active also
against gametocytes (the sexual stage responsible for trans-
mission of the parasite to mosquitoes) and hypnozoites
(dormant liver stages responsible for the malaria relapses
characteristic of P. vivax).2,3
Looking back in time we can find a similar situation in malarial
chemotherapy. In 1970s resistance to chloroquine (1), the main
antimalarial drug at the time, was dramatically increasing.4
Chloroquine resistance was observed first in Asia (Thailand in
1957) and South America (Colombian−Venezuelan border in
1959) and, almost two decades later, in Africa (Kenya and
Tanzania in 1978). In the period 1960−1970s, the Experimental
Therapeutics Division of the Walter Reed Army Institute of
Research (WRAIR) developed the largest drug discovery
program ever addressed in malaria history because of the
Vietnam War where up to 1% of US troops suffered from malaria.
An extensive screening campaign was pursued and 250,000
potential antimalarial compounds were screened. Two related
compounds presenting a phenyl-amino-alcohol scaffold were
identified: compounds 142,490 (mefloquine (MQ, 2)-lariam)
and 171,699 (halofantrine (3)-halfan) (Figure 1). These
Figure 1. Exemplars of common antimalarials.
Received: January 14, 2014
Accepted: March 12, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
logical illnesses. Mefloquine has central nervous system and
gastrointestinal tract toxicity, whereas halofantrine has cardio-
toxic effects.5,6 Despite many unknowns, aminoalcohols have
been the subject of intense research over the last 40 years. A third
representative of this chemical series, lumefantrine (4), is
currently used in combination with artemether (5) for first-line
acute therapy. This combination, marketed as Coartem,
represents 75% of all ACT treatments used in the clinic.
Coartem provides a rapid relief of symptoms due to the fast
killing mode of action of Artemether and prevents recrudescence
due to the long half-life (4 days) of lumefantrine.
Representatives of the 2-amino-1-phenylethanol (APE) series
have been found in the GlaxoSmithKline’s Tres Cantos
Antimalarial Set (TCAMS) (6 and 7, Figure 2).7,8 These
molecules were attractive since they were structurally simpler
than “classical” aminoalcohols and showed amenable phys-
icochemical properties (Table 1).
Figure 3. Oral PK profile for compounds 6 and 7.
These molecules display a robust in vitro parasitological
profile: parasite cultures treated with compound 6 at 10 × IC50
showed a pycnotic phenotype only 24 h after commencing
exposure. This phenotype is characteristic of compounds with a
fast-killing antimalarial mode of action as is the case of
chloroquine or artemisinin.14 Compounds with a slower mode
of action such as atovaquone, a mitochondrial bc1 complex
inhibitor, exerts its antimalarial effect later in the life-cycle and
stop cultures in the trophozoite stage. An additional result
supporting a fast speed of action for these compounds is the
reduction of more than 4 orders of magnitude in the number of
viable parasites observed when cultures are exposed to 6 for 72 h
at 10 × IC50. A similar reduction of viability occurs with
chloroquine treated parasites.
Figure 2. TCAMS-APES derivatives selected.
Molecules are equally potent in vitro when assayed against the
wild-type 3D7 strain and resistant strains such as HB3
(moderately resistant to pyrimethamine), Dd2 (chloroquine
and pyrimethamine resistant), TC08 (pyrimethamine resistant),
T9/94 (chloroquine resistant), V1/S (chloroquine and
pyrimethamine resistant), FCR3 (chloroquine, atovaquone,
and cycloguanil resistant), Tm90C2A (chloroquine and
pyrimethamine resistant), and Tm90C2B (chloroquine, pyr-
imethamine, and atovaquone resistant), with potencies in the
nanomolar range (Table 1).
To determine the 3D-structure−activity relationship (SAR)
we first started by determining the optical purity (not showed in
Chembl database) of the hits by using a chiral solvating agent
(Pirkle’s reagent,15 ((S)-(+)-1-(9-anthryl)-2,2,2-trifluoroetha-
nol)). This experiment revealed that the hit was a mixture of
enantiomers. This result was confirmed by c-HPLC.
The compounds 6 and 7 were found efficacious in vivo against
P. berghei in a screening assay recently published.13 These
compounds were initially deprioritized for further progression
after in silico filtering of the TCAMS9−11 because compounds 6
and 7 had an amino-phenyl-ethanol core similar to mefloquine.12
However, compounds 6 and 7 clearly reduced parasitemia in P.
berghei-infected mice with respect to the vehicle group (64 and
76%, respectively) upon qd oral administration during two
consecutive days despite presenting a relatively high in vitro IC50
(Table 1). Interestingly, compounds 6 and 7 showed a fast
absorption and high blood exposure upon single dose oral PK
analysis in the in vivo screening conditions (Figure 3). These
data correlated well with a good solubility and low intrinsic
clearance (Cli) in liver mouse microsomes (Table 1). As a
preliminary measure of toxicity we decided to evaluate these
compounds in a panel of mammalian cell lines (HepG2, L1210,
Neuro2A, H9c2(2−1), and MDCK, Table 1), and the results
showed low risk of cytotoxicity. From a developability point of
view, the compounds did not present any issues related with
3A4CYP inhibition (>30 μM).
The enantiomers of 6 and 7 (13−16, Table 2) were separated
using preparative c-HPLC and their stereochemistry assigned by
ab initio vibrational circular dichroism (VCD), an analytical
technique for determining absolute stereochemistry.16 Exper-
imental and theoretical data shown in Figure 4 for 13 and 14
Table 1. Complete Profile for 6 and 7
compd 6
compd 7
LE, LLE, Mw
0.40, 2.42, 289
0.43, 2.75, 309
chromlogD 7.4/PFI
3.8/4.8
4.5/5.5
Pf IC50 μM (3D7A)
0.4
0.5
efficacy (mg/kg) P. berghei
ED50 < 50
ED50 < 50
in vitro CL (mL/min·g), T1/2 (min) (mouse)
protein binding mouse plasma (%)
P450 3A4 (vivid red/vivid green) μM
solubility (μg/mL) PBS/FaSSIF/FeSSIF/SGF
Tox50 (μM) (HepG2, Jurkat, CHP212, MDCK, H9C2(2−1))
PRR (parasite reduction rate) (72 h)
Ratio 3D7/TC08, HB3, T9/94, Dd2, V1/S, FCR3, Tm90C2A, Tm90C2B
0.5, >30
0.3, > 30
91.7
95.5
>50/50
>50/31.6
N.D.
>600, >600, >600, >600
>50, >50, >50, >50, >50
48.8, >50, 48, >50, >50
fast
N.D.
∼1
∼1
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ACS Medicinal Chemistry Letters
Letter
(S)-MPA esters].17 The assignment is based on the existence of a
correlation between the chemical shifts of those derivatives and
their stereochemistry (absolute configuration) (Figure 5).
Table 2. Key 3D-SAR Data
compd configuration
X
R3
R4
IC50 (μM) Pf 3D7A
6
rac-threo
rac-erythro
rac-threo
rac-erythro
rac-threo
rac-erythro
rac-threo
(S,S)
tert-pentyl
tert-pentyl
tert-pentyl
tert-pentyl
tert-butyl
tert-butyl
tert-butyl
tert-pentyl
tert-pentyl
tert-butyl
tert-butyl
tert- pentyl
tert- pentyl
H
CF3
CF3
Cl
0.4
>5
8
H
9
Cl
0.2
3.9
0.9
>5
10
11
12
7
Cl
Cl
Figure 5. Key NOE for signals for oxazolidine derivative (left).18 ΔT1T2
values (ppm, 298 K, CDCl3) obtained for the bis-(R)-MPA and bis-(S)-
MPA esters (right).19
Cl
Cl
Cl
Cl
CF3
H
Cl
0.5
1.4
0.5
0.6
0.3
0.5
0.4
13
14
15
16
17
18
CF3
CF3
Cl
(R,R)
H
To understand the 3D-SAR, we started by comparing the
antiplasmodial activity for the threo and erythro derivatives of
three compounds (6, 9, and 11 versus 8, 10, and 12, respectively;
Table 2). We observed that in all the cases the threo racemic
mixture ((R,R) and (S,S)) was significantly more potent than the
erythro one ((R,S) and (S,R)). However, when we analyzed the
threo enantiomers separately for 6, 7, and 9, no clear differences
can be argued (pairs 13−14, 15−16, and 17−18, Table 2,
respectively). In conclusion, as result of this SAR study shown in
Table 2 we can say that the series presents a clear preference for
the threo derivatives, while no clear differences are detected
between the enantiomers. This is an important difference with,
for example, mefloquine in which the four diastereomers present
the same in vitro potency although the difference in the PK
supports the use of the erythro isomers instead of the threo.20
In fact, with the objective of rationalizing the stereospecificity
observed for the TCAMS aminoalcohols, we used Mefloquine as
model system by means of flexible alignments using the MOE
program.21 The flexible alignment of the (R,R) isomer of 6 with
+(R,S) mefloquine gave a good superimposition (Figure 6a).
Similar good superimposition was observed between the (R,S)
(S,S)
CF3
CF3
Cl
(R,R)
Cl
(S,S)
Cl
(R,R)
Cl
Cl
Figure 4. Blue line corresponding to enantiomer E1 (13) and red line
corresponding to enantiomer E2 (14) of 6.
illustrate how VCD analysis was applied to various representa-
tives of the APE series. In the top panel, VCD spectra observed
for 13 and 14 in the fingerprint region (uncorrected for baseline
artifacts) are compared. The spectral patterns in the two
highlighted regions are mirror images, confirming these
molecules are enantiomers. The baseline corrected VCD
spectrum of 13 is compared to VCD spectra calculated for (a)
Model 1, the threo model with (S,S) configuration, and (b)
Model 2, the erythro model with (R,S) configuration in the
middle and bottom panels, respectively. While the spectrum of
Model 1 appears to be a good match with 13, the one calculated
for Model 2 clearly is not, supporting assignment of Model 1 as
the correct stereoisomer of 13. This assignment was confirmed
using CompareVOA (BioTools, Inc. Jupiter, FL), an algorithm
for quantifying the agreement between experimental and
theoretical VCD spectra. Results from the CompareVOA
analysis indicated that only an assignment based on Model 1
would be reliable, with an estimated confidence limit >99% (as
opposed to Model 2, with an estimated confidence limit <75%).
On the basis of these findings, 13 was assigned as the (S,S)
enantiomer and 14 as the (R,R) enantiomer (Figure 4).
Figure 6. Flexible alignment of (R,R) and (R,S) isomers of 6 with
mefloquine. Converged superposition of the (R,R) isomer of 6 with
+(R,S) mefloquine; (b) superposition of the (R,S) isomer of 6 with
+(R,S) mefloquine; (c) superposition of the (R,R) isomer of 6 with +(S,
R) mefloquine; (d) superposition of the (R,S) isomer of 6 with +(S,R)
mefloquine. Mefloquine carbon atoms are shown in light gray, 6 in dark
gray. No hydrogens are shown for the sake of clarity.
This result was confirmed using nuclear Overhauser effect
(NOE) experiments to determine the relative configuration and
the formation of chiral esters with the (R) and (S) enantiomers of
the methoxyphenylacetic acid (MPA) and comparison of the
ΔδRS signs NMR spectra of the resulting diastereomers [(R)- and
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ACS Medicinal Chemistry Letters
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Table 3. Key 2D SAR Data
compd
configuration
R2
R3
R4
X
Y
Z
W
IC50 (μM) Pf 3D7A
19
20
21
22
23
24
25
26
27
28
29
30
threo
H
H
H
H
H
H
H
H
H
H
H
H
H
CF3
CF3
CF3
CF3
Cl
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
>5
>5
5
threo
H
tert-pentyl
Phe
Me
H
H
H
H
H
H
H
H
H
H
threo
H
threo
H
cyclohexyl
tert-butyl
tert-butyl
cyclohexyl
cycloheptyl
cyclooctyl
Bn
5
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
CF3
Cl
Cl
Cl
Cl
Cl
Cl
H
4.3
>5
0.72
0.16
0.07
0.7
>5
>5
Cl
H
Cl
H
Cl
H
Cl
H
Cl
H
Cl
H
2-Me-naphtalene
tert-butyl
H
Me
isomer of 6 and +(R,S) isomer of mefloquine (Figure 6b). This
should indicate that the origins of stereospecificity of our
aminoalcohol series and mefloquine are different. On the
contrary, flexible alignments of both the (R,R) and (R,S) isomers
of 6 to −(S,R) mefloquine gave much worse alignments (Figure
6c,d, respectively). Therefore, again similar superimposition
behavior is seen for the two isomers of (6), but in this case, the
observed alignments are not as good as with the +(R, S) isomer.
Regarding the 2D-SAR, these are the key conclusions: we
know that free-amine compound (19) is inactive (Table 3) and
that secondary amines (6) are preferred versus tertiary (20)
(Table 3). In fact, for compounds related to 6, only n-alkyl
derivatives have resulted inactive (either phenyl (21, Table 3) as
well as cyclo-alkyl (22, Table 3) derivatives presented an PfIC50
of 5 μM). A loss in activity was also observed in the demethylated
derivative of 7 (23, Table 3). Another critical observation is the
change in the SAR when the 3,4-di-chloro substitution is used
(Table 3) at the left-hand side of the molecule instead of the p-
CF3 (6) or the 3-CF3-4-Cl (7). In this case, the demethylated
compound (24, Table 3) is inactive but the cyclo-alkyl derivatives
(25−27, Table 3) present a low IC50. In fact, while increasing the
size of the cycle a lower IC50 was obtained, although it is not
related to a simple increase in lipophilicity as aromatic moieties
(28 and 29, Table 3) present IC50s of 0.7 and >5 μM. In
conclusion, results shown that opportunities for improving
potency are possible without increasing lipophilicity. Finally, this
first SAR study has revealed that the aromatic ring must be
substituted to observe antiplasmodial activity (30, Table 3).
To finalize this early profiling of this chemical series we
decided to compare the TCAMS compound with the closed
aminoalcohol, mefloquine. Obviously both contain the amino-
alcohol scaffold but from a 2D perspective, mefloquine presents a
more lipohilic aromatic moiety and a cycle-tertiary amine, while
the TCAMS compounds present a phenyl moiety and a linear
secondary amine. We have already discussed the differences from
a 3D point of view prior. Finally, two assays were carried out in
order to delve into this subject: we compare their capacity to
inhibit the heme-polymerization and their safety profile by
comparing their promiscuity against a panel of receptors, ion
channel, enzymes, and transporters.
clear what is the mechanism of hemozoin formation, but Pisciotta
et al.17 have shown that it could be formed in a lipid body dubbed
a lipid nanosphere inside the vacuole. Evidence for the
mechanism of action of the aryl methanols such as quinine
(QN), mefloquine, and halofantrine (Hf) is less clear-cut. These
drugs have been shown to form complexes with Fe(III)PPIX and
to inhibit formation of β-hematin, the synthetic counterpart of
hemozoin, and also to influence the growth of β-hematin crystals.
The β-hematin formation assays revealed that mefloquine is a
potent inhibitor (IC50 12.15 μM), while 6 and 7 do not present
any activity up to 100 μM.
In vitro pharmacological profiling involved the screening of
compounds against a broad range of human targets (receptors,
ion channels, enzymes, and transporters) that are distinct from
the intended therapeutic target (or targets) in order to identify
specific molecular interactions that may cause adverse drug
reaction in humans. This panel of assays was done with
mefloquine (2), the threo mixtures of both hits (6 and 7), and
enantiomers of 7 (15 and 16). Although some key differences
were found (i.e., inhibition of serotonin), the safety profile for all
the compounds assayed is very similar (Figure 7), and some
Figure 7. Bit map of selected key compounds (y axis) when tested
against a panel of human receptors, enzymes, ion channels, and
transportes (x axis). Color code: green/orange/red, low/medium/high
risk. Light gray means no data.
alerts were detected. These alerts are related to cardiovascular
system (CVS) and central nervous system (CNS), like Ca and
hERG channels and some serotonin isoforms. The cleanest
profile is of one of the isomers, 16, but this still shows some alerts
related to CNS and CVS. These alerts anticipate similar issues
It is well-known that P. falciparum detoxifies host hemoglobin-
derived ferriprotoporphyrin IX (Fe(III)PPIX) in an acidic
digestive vacuole mainly by converting it to hemozoin. It is not
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ACS Medicinal Chemistry Letters
Letter
A.; MacDonald, S. J. F.; Santos Martínez, M.; Sanz, L. M.; Gamo, F. J.;
Fernandez, E. Cyclopropyl Carboxamides: A New Oral Antimalarial
Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS). ACS
Med. Chem. Lett. 2011, 2, 840−844.
during the development of these compounds, although further
analysis should be made.
In conclusion, in this communication we show a case study of
small molecules as antimalarials, which present in vivo efficacy
when administered orally. The preliminary SAR shows
opportunities to increase the potency, but the safety profile
does not preclude the same side-effects as mefloquine. However,
this case study is very encouraging to continue the quest for a
differential antimalarial regarding the physicochemical profile.
́ ́
(11) Calderon, F.; Vidal, J.; Burrows, J.; de la Rosa, J. C.; Jimenez-Díaz,
M. B.; Mulet, T.; Prats, S.; Solana, J.; Witty, M.; Gamo, F. J.; Fernandez,
E. A Divergent SAR Study Allows Optimization of a Potent 5-HT2C
Inhibitor to a Promising Antimalarial Scaffold. ACS Med. Chem. Lett.
2012, 3, 373−377.
(12) TCAMS was scored (see ref 9 for details). Both hits presented a
score of 16 over 30 (being the cutoff 15).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Jimen
Marchal, N.; Garuti, H.; Gom
S.; Fraile, M. T.; Calderon, F.; Fernan
Wilson, D. M.; García-Bustos, J. F.; Gamo, F. J.; Angulo-Barturen, I. A
New in Vivo Screening Paradigm to Accelerate Antimalarial Drug
Discovery. PLoS One 2013, 8, e66967.
(14) Sanz, L. M.; Crespo, B.; De-Cozar, C.; Ding, X. C.; Llergo, J. L.;
Burrows, J. N. P. falciparum in Vitro Killing Rates Allow to Discriminate
between Different Antimalarial Mode-of-Action. PLoS One 2012, 7,
e30949.
(15) Hanna, G. M. 1H-NMR Studies of Drugs with Chiral Solvating
Agent: The Direct Enantiomeric Purity Determination of the Chiral
Anesthetic, Prilocaine. Enantiomer 2000, 5, 303−312 The compound (1
mg approx.) under study is solved in 700 μL of CDCl3, and then 10−15
equiv of Pirkle’s reagent was added.
́
ez-Díaz, M. B.; Viera, S.; Ibanez, J.; Mulet, T.; Magan-
́
́
̃
■
́
ez, V.; Cortes
́
-Gil, L.; Martínez, A.; Ferrer,
S
́
́
dez, E.; Shultz, L. D.; Leroy, D.;
AUTHOR INFORMATION
Corresponding Author
*(F.C.) E-mail: felix.r.calderon-romo@gsk.com.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
■
Funding
(16) Freedman, T. B.; Cao, X.; Dukor, R. K.; Nafie, L. A. Absolute
Determination of Chiral Molecules in the Solution State Using
Vibrational Circular Dichroism. Chirality 2003, 15, 743−758.
GlaxoSmithKline acknowledges financial support from Medi-
cines for Malaria Venture (MMV).
Notes
́
(17) Seco, J. M.; Quinoa, E.; Riguera, R. The Assignment of Absolute
̃
The authors declare no competing financial interest.
Configuration by NMR. Chem. Rev. 2004, 104, 17−117.
(18) Oxazolidine derivative was easily prepared by adding p-
toluenesulfonic acid to a solution of 6 and formaldehyde in THF.
(19) MPA-esthers were prepared by adding DMAP to a solution of 6,
EDCI, and (R) or (S)-2-methoxy-2-phenylacetic acid in dichloro-
methane (DCM).
(20) Basco, L. K.; Gillotin, C.; Gimenez, F.; Farinotti, R.; Le Bras, J. In
Vitro Activity of the Enantiomers of Mefloquine, Halofantrine and
Enpiroline against Plasmodium falciparum. Br. J. Clin. Pharm. 1992, 33,
517−520.
(21) The Molecular Operating Environment, version 2010.10; Chemical
Computing Group, Inc.: Montreal, Canada, 2010. http://www.
chemcomp.com.
ACKNOWLEDGMENTS
■
We thank our colleagues from Pharmacology Department and
Biology for the measurement of the ADMET properties of
compounds described in this communication.
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