Evaluation of aminohydantoins as a novel class of antimalarial agents

Article abstract of DOI:10.1021/ml400412x

Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malar

Full text of DOI:10.1021/ml400412x

Letter
pubs.acs.org/acsmedchemlett
Evaluation of Aminohydantoins as a Novel Class of Antimalarial
Agents
Marvin J. Meyers,†,* Micky D. Tortorella,‡ Jing Xu,‡ Limei Qin,‡ Zhengxiang He,‡ Xingfen Lang,‡
Wentian Zeng,‡ Wanwan Xu,‡ Li Qin,‡ Michael J. Prinsen,† Francis M. Sverdrup,†
Christopher S. Eickhoff,† David W. Griggs,† Jonathan Oliva,† Peter G. Ruminski,† E. Jon Jacobsen,†
Mary A. Campbell,† David C. Wood,† Daniel E. Goldberg,§ Xiaorong Liu,‡ Yongzhi Lu,‡ Xin Lu,‡
Zhengchao Tu,‡ Xiaoyun Lu,‡ Ke Ding,‡ and Xiaoping Chen‡,*
†Center for World Health and Medicine, Saint Louis University, Saint Louis, Missouri 63104, United States
‡Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
§Howard Hughes Medical Institute, Washington University School of Medicine, Departments of Molecular Microbiology and
Medicine, Saint Louis, Missouri 63110, United States
S
* Supporting Information
ABSTRACT: Given the threat of drug resistance, there is an
acute need for new classes of antimalarial agents that act via a
unique mechanism of action relative to currently used drugs.
We have identified a set of druglike compounds within the
Tres Cantos Anti-Malarial Set (TCAMS) which likely act via
inhibition of a Plasmodium aspartic protease. Structure−
activity relationship analysis and optimization of these
aminohydantoins demonstrate that these compounds are
potent nanomolar inhibitors of the Plasmodium aspartic
proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group,
such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of
human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as
an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.
KEYWORDS: Malaria, antimalarial, aminohydantoin, medicinal chemistry, aspartic protease inhibitors
alaria is a devastating mosquito-borne infectious disease
caused by a parasite of the genus Plasmodium, placing
inhibitors with the potential to be a good starting point for
antimalarial drug discovery. This manuscript details our
evaluation of this series of compounds as leads for optimization
as antimalarial drugs with a novel mechanism of action as
aspartic protease inhibitors.
M
over one billion people at high risk for infection. According to
the World Health Organization, there were an estimated 225
million cases of malaria in 2010 with 610,000−971,000 deaths.1
Especially hard hit is sub-Saharan Africa, where 80% of the
deaths occur, mostly in children under the age of 5 years old.
Although there are a number of drugs used to treat the disease,
resistance to most of these drugs is widespread.2 The
introduction of artemisinin and artemisinin combination
therapies (ACTs) in 2005 has begun to reverse the trend.
While this is a good sign, there have been reports of resistance
to artemisinin in Southeast Asia.3 As a consequence, there is an
urgent push for developing antimalarial therapies targeting
novel modes of action. Drug discovery efforts in this area have
been recently reviewed.4−6
Despite the urgent need, most antimalarial drugs in late stage
clinical development do not target new mechanisms of action.
Rather, many of these efforts have been focused on enhancing
existing antimalarials, such as artemisinin. Recently, scientists at
GlaxoSmithKline and elsewhere have published on the
antimalarial activity of thousands of compounds.7,8 Within
this data set, we have identified a class of aspartic protease
P. falciparum, the most lethal to man of the Plasmodium
species, has multiple aspartic proteases,9,10 including Plasmep-
sin V (PM-V), which has been demonstrated to be essential to
the parasite’s survival due to its role in the export of hundreds
of Plasmodium proteins to the host erythrocyte.11,12 Most of the
early drug discovery efforts in this area have focused on
inhibition of the plasmepsins of the digestive vacuole (PM-I, II,
IV, and III or HAP), but these efforts have not been very
successful due to the redundancy of the function of the
digestive vacuole plasmepsins and other proteases. The
function of the other plasmepsins (PM-VI, VII, VIII, IX, X)
is unknown. Recently, the Plasmodium signal peptide peptidase
(Pf SPP), an aspartic protease member of a family of
Received: October 14, 2013
Accepted: December 6, 2013
Published: December 6, 2013
© 2013 American Chemical Society
89
dx.doi.org/10.1021/ml400412x | ACS Med. Chem. Lett. 2014, 5, 89−93

ACS Medicinal Chemistry Letters
Letter
intramembrane cleaving proteases, has been demonstrated to
be essential to parasite survival in both blood and liver
stages.13,14
From the TCAMS collection, we identified 35 examples of
aminohydantoins, with antimalarial activities ranging from 140
to 1500 nM, as exemplified by the racemate TCMDC-136879
(4), which had a published IC50 of 140 nM.7 We resynthesized
compound 4 according to the procedure in Scheme 1, wherein
It is anticipated that inhibition of one or more aspartic
proteases would be lethal to the parasite. However, there are
currently few tools available to identify inhibitors of these more
promising aspartic protease targets in an efficient manner. For
example, the only known inhibitors of PM-V are pepstatin A
and HIV protease inhibitors, such as lopinavir and ritonavir.11,12
These inhibitors are very weak inhibitors of PM-V (IC50 >20
μM) and, due to their large molecular weights and
peptidomimetic character, make relatively poor starting points
for a new antimalarial drug discovery program. Recently,
optimization of the antimalarial activity of a hydroxylethylamine
series was reported, presumably activating via an aspartic
protease mechanism.15
a
Scheme 1. General Synthesis of Aminohydantoins
a
Reagents and conditions: (a) KOH, DMSO, heat. (b) X = S, t-
BuOOH, NH4OH, MeOH.
Given the loose sequence homology between the aspartic
protease β-secretase (BACE) and PM-V and the key role of the
dual aspartic acid residues in the protease active site, we
hypothesized that inhibitors of BACE may inhibit some
members of the family of Plasmodium aspartic proteases as
well. One of the scaffolds we selected was the aminohydantoin
core common to BACE screening hit 1 and related optimized
compounds such as 2 and 3.16,17 Compounds 2 and 3 are orally
bioavailable, demonstrating the druglike nature of this chemo-
type. Furthermore, there are several X-ray crystal structures that
demonstrate the key interactions between the protonated
aminohydantoin core and the aspartic acid residues of the
BACE active site (Figure 1).16 We used this aminohydantoin
diketone 5 was condensed with the corresponding thiourea 6 to
give thiohydantoin 7. Thiohydantoin 7 was then converted to
the aminohydantoin to give 4. Compound 4 was assayed for
activity in the Pf 3D7 infected RBC assay.18 Compound 4 has a
more modest Pf 3D7 IC50 of 2.76 μM in our hands but,
interestingly, is also a potent inhibitor of PM-II (IC50 = 12 nM)
and a modest inhibitor of the PM-V enzyme12 (IC50 = 977
nM). Given this data, we initiated a medicinal chemistry effort
to prepare additional analogs to determine our ability to
optimize for antimalarial potency, develop SAR, and under-
stand the mechanism of action of this novel class of antimalarial
compounds.
Our initial efforts were to replace the flexible, lipophilic
phenylbutyl side chain R1 and its chiral center. Analogs
containing simple phenyl and p-methoxyphenyl were readily
prepared from commercially available diketones (Scheme 1).
The Pf 3D7 IC50 values for representative compounds are
shown in Table 1. Compounds prepared in the R2/R3 p-
methoxyphenyl series were approximately 10-fold more potent
than those in the unadorned phenyl series (e.g., 4 vs 8a, 8f vs
8g, and 8o vs 8p). Simple replacement of the phenylbutyl side
chain with smaller alkyl groups, such as methyl, ethyl, and
propyl, resulted in size-dependent losses in potency (8b−d).
Large flexible groups, such as benzyl and phenethyl (8g−i), and
secondary branched alkyls, such as isopropyl (8j), were
tolerated but not tert-butyl (8k). Cyclic alkyl groups were
identified to provide an optimal combination of potency and
reduced lipophilicity (8n, 8p, 8q).
Cyclohexyl analog 8p was selected for further optimization
studies, as derivitization of the cyclohexyl ring could be
accomplished without adding additional stereocenters to the
compounds (9a−g). Pyran derivative 9a has equivalent potency
to cyclohexyl 8p while reducing the lipophilicy by 2 orders of
magnitude. In contrast, the presence of an alcohol on the
cyclohexyl ring (9b) was not tolerated. N-Alkylated and N-
acylated piperidines (9d, 9e) are also suitable replacements for
the cyclohexyl ring while the more polar NH piperidine was not
tolerated (9c). Extension of the cyclohexyl (9f) and pyran (9g)
rings by one carbon resulted in nearly identical potencies to
those of the corresponding analogs 8p and 9a.
Figure 1. Medicinal chemistry strategy.
core to perform substructure searches on the more than 13,000
compounds (TCAMS) known to have antimalarial activity in Pf
3D7 infected red blood cells (RBC) published by Glax-
oSmithKline.7 Our strategy is outlined in Figure 1.
Chart 1. Example Aminohydantoin BACE Inhibitors with
Common Core Colored Blue
Having satisfactorily improved potency against the parasite
by approximately 10-fold, we turned our attention toward
evaluating the SAR of the aryl rings while keeping R1 constant
as the cyclohexyl ring. While most of these substitutions
elevated the lipophilicity of the compounds, our aim was to
develop the SAR and to see if the SAR was consistent with
90
dx.doi.org/10.1021/ml400412x | ACS Med. Chem. Lett. 2014, 5, 89−93

ACS Medicinal Chemistry Letters
Letter
Table 1. SAR Analysis of N-R1 Substituents
Table 2. SAR Analysis of Aryl Substituents
cmpd
10a
R1
R2
R3
Pf 3D7 IC50 (μM) cLogP
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
Me
3-OMe
4-OMe
3-OMe
4-OCF3
4-OEt
3-OMe
H
0.768
0.533
0.917
2.20
3.9
4.1
4.1
7.1
4.6
5.3
5.3
5.5
5.5
5.7
4.5
4.5
4.7
4.9
4.5
5.1
5.7
5.8
5.8
( )-10b
( )-10c
10d
H
4-OCF3
4-OEt
4-Me
3-Me
4-Cl
10e
0.466
1.26
10f
4-Me
10g
3-Me
0.533
1.07
10h
4-Cl
10i
3-Cl
3-Cl
1.06
( )-10j
( )-10k
( )-10l
( )-10m
( )-10n
( )-10o
10p
3-Ph
4-OMe
4-OMe
3-OMe
H
1.49
3-(3-pyr)
3-(3-pyr)
3-(3-pyr)
3-(2-pyr)
3-(4-pyr)
3-(3-pyr)
3-OPh
3-OBn
3-(3-pyr)
0.595
0.787
0.75
4-OMe
3-OMe
3-(3-pyr)
H
1.81
0.318
0.725
0.424
0.641
6.88
( )-10q
( )-10r
( )-11
H
H
ring. This substitution pattern allows the biaryl group of the
inhibitor to occupy both the S1 and the S3 binding pockets
simultaneously (Supporting Information; Figure S1). Since this
general aspartic protease active site topography might be
present in our Plasmodium target, we prepared derivatives such
as 10j−p (Table 2). Phenyl derivative 10j resulted in only a
modest 3- to 4-fold loss of potency. As has been observed with
BACE,17 replacement of the phenyl ring with a 3-pyridyl ring
(10k) results in improved potency relative to phenyl.
Interestingly, the methoxy group on the second aryl ring has
a negligible effect on potency (10l, 10m). 4-Pyridyl substitution
(10o) had a similar effect to that of 3-pyridyl while 2-pyridyl
(10n) was more similar to phenyl. Phenyl and benzyl ethers
10q and 10r demonstrated a relatively tolerant substitution
pattern at this position.
Given the consistency of the SAR with an aspartic protease
binding site, we evaluated a subset of these antimalarial
compounds for inhibition of Plasmodium aspartic proteases
PM-II and PM-IV (Supporting Information; Table S2). Most of
the aminohydantoins evaluated are potent inhibitors of both
PM-II and PM-IV, some in the single digit nanomolar range.
Compounds with weaker 3D7 potency tended to have weaker
PM-II and PM-IV activity (9b and 9c). We assayed ∼80
analogs in our collection for PM-II activity and plotted this
potency versus 3D7 potency (Supporting Information; Figure
S2). While there is a loose correlation between PM-II potency
and 3D7 potency, there is a 30−100 fold shift in potency.
Furthermore, it has been previously demonstrated that
inhibition of Plasmepsins I−IV is insufficient to kill the
parasite.19−21 These data suggest that the observed PM-II and
PM-IV activity may be indicative of inhibition of one or more
other, albeit unidentified, Plasmodium aspartic proteases.
Additionally, the more potent compounds (e.g., 8p, 10a,
10m) appear to be inactive against PM-V (data not shown).
To further demonstrate the likelihood of these compounds
inhibiting an aspartic protease binding site, we also prepared
two simple analogs of compound 8p wherein the imino
nitrogen atom was replaced with oxygen (7a) and with sulfur
(7b), both of which are unable to form the requisite hydrogen
bonding network to the catalytic aspartic acid residues (see
inhibition of an aspartic protease active site (Table 2). More
elaborate substitution patterns of the aryl rings in the R2 and R3
position required synthesis of diketone 5 by well-known
methods (see Supporting Information).
Moving the methoxy groups to the 3-position results in only
a 2-fold loss of potency (10a vs 8p) while deletion of the
second methoxy group had a negligible effect on potency
(10b−c). Replacement of methoxy with triflouromethoxy
(10d) had a detrimental effect on potency while the ethoxy
(10e) analog was equipotent. The more lipophilic methyl and
chloro derivatives were tolerated in the 4- and 3-positions but
did not enhance potency (10f−i).
Many advanced aminohydantoin inhibitors of BACE (e.g., 2
and 3) exhibit an aryl group in the 3-position of the aromatic
91
dx.doi.org/10.1021/ml400412x | ACS Med. Chem. Lett. 2014, 5, 89−93

ACS Medicinal Chemistry Letters
Letter
Figure 1). These minor changes resulted in complete loss of
3D7, PM-II, and PM-IV potency, consistent with an aspartic
protease mechanism of action (Supporting Information Table
S2).
obtained, with complete elimination of parasitemia achieved at
300 mpk (Figure 2). In this experiment, all of the mice survived
It is also evident that while these compounds are potent
inhibitors of Plasmodium PM-II and PM-IV, they are poor
inhibitors of human aspartic proteases BACE, CatD, and CatE
(Supporting Information Table S2). Lead compound cyclo-
hexyl 8p is >1000-fold selective for PM-II over BACE and
CatD and ∼300-fold over CatE. Compounds containing the S3-
occupying aryl ring, such as 10m, also retained greater than
1000-fold selectivity over BACE and CatD and ∼200-fold over
CatE. Furthermore, comparator compound 11 with a methyl
group in place of the cyclohexyl substituent in the R1 position
demonstrates the importance of the cyclohexyl group (or a
secondary alkyl group) in enhancing antimalarial 3D7 and PM-
II potency while reducing potency against BACE (11 vs 10m).
Compounds with larger but more flexible R1 side chains (4, 9f,
and 9g) were found to be less selective.
In order to evaluate this series for its potential as oral
antimalarial agents, compound 8p and closely related 9a, 9f,
and 9g were further profiled (Supporting Information, Table
S1). All four compounds retained nearly equivalent potency
against 3D7 at 48 h and against the chloroquine- and
pyrimethamine-resistant Dd2 strain, indicating the novel
mechanism of action and the potential utility of this class of
antimalarials in targeting drug resistant parasites.
Figure 2. Dose−response of compound 8p and CQ in the P. chabaudi
ASCQ-infected murine four-day suppressive test. Four hours after
infection, compound 8p was dosed orally once daily for four days.
Parasitemia was determined on Day 4 postinoculation. The vehicle
group was within error of the four lowest doses of compound 8p.
at least 10 days post-treatment with 8p. 100% suppression of
parasitemia was achieved in 10 of 12 animals in the 150 and
300 mpk dose groups.
In conclusion, the SAR analysis of the aminohydantoin class
of antimalarial compounds presented here demonstrates that
these compounds are potent nanomolar inhibitors of the
Plasmodium aspartic proteases PM-II and PM-IV and likely one
or more other Plasmodium aspartic acid proteases. Incorpo-
ration of a bulky group, such as a cyclohexyl group, on the
aminohydantion N-3 position gives enhanced antimalarial
potency while reducing inhibition of human aspartic proteases
such as BACE. Compound 8p (CWHM-117) presents a
promising lead for optimization as an antimalarial drug with a
low molecular weight, modest lipophilicity, oral bioavailability,
and in vivo antimalarial activity in mice. Efforts are underway to
further improve the whole cell potency in 3D7 and Dd2 strains
and potency in in vivo models of malaria.
The compounds were also profiled against a number of
human enzymes and cell lines (Supporting Information Table
S1). The compounds were found to have limited activity in a
HepG2 cytotoxicity assay and against most CYP enzymes
evaluated, with the exception of CYP3A4. Compound 8p
showed good metabolic stability in mouse, rat, and human liver
microsomes (MLM, RLM, and HLM, respectively) and is orally
bioavailable in rats with a half-life of 2.9 h.
Given the overall properties of compound 8p, we elected to
characterize compound 8p and related compounds in the in
vivo P. chabaudi murine Peter’s 4-day suppressive test (Table
3).18 Parasitemia levels were determined 24 h after the last
Table 3. Oral in Vivo Efficacy of Lead Compounds (P.
chabaudi ASS-Infected Murine Four-Day Suppressive Test)
ASSOCIATED CONTENT
* Supporting Information
Supporting tables, experimental procedures, characterization of
compounds, and assay methods. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
d
plasma [cmpd] (ng/mL)
S
b
c
cmpd dose (mpk)
%Inh of parasitemia
1 h
6 h
nd
24 h
a
CQ
8p
9a
9f
4.5
99.99
89
nd
nd
575
29
100
110
100
100
2790
4140
2517
3393
nd
e
63
AUTHOR INFORMATION
Corresponding Authors
*M.J.M.: E-mail: mmeyers8@slu.edu.
*X.C.: E-mail: chen_xiaoping@gibh.ac.cn.
73
2187
3027
7
■
9g
41
10363
123
a
b
nd = not determined. Four hours after infection, compounds were
c
dosed orally once daily for four days. Determined on Day 4
postinoculation. Compound concentration in the plasma determined
1, 6, and 24 h post last dose on Day 3. Determined at 30 min post
d
Funding
e
Research reported in this publication at Saint Louis University
was supported by Saint Louis University and the National
Institute Of Allergy And Infectious Diseases of the National
Institutes of Health under Award Number R01AI106498.
Research reported in this publication at the Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of
Sciences, was supported by Bureau of Science and Information
Technology of Guangzhou Municipality, Grant Number
2009Z1-E841, and Natural Science Foundation of China
(NSFC). D.E.G. is supported by the National Institutes of
dose.
treatment. Compound 8p gave a strong effect (89% inhibition)
at 100 mpk, while closely related 9a, 9f, and 9g were efficacious
but to a lesser extent than 8p. These results may be explained in
part by the apparent shorter half-lives of these compounds
relative to 8p. At 24 h postdose, only compound 8p has greater
than 1 μM concentration in the plasma. In a separate
experiment with 8p, a clear dose−response relationship was
92
dx.doi.org/10.1021/ml400412x | ACS Med. Chem. Lett. 2014, 5, 89−93

ACS Medicinal Chemistry Letters
Letter
(12) Russo, I.; Babbitt, S.; Muralidharan, V.; Butler, T.; Oksman, A.;
Goldberg, D. E. Plasmepsin V licenses Plasmodium proteins for export
into the host erythrocyte. Nature 2010, 463, 632−636.
(13) Li, X.; Chen, H.; Bahamontes-Rosa, N.; Kun, J. F.; Traore, B.;
Crompton, P. D.; Chishti, A. H. Plasmodium falciparum signal peptide
peptidase is a promising drug target against blood stage malaria.
Biochem. Biophys. Res. Commun. 2009, 380, 454−9.
Health under Award Number AI047798. The content is solely
the responsibility of the authors and does not necessarily
represent the official views of Saint Louis University, the
Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, the Natural Science Foundation of China,
or the National Institutes of Health.
Notes
(14) Harbut, M. B.; Patel, B. A.; Yeung, B. K.; McNamara, C. W.;
Bright, A. T.; Ballard, J.; Supek, F.; Golde, T. E.; Winzeler, E. A.;
Diagana, T. T.; Greenbaum, D. C. Targeting the ERAD pathway via
inhibition of signal peptide peptidase for antiparasitic therapeutic
design. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 21486−91.
(15) Ciana, C. L.; Siegrist, R.; Aissaoui, H.; Marx, L.; Racine, S.;
Meyer, S.; Binkert, C.; de Kanter, R.; Fischli, C.; Wittlin, S.; Boss, C.
Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine
scaffold. Bioorg. Med. Chem. Lett. 2013, 23, 658−62.
(16) Malamas, M. S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu, Y.;
Wagner, E.; Fan, K.; Chopra, R.; Olland, A.; Bard, J.; Jacobsen, S.;
Magolda, R. L.; Pangalos, M.; Robichaud, A. J. Design and synthesis of
5,5′-disubstituted aminohydantoins as potent and selective human
beta-secretase (BACE1) inhibitors. J. Med. Chem. 2010, 53, 1146−58.
(17) Cumming, J. N.; Smith, E. M.; Wang, L.; Misiaszek, J.; Durkin,
J.; Pan, J.; Iserloh, U.; Wu, Y.; Zhu, Z.; Strickland, C.; Voigt, J.; Chen,
X.; Kennedy, M. E.; Kuvelkar, R.; Hyde, L. A.; Cox, K.; Favreau, L.;
Czarniecki, M. F.; Greenlee, W. J.; McKittrick, B. A.; Parker, E. M.;
Stamford, A. W. Structure based design of iminohydantoin BACE1
inhibitors: identification of an orally available, centrally active BACE1
inhibitor. Bioorg. Med. Chem. Lett. 2012, 22, 2444−9.
(18) Li, X.; He, Z.; Chen, L.; Li, Y.; Li, Q.; Zhao, S.; Tao, Z.; Hu, W.;
Qin, L.; Chen, X. Synergy of the antiretroviral protease inhibitor
indinavir and chloroquine against malaria parasites in vitro and in vivo.
Parasitol. Res. 2011, 109, 1519−24.
(19) Liu, J.; Gluzman, I. Y.; Drew, M. E.; Goldberg, D. E. The role of
Plasmodium falciparum food vacuole plasmepsins. J. Biol. Chem. 2005,
280, 1432−7.
(20) Omara-Opyene, A. L.; Moura, P. A.; Sulsona, C. R.; Bonilla, J.
A.; Yowell, C. A.; Fujioka, H.; Fidock, D. A.; Dame, J. B. Genetic
disruption of the Plasmodium falciparum digestive vacuole plasmep-
sins demonstrates their functional redundancy. J. Biol. Chem. 2004,
279, 54088−96.
(21) Moura, P. A.; Dame, J. B.; Fidock, D. A. Role of Plasmodium
falciparum digestive vacuole plasmepsins in the specificity and
antimalarial mode of action of cysteine and aspartic protease inhibitors.
Antimicrob. Agents Chemother. 2009, 53, 4968−78.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Eva Istvan for supplying the
PM-II and PM-IV DNA constructs, and Felix Calderon, Elena
Fernandez Alvaro, Lluis Ballell-Pages, Esther Pilar Fernandez-
Velando, Inigo Angulo-Barturen, and Santiago Ferrer-Bazaga
for helpful discussions.
ABBREVIATIONS
■
ACT, artemisinin combination therapy; PM, plasmepsin; HAP,
histo-aspartic peptidase; SPP, signal peptide peptidase; HIV,
human immunodeficiency virus; SAR, structure−activity
relationships; BACE, β-site APP cleaving enzyme 1; TCAMS,
Tres Cantos Antimalarial Set; RBC, red blood cells; CatD,
cathepsin D; CatE, cathepsin E; MLM, mouse liver micro-
somes; RLM, rat liver microsomes; HLM, human liver
microsomes; PK, pharmacokinetics; PPB, plasma protein
binding; CYP, cytochrome P450; CQ, chloroquine; mpk,
milligrams per kilogram
REFERENCES
■
(1) World Malaria Report 2012; World Health Organization: 2012.
(2) Hyde, J. E. Drug-resistant malaria. Trends Parasitol. 2005, 21,
494−8.
(3) Dondorp, A. M.; Yeung, S.; White, L.; Nguon, C.; Day, N. P.;
Socheat, D.; von Seidlein, L. Artemisinin resistance: current status and
scenarios for containment. Nat. Rev. Microbiol. 2010, 8, 272−80.
(4) Burrows, J. N.; Chibale, K.; Wells, T. N. C. The State of the Art
in Anti-malarial Drug Discovery and Development. Curr. Top. Med.
Chem. 2011, 11, 1226−1254.
(5) Burrows, J. N.; Burlot, E.; Campo, B.; Cherbuin, S.; Jeanneret, S.;
Leroy, D.; Spangenberg, T.; Waterson, D.; Wells, T. N.; Willis, P.
Antimalarial drug discoverythe path towards eradication. Para-
sitology 2013, 1−12.
(6) Biamonte, M. A.; Wanner, J.; Le Roch, K. G. Recent advances in
malaria drug discovery. Bioorg. Med. Chem. Lett. 2013, 23, 2829−43.
(7) Gamo, F. J.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.;
Lavandera, J. L.; Vanderwall, D. E.; Green, D. V.; Kumar, V.; Hasan, S.;
Brown, J. R.; Peishoff, C. E.; Cardon, L. R.; Garcia-Bustos, J. F.
Thousands of chemical starting points for antimalarial lead
identification. Nature 2010, 465, 305−10.
(8) Calderon
E.; Gamo, F. J.; Lavandera, J. L.; Leon
́
, F.; Barros, D.; Bueno, J. M.; Coteron
́ ́
, J. M.; Fernandez,
́
, M. L.; Macdonald, S. J. F.;
Mallo, A.; Manzano, P.; Porras, E.; Fiandor, J. M.; Castro, J. An
Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality
Starting Points from the TCAMS. ACS Med. Chem. Lett. 2011, 2, 741−
746.
(9) Coombs, G. H.; Goldberg, D. E.; Klemba, M.; Berry, C.; Kay, J.;
Mottram, J. C. Aspartic proteases of Plasmodium falciparum and other
parasitic protozoa as drug targets. Trends Parasitol. 2001, 17, 532−7.
(10) Meyers, M. J.; Goldberg, D. E. Recent advances in plasmepsin
medicinal chemistry and implications for future antimalarial drug
discovery efforts. Curr. Top. Med. Chem. 2012, 12, 445−55.
(11) Boddey, J. A.; Hodder, A. N.; Gunther, S.; Gilson, P. R.;
Patsiouras, H.; Kapp, E. A.; Pearce, J. A.; de Koning-Ward, T. F.;
Simpson, R. J.; Crabb, B. S.; Cowman, A. F. An aspartyl protease
directs malaria effector proteins to the host cell. Nature 2010, 463,
627−31.
93
dx.doi.org/10.1021/ml400412x | ACS Med. Chem. Lett. 2014, 5, 89−93