Design and synthesis of simplified speciophylline analogues and β-carbolines as active molecules against Plasmodium falciparum

Article abstract of DOI:10.1002/ddr.21494

A structure–activity relationship study of active molecules against chloroquine-resistant Plasmodium falciparum K1 strain is reported. Structurally simplified analogues of antiplasmodial active alkaloids presented similar levels of activity as their corresponding natural products extracted from Guiera senegalensis and Mitragyna inermis with IC₅₀ values on chloroquine-resistant P. falciparum K1 strain of up to 10.6 μM for spirooxindoles and 13.8 μM for β-carbolines. The identification of such simpler and cheaper structural analogues is crucial to efficiently study these natural products' action mode as well as developing new cures against malaria.

Full text of DOI:10.1002/ddr.21494

Received: 25 July 2018
DOI: 10.1002/ddr.21494
Revised: 3 November 2018
Accepted: 6 November 2018
R E S E A R C H A R T I C L E
Design and synthesis of simplified speciophylline analogues
and β-carbolines as active molecules against Plasmodium
falciparum
1
2
3
4
5
David Pierrot | Véronique Sinou | Sok-Siya Bun | Daniel Parzy | Nicolas Taudon |
1
3
1
Jean Rodriguez | Evelyne Ollivier | Damien Bonne
Enabling Technologies
Strategy, Management & Health Policy
Hit, Lead &
Candidate Discovery
Preclinical Research
& Development
Clinical
Research
Post-Market
Research
1
Aix Marseille Univ, CNRS, Centrale Marseille,
Abstract
iSm2, France
2
A structure–activity relationship study of active molecules against chloroquine-resistant Plasmo-
dium falciparum K1 strain is reported. Structurally simplified analogues of antiplasmodial active
alkaloids presented similar levels of activity as their corresponding natural products extracted
from Guiera senegalensis and Mitragyna inermis with IC50 values on chloroquine-resistant
P. falciparum K1 strain of up to 10.6 μM for spirooxindoles and 13.8 μM for β-carbolines. The
identification of such simpler and cheaper structural analogues is crucial to efficiently study
these natural products' action mode as well as developing new cures against malaria.
Aix Marseille University, UMR MD1,
Marseille, France
3
CNRS, IRD, IMBE, FAC PHARM, Aix Marseille
University, Avignon Université, Marseille,
France
4
Department of Biology, K-plan, Marseille,
France
5
Département des plateformes et recherche
technologique, Institut de Recherche
Biomédicale des Armées (IRBA), Brétigny-sur-
Orge, France
KEYWORDS
antimalarial activity, speciophylline, spirooxindoles, β-carbolines
Correspondence
Damien Bonne, Centrale Marseille, iSm2, Aix
Marseille University, Marseille, France.
Email: damien.bonne@univ-amu.fr
Funding information
Centrale Marseille; Aix-Marseille Université;
Centre National de la Recherche Scientifique
1
| INTRODUCTION
most virulent with high mortality and morbidity rate (Krungkrai &
Krungkrai, 2016). Antimalarial drug resistance of P. falciparum is one
Malaria remains a major public health problem around the world. In
of the greatest challenges confronting malaria control. Artemisinin-
based combination therapies (ACTs) which combine an artemisinin
derivative with a partner drug are the most effective antimalarial med-
icines available today. Currently, three ACTs are used as the first-
line treatment for falciparum malaria in most endemic countries:
artemether–lumefantrine, artesunate–mefloquine, and dihydroartemisinin–
piperaquine (World Health Organization, 2015). However, a decline in
ACT efficacy has been recently seen in Southeast Asia (World Health
Organization, 2017a, 2017b). This represents a major concern for
global public health especially as very few new compounds are cur-
rently in the development pipeline (Phyo & Nosten, 2018). Therefore,
2
4
016, there were an estimated 216 million malaria cases causing
45 hundred deaths, primarily children under the age of 5 in Africa
(
World Health Organization, 2017a, 2017b). Among the six species of
malaria parasites that infect humans, Plasmodium falciparum is the
Abbreviations: IC50, half-maximal inhibitory concentration; HRP2-ELISA, histi-
dine-rich protein 2 enzyme-linked immuno-sorbent assay; 5-FU, 5-fluorouracil;
MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; dr, diaste-
reomeric ratio; CBz, carboxybenzyl; Ts, tosyl; Bn, benzyl; rt, room temperature;
0
EDCI, N-(3-dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride; DMAP,
dimethylaminopyridine; DMF, dimethylformamide; Boc
dicarbonate.
2
O, di-tert-butyl
Drug Dev Res. 2018;1–5.
wileyonlinelibrary.com/journal/ddr
© 2018 Wiley Periodicals, Inc.
1

2
PIERROT ET AL.
the study of alternative action mechanisms would enable the devel-
opment of new and complementary curative agents against
P. falciparum. One major approach for the discovery of new drugs
relies on the exploration of Nature as a source of novel active mole-
cules and scaffolds. Based on this observation and considering that
about 80% of the African population used traditional medicine to treat
malaria, work has been carried out jointly by the faculties of pharmacy
of Marseille and Bamako on the antiplasmodial activity of various pre-
pared herbal remedies (Ancolio et al., 2002; Traore-Keita et al., 2000).
Several active plants have been identified including Mitragyna inermis,
an endemic plant in tropical Africa. Among the various tetracyclic and
oxindolic tetracyclic and pentacyclic indole alkaloids isolated from
platform of different simplified speciophylline analogues having a
0
spiro[pyrrolidin-3,3 -oxindole] core, and test their antiplasmodial
activity as well as their toxicity to shed light on the possible nature of
the active pharmacophore.
2
| RESULTS AND DISCUSSION
Our strategy relies on the versatility of an intramolecular Mannich
reaction of commercially available 2-oxotryptamine hydrochloride (1)
(
Dörnyei, Incze, Kajtár-Peredy, & Szántay, 2002; Harley-Mason &
Ingleby, 1958; Incze, Dörnyei, Kajtár-Peredy, Szántay, 1999;
&
Jansen & Richards, 1965; Oishi, Nagai, & Ban, 1968) with simple car-
bonyl compounds 2 (aldehydes or ketones) (Scheme 1). After optimi-
zation of the reaction conditions the combination of sodium acetate
with magnesium sulfate was found efficient and reproducible and the
desired spirooxindoles 3a-f were obtained in moderate to good yields
and low to moderate diastereoselectivities.
0
Mitragyna inermis, speciophylline featuring a spiro[pyrrolidin-3,3 -oxi-
ndole] core, showed encouraging in vitro antiplasmodial activity on
the chloroquine-resistant strain W2 (IC50 = 42 μM, Figure 1) and was
retained for further optimization (Fiot et al., 2005). Although its IC50 is
high relative to artemisinin or chloroquine, this concentration of inter-
est should be put into perspective with its lifetime in the body (Sinou
et al., 2010).
Three of these spirooxindoles were alkylated to have closer struc-
tures to the one of speciophylline and to evaluate the effect of
N-alkylation on biological activity (Scheme 2). Hence, three spirooxin-
A preliminary study has demonstrated hepatic cellular activity
induced by speciophylline with no hepatotoxic effect (Toure, Balan-
sard, Pauli, & Scotto, 1996). Cytotoxicity studies have also been con-
ducted on mixtures of alkaloids containing, among others,
speciophylline. The toxicity of speciophylline in the rodent has been
studied and shows a good tolerance, which suggests that it could be
used as a treatment in humans (Monjanel-Mouterde et al., 2006). Its
mode of action is however unknown; and it seems possible that this
molecule operates via an original mechanism. Indeed, although not all
known pharmacological targets have yet been tested, no specific
interaction could be detected with chloroquine and no significant
effect could be found either on the crystallization of heme of hemo-
globin or on the production of free radicals.
1
2
doles 3a, 3b, and 3g (R = H, R = (5,5-dimethyl-1,3-dioxan-2-yl)
methyl) were reacted with but-2-yne bromide in the presence of
potassium carbonate. The products 4a-c were obtained with lower
diastereomeric ratio, which can be explained by an increased rate of
the retro-Mannich reaction, leading to partial epimerization, once the
amine function is tertiarized (Seaton, Nair, Edwards, & Marion, 1960;
Wenkert, Udelhofen, & Bhattacharyya, 1959).
A previous study reported antiplasmodial activity for total alka-
loids of Guiera senegalensis leaves and roots. Among the alkaloids
identified in this plant, the β-carbolines, harman, and tetrahydrohar-
man showed significative activity. A synergistic association between
alkaloids from Guiera senegalensis and those of Mitragyna inermis has
been found, and might explain the combination of both plants in tradi-
tional remedies to treat malaria (Fiot et al., 2006). An additive combi-
nation between β-carbolines isolated from Guiera senegalensis and
speciophylline isolated from Mitragyna inermis has been observed.
Other naturally occurring β-carboline has been found to possess anti-
malarial properties (Ashok, Ganguly, & Murugesan, 2013; Chan,
Pearce, Page, Kaiser, & Copp, 2011). In addition, Yeung and coworkers
have reported antiplasmodial activity for a series of spirotetrahydro-
β-carbolines (Yeung et al., 2010), while Kara's team described in vivo
antimalarial activity of the β-carboline alkaloid manzamine A (Ang,
Holmes, Higa, Hamann, & Kara, 2000). Moreover, it is known that
spirooxindole natural products originate from the corresponding
β-carboline precursors by oxidative processes, which supports the bio-
logical evaluation of these two families of compounds (Wang & Gane-
san, 2000; Yu, Guo, Jian, Chen, & Xu, 2018; Zinnes & Shavel Jr, 1966).
We started our investigation by synthesizing a series of β-carbolines
The spirooxindole subunit constitutes an important pharmaco-
phore found in many natural products (Trost & Brennan, 2009) dis-
playing important biological activities (Antonchick et al., 2010;
Galliford & Scheidt, 2007; Santos, 2014; Ye, Chen, Wold, Shi, & Zhou,
2
016; Yu, Yu, & Liu, 2015) and has been the center of many synthetic
efforts (Cheng, Ishihara, Tan, & Barbas III, 2014; Liang & Wang, 2013).
Danishefsky and coworkers showed that structurally simpler ana-
0
logues of the alkaloid spirotryprostatin A, displaying only the 3,3 -pyr-
rolidinyl-spirooxindole core, were more active than the parent natural
product as cell cycle inhibitors (Edmondson, Danishefsky, Sepp-Loren-
zino, & Rosen, 1999). Interestingly, the configuration of the spirooxin-
dole's stereogenic center (C3) appeared unimportant in this specific
case, with similar biological activity for both epimers. Based on this
observation, we decided to develop a simple and robust synthetic
(
Scheme 3). Compound 7 was prepared by a Pictet-Spengler reaction
between tryptamine hydrochloride (5) and carbethoxypyruvic acid (6).
The amino group was then protected by either a carbobenzyloxy or a
tosyl group (8a and 8b, respectively). Alternatively, the amine was
converted to the corresponding amide 8c by coupling with (E)-but-
2-enoic acid. In addition, alkylation of the amine was undertaken using
FIGURE 1 Structure of speciophylline

PIERROT ET AL.
3
SCHEME 3 Synthesis of β-carbolines. Reaction conditions:
a) BnCOCl, Et N, DMPA, CH Cl , rt, 12 hr. (b) TsCl, Et N, CH
4 hr. (c) (E)-but-2-enoic acid, EDCI, DMAP, CH Cl , rt, 3 hr. (d) but-
-yne bromide, K CO , DMF, rt, 16 hr
(
3
2
2
3
2 2
Cl , rt,
2
2
2
2
2
3
the growth of parasite activity, which was determined by a home-
made HRP2-ELISA based assay. The first analysis revealed that com-
pound 3b possessing a p-methoxybenzyl group at 11-position was the
most active among the screened spirooxindoles. This compound (IC50
of 10.6 μM) was slightly more potent than speciophylline (IC50 of
42.1 ꢀ 7.7 μM). The other spirooxindoles (3a, 3c-f) showed no or only
moderate activity (>50 μM). In the next step, three N-alkylated spir-
ooxindole derivatives (4a-4c) were tested for their in vitro antimalarial
activity. The two separated and independently tested diastereomeric
forms of 4a, 4b, and 4c had similar IC50 values for K1 strain. These
were generally slightly lower than those obtained with the similarly
secondary amine analogues (compare compound 4a with 3a), comparable
to the activity of speciophylline. Finally, β-carboline derivatives were
tested in vitro for antimalarial activity. The compounds 9a, 9c-d, 10,
and 11 into which a BOC protecting group was introduced at the
indole nitrogen atom had the greatest activity with IC50 ranging
between 13.8 μM and 29.8 μM for K1 strain. The most promising
β-carboline compounds 9a, 9c, and 10 were about 3-fold more active
than speciophylline.
SCHEME 1 Synthesis of spirocyclic oxindoles 3a-g via intramolecular
Mannich reaction
Next, nine compounds were screened for their in vitro cytotoxic-
ity against HT29 colon adenocarcinoma cancer cell line using MTT
colorimetric method with 5-FU as positive control (Table 2). Among all
SCHEME 2 Alkylation of spirooxindoles 3a-c
the same reaction conditions than before (Scheme 2) and the desired
β-carboline 8d was obtained in 52% yield. Finally, the indole nitrogen
atom of 8a-8d was protected as a tert-butoxycarbonyl group and the
corresponding products 9a-9d were obtained in good to excellent
yields.
Further functionalizations of 8a were conducted on the ester
function (Scheme 4). Hence, conversion of the ester into the Weinreb
amide was accomplished and the compound 10 was obtained in 83%
yield. Instead, the alcohol 11 was synthesized in moderate yield (48%)
from 8a by reduction using diisobutylaluminum hydride.
The antimalarial effect of the listed molecules in Table 1 was
tested against the chloroquine-resistant K1 P. falciparum strain, using
synchronized cultures. They were screened for their ability to inhibit
SCHEME 4 Further functionalizations of β-carbolines

4
PIERROT ET AL.
TABLE 1 In vitro activity of chloroquine, speciophylline, and several
derivatives against chloroquine-resistant K1 Plasmodium falciparum
strain
4
4
| EXPERIMENTAL SECTION
.1 | Evaluation of in vitro antimalarial activity
Compound
IC50 (μM)
0.21 ꢀ 0.01
42.1 ꢀ 7.7
>100
Compound
IC50 (μM)
a
Chloroquine
The chloroquine-resistant P. falciparum K1 strain (BEI Resources,
MR4/ATCC, Manassas, VA) was cultured in complete medium consist-
ing of RPMI 1640 medium (Gibco) supplemented with 50 mg/L hypo-
a
Speciophylline
3
3
3
3
3
3
4
4
4
4
a
4c (dia 1)
35.4
55.3
37.1
35.0
>125
15.5
15.0
29.8
13.8
21.4
b
10.6
4c (dia 2)
8b
xanthine (Sigma), 25 mM NaHCO
3
(Sigma), 20 mg/L gentamycin
ꢁ
c
>100
(Sigma), and 10% human serum, at 37 C and under an atmosphere
d
55.1
8c
2 2 2
containing 5% CO , 10% O , and 85% N (Trager & Jensen, 1976).
e
63.8
8d
Cultures were synchronized by sorbitol treatments (Lambros & Van-
derberg, 1979). Stock solutions of compounds were prepared in sterile
DMSO and later dilutions were made in serum-free culture medium.
Ring stage parasite cultures (1.5% hematocrit, 0.5% parasitemia) were
exposed to increasing concentrations of compounds in 96-well plates.
Chloroquine and speciophylline were used as reference drugs. DMSO
alone (without compound) at a concentration equal to that in drug-
treated cell samples was used as control. The plates were incubated
f
>100
9a
a (dia 1)
a (dia 2)
b (dia 1)
b (dia 2)
29.4
9c
17.3
9d
11.2
10
13.9
11
a
Results expressed as mean ꢀ SD.
ꢁ
TABLE 2 Cytotoxicity of compounds 1–9 against HT29 human
72 hr, at 37 C in an atmosphere of 5% CO
2 2
, 10% O , and 85% N
2
cancer cell line
ꢁ
and then frozen at −80 C. The revelation of parasite growth was
realized using a homemade HRP2-based ELISA assay (Nakweti, Sinou,
Luyindula, Sabot, & Franche, 2018). Briefly, 1 μg/mL of anti-HRP2 IgG
(MPFM-55A, Immunology Consultants Laboratories, Inc., Portland,
OR) in PBS was immobilized overnight in a 96-well plate, which was
then blocked with 5% skimmed milk in PBS for 2 hr. Samples were
then diluted in PBS with 1% Tween 20 and 5% skimmed milk and
added to the plate for 1 hr. Finally, mouse peroxidase conjugated
detection antibody (MPFG-55P, IgG, Immunology Consultants Labora-
tories) diluted in PBS with 1% Tween 20 and 5% skimmed milk was
added for 1 hr. Signal was visualized with a commercially available
a
Compound
IC50 (μM)
>100
3
3
3
3
3
3
4
4
4
5
a
b
67.7 ꢀ 12.2
>100
c
d
>100
e
>100
f
>100
a
65.9 ꢀ 9.6
85.8 ꢀ 10.9
79.4 ꢀ 4.6
>100
c
b
b
-FU
0 0
,3 ,5,5 -tetramethylbenzidine (TMB) substrate (TMB Chromogen
3
a
Each value is expressed as mean ꢀ SD of three independent
Solution Single, Zymed Laboratories, Inc., South San Francisco, CA,
and stopped with 1 M sulfuric acid after 10 min. Absorbance was read
at 450 nm with a Safire spectrophotometer (Tecan, Austria) using the
Magellan data analysis software (Tecan, Austria). The 50% inhibitory
concentrations (IC50) were calculated by nonlinear regression analysis
from the dose response relationship as fitted by software ICEstimator
1.2 (http://www.antimalaria-icestimator.net) (Le Nagard, Vincent,
Mentré, & Le Bras, 2011).
determinations.
Positive control.
b
tested samples, only four compounds (3b, 4a-4c, Table 2) exhibited
moderate cytotoxic activity against HT29 cell line (Table 2). The pro-
tected alcohol 3b and its alkylated analog 4b exhibit cytotoxicity
which may be partly responsible for its activity. Moreover, the intro-
duction of the alkyne chain on the nitrogen atom leads to increased
cytotoxicity and can explain the increase antiplasmodial activity.
4
.2 | Synthesis of spirooxindoles and β-carbolines
Experimental procedures and spectral data for new compounds are
detailed in the Supporting Information which is available online.
3
| CONCLUSIONS
In conclusion, we have shown that simplified and easily accessible
analogues of speciophylline had similar ranges of antiplasmodial activ-
ity as the natural product. It seems that the spirooxindole moiety
could be responsible for this biological activity. Moreover, we found
that simple β-carboline analogues presented comparable activities to
the best spirooxindoles derivatives in this study. These results pave
the way for further studies towards the understanding of speciophyl-
line's mode of action and the synergy between the alkaloids from
Guiera senegalensis and Mitragyna inermis.
ACKNOWLEDGMENTS
We thank the Direction Générale de l'Armement (DGA) and the Région
PACA for a doctoral fellowship to D. P. Financial support from the
Centre National de la Recherche Scientifique (CNRS), Aix-Marseille
Université and Centrale Marseille is gratefully acknowledged.
ORCID
Damien Bonne
https://orcid.org/0000-0003-4479-4626

PIERROT ET AL.
5
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How to cite this article: Pierrot D, Sinou V, Bun S-S, et al.
Design and synthesis of simplified speciophylline analogues
and β-carbolines as active molecules against Plasmodium falci-
parum. Drug Dev Res. 2018;1–5. https://doi.org/10.1002/ddr.
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