Synthesis of metergoline analogues and their evaluation as antiplasmodial agents

Article abstract of DOI:10.1039/c3md00310h

A series of compounds based on metergoline were synthesized and evaluated in vitro for their antiplasmodial activity against the chloroquine-sensitive NF54 strain of the malaria parasite Plasmodium falciparum. These compounds were also screened for their cytotoxicity towards a mammalian cell line. Some of the compounds exhibited superior antiplasmodial activity with a good selectivity index relative to metergoline.

Full text of DOI:10.1039/c3md00310h

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Synthesis of metergoline analogues and their
evaluation as antiplasmodial agents†
Cite this: Med. Chem. Commun., 2014,
, 165
5
a
a
a
b
a
Kawaljit Singh, Gurminder Kaur, Faith Mjambili, Peter J. Smith and Kelly Chibale*
A series of compounds based on metergoline were synthesized and evaluated in vitro for their
antiplasmodial activity against the chloroquine-sensitive NF54 strain of the malaria parasite Plasmodium
falciparum. These compounds were also screened for their cytotoxicity towards a mammalian cell line.
Some of the compounds exhibited superior antiplasmodial activity with a good selectivity index relative
to metergoline.
Received 16th October 2013
Accepted 7th December 2013
DOI: 10.1039/c3md00310h
www.rsc.org/medchemcomm
documented use of plant material in traditional medicines for
the treatment of the disease. The aforementioned encouraged
Introduction
6,7
Malaria caused by plasmodia species continues to pose serious us to investigate the potential of metergoline, a semi-synthetic
mortality and morbidity problems. The World Health Organi- ergoline alkaloid derived from the ergoline backbone, which
8
zation has estimated that in 2010, there were 219 million occurs naturally in lower fungi of the genus Claviceps (Fig. 2).
documented cases of malaria. The disease killed between Metergoline is used clinically in disorders associated with
6
60 000 and 1.2 million people in that year, many of whom were hyperprolactinemia, in the inhibition of lactation and in the
1
9
children in Africa. Of the plasmodia species known to cause prophylaxis of migraine headaches. Metergoline has been
1
0,11
malaria, Plasmodium falciparum is the most problematic, mainly documented to have in vitro antifungal activity,
and has been
2
due to its high prevalence and virulence. Currently, there are investigated in the management of psychiatric disorders like
no vaccines available for malaria. For this reason, control relies
on chemotherapy and insect control measures. Antimalarial
drug treatment failure due to emergence of resistance toward
standard antimalarial agents remains a major contributor to
3
the burden of malaria. Thus, the search for novel, structurally
diverse, and affordable drugs with novel mechanisms of action
has become critical in the quest to control and potentially
eradicate malaria.
Since development of new drugs is a lengthy and costly
undertaking, one of the recognised strategies to discover new
therapies against certain diseases is to reposition, repurpose or

nd new uses for drugs that are already used for other indica-
4,5
tions. A number of drugs have been repositioned for the
treatment of malaria in the past few decades. Chemical struc-
4
tures of some selected drugs that have been repositioned for the
treatment of malaria are shown in Fig. 1.
On the other hand the potential of natural products as a
source of antimalarial drugs has been ably demonstrated by the
antimalarial drugs quinine and artemisinin from Cinchona
officinalis and Artemisia annua, respectively, along with the well
a
Department of Chemistry and Institute of Infectious Disease & Molecular Medicine,
University of Cape Town, Rondebosch 7701, South Africa. E-mail: Kelly.Chibale@
uct.ac.za; Fax: +27-21-6505195; Tel: +27-21-6502553
b
Medical School, University of Cape Town, K45, OMB, Groote Schuur Hospital
Observatory, 7925, South Africa
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c3md00310h
Fig. 1 Selected drugs that have been repositioned for the treatment of
malaria.
1
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aromatic, heterocyclic aromatic as well as aliphatic carboxylic
acids (acyclic and cyclic) were used in these reactions. The
selection of the aromatic substituent was mainly based on the
lipophilic (p) and electronic (s) considerations as dened by
17
Craig's plot. In the present study, –F, –Cl, –Br, I, –CF
and –NO substituents were selected to represent electron-
withdrawing (+s) and hydrophobic (+p) substituents; –CN,
COCH and –SO Me were selected for their electron-with-
3 3
, –OCF
2
–
3
2
drawing and hydrophilic (+s/ꢀp) properties, while –OMe group
was representative of electron-donating and hydrophilic (ꢀs/
ꢀ
p) substituent; –SMe, –Et, –nPr and –NMe represented elec-
2
tron-donating and hydrophobic (ꢀs/+p) substituents. All target
Fig. 2 Structure of metergoline.
compounds were puried using column chromatography and
obsessive compulsive disorder, carbon dioxide induced anxiety fully characterized by a range of analytical and spectroscopic
9
,12–14
and premenstrual syndrome.
identied as a novel chemosensitizer to tackle transporter- evaluated for in vitro antiplasmodial activity against the chlo-
Recently, metergoline was techniques (see ESI†). All the synthesized compounds were
15
mediated chloroquine resistance in P. falciparum. In addition roquine-sensitive (CQS) NF54 strain of P. falciparum, and for
quantitative High Throughput Screen (HTS) for delayed death cytotoxicity against a mammalian cell-line, Chinese Hamster
inhibitors of the malaria parasite plasmid on a National Insti- Ovarian (CHO) cell line (Table 1). CQ and artesunate were used
tute of Health (NIH) molecular library also found metergoline to as the reference drugs.
have antiplasmodial activity with an IC50 value of 7.4 mM.
The human system prole of metergoline is well known as it is ycarbamate group from metergoline 1 (Scheme 1), showed
16
Compound 2 obtained aer the removal of benzylox-
9–14
already in clinical use for the treatment of other indications.
activity (IC50, 3.6 mM) comparable to that of metergoline (IC50,
This makes metergoline a promising new antiplasmodial scaf- 3.7 mM) (Table 1), suggesting that the benzyloxycarbamate
fold for repositioning via medicinal chemistry approaches. In group of metergoline may not contribute to the observed anti-
view of this, we explored the potential of this compound as an plasmodial activity. Reaction of amine 2 with various carboxylic
antiplasmodial agent by performing structural modications acids yielded amides with varying activities. Most of the amides
aimed at improving selective antiplasmodial activity.
exhibited micromolar potencies against the NF54 strain of P.
falciparum, with 28 of the 36 compounds having IC50 values
between 0.5 mM and 20 mM (Table 1). First of all, we evaluated
the effect on antiplasmodial activity of aromatic amides
Results and Discussion
In the present study, the ergoline backbone of metergoline was substituted at the 4-position of the phenyl ring. Unsubstituted
retained while the benzyloxycarbamate group was replaced with aromatic amide derivative 3 was found to have poor activity as
various amide groups. The rst step towards structural modi- compared to metergoline with an IC50 value of 24.4 mM.

cation of metergoline involved the removal of the benzylox- Substitution with electron-withdrawing and hydrophobic
ycarbamate group (Fig. 2). This was achieved by the catalytic groups at the 4-position of the phenyl ring yielded compounds
cleavage of commercially available metergoline 1 by hydroge- with varying activities (Table 1, compounds 4–10). Introduction
nation using Pd/C as a catalyst in methanol at room tempera- of a uorine atom (4) and –OCF group (8) at the para-position
3
ture to afford the key amine intermediate 2 (Scheme 1). EDCI- of the phenyl ring resulted in reduced activity. However, intro-
mediated coupling of amine 2 with various carboxylic acids duction of bromo (5), iodo (6), triuoromethyl (7), nitro (9) and
afforded target compounds in reasonable yields (Table 1). chloro (10) groups at the para-position resulted in improved
Compounds 13, 14, 28, 33 and 35 were synthesized by reacting antiplasmodial activities as compared to metergoline
1
amine 2 with the respective acid chlorides in DCM. Substituted (Table 1). In this series, 4-NO substituted amide derivative 9
2
2
Scheme 1 Reagents and conditions: (i) MeOH, H , 10% Pd/C (50% moisture), RT, 16 h. (ii) RCOOH, EDCI, HOBt, DIPEA, DCM, RT, 24 h or RCOCl,
DCM, RT, 3 h.
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was found to be most active with an IC50 value of 0.5 mM and selectivity index value of 33 (Table 1). Heterocyclic alkyl amide
selectivity index value 11. 38 showed better activity (IC , 1.2 mM) as compared to meter-
5
0
In addition, the activity of 4-chloro-substituted derivative goline, alkyl as well as cycloalkyl amides. Here the heteroatom
(10) was also compared with its regioisomers, 2-chloro (11), 3- might be playing an important role in maintaining the favorable
chloro (12) as well as 3,4-dichloro (13) and 2,4-dichlorosub- interactions required for antiplasmodial activity.
stituted (14) amide derivatives and compound 10 was found to From a structure–activity relationship viewpoint, a few
be the most active among them with an IC50 value of 1.3 mM. observations can be made. It is clear that aromatic amide
These results clearly indicated a preference for a para- derivatives (3–22) have a much greater impact on anti-
substituted phenyl ring over the ortho-, meta- and disubstituted plasmodial activity compared to aliphatic amide derivatives
phenyl rings. Derivatives substituted at the para-position with (28–36). These results suggest that the aromatic moiety is
electron-withdrawing and hydrophilic groups like –CN, –COMe necessary to maintain the favourable interactions that maybe
and –SO Me were also synthesized. The 4-CN substituted responsible for antiplasmodial activity. Among aromatic amide
2
derivative 15 showed superior activity with an IC50 value of 0.6 derivatives, para-substituted derivative (10) is more active
mM and demonstrated the best selectivity index value of 188 compared to -ortho, -meta as well as disubstituted amide
(Table 1). However, introduction of –COMe (16) and –SO
2
Me derivatives (11–14). Among aliphatic amide derivatives, cyclic
(17) at the 4-position of the phenyl ring resulted in decreased aliphatic amide derivative (37) was found to be more active and
activity. Introduction of an electron-donating and hydrophilic less cytotoxic as compared to acyclic aliphatic amide derivatives
OMe group at the para-position of the phenyl ring yielded (28–36). Heterocyclic aliphatic amide 38 was found to be the
amide derivative 18 with reduced activity (IC50 ¼ 8.4 mM, Table second most active derivative, reecting the favourable inter-
). However, introduction of an electron-donating and hydro- actions of such systems required for antiplasmodial activity.
phobic groups at the para-position of the phenyl ring yielded In conclusion, a series of compounds have been synthesized
compounds with varying activities (19–22). Amide derivatives and evaluated for antiplasmodial activity through a drug repo-
substituted with –SMe (19), –Et (20) and –N(CH (22) groups sitioning approach. Structural modications were performed
–
1
3 2
)
were found to be less active as compared to metergoline 1 but on metergoline with aromatic, heteroaromatic, aliphatic and
introduction of –nBu group (21) resulted in improved activity aliphatic cyclic amides replacing the benzyloxycarbamate
(
IC50 ¼ 2.0 mM). SAR studies concerning the various substitu- group. Some of the analogues exhibited improved anti-
tion patterns around the phenyl nucleus suggested that most plasmodial activity relative to metergoline against the chloro-
compounds with hydrophobic substituents (5–10, 12–14 and quine-sensitive (CQS) NF54 strain of P. falciparum. Compound
19–21, Table 1) were found to be generally more active than 15, with the cyano substituent in the 4-position of the phenyl
those derivatives with hydrophilic substituents (16–18, Table 1) ring was found to be the most active and with the highest
with the exception of the most active compound 15. Thus, the selectivity index. Overall this work demonstrates the potential of
electronic properties of the substituents did not have a signi- metergoline as a promising potential novel antimalarial
cant impact on the antiplasmodial activity of the compounds. template for repositioning purposes.
Within the context of cytotoxicity, compounds which had the
phenyl ring substituted with hydrophobic groups showed
signicant cytotoxicity on the CHO cell line and therefore dis-
Acknowledgements
played a low selectivity index. The activity of these compounds The University of Cape Town, South African Medical Research
could presumably be due to their cytotoxicity. The best combi- Council, and South African Research Chairs initiative of the
nation of activity and selectivity was found with compound 15 Department of Science and Technology administered through
having an activity of 0.6 mM and a selectivity index of 188. the South African National Research Foundation are gratefully
Heterocyclic aromatic amides, nicotinamide (23), iso- acknowledged for support (KC).
nicotinamide (24), picolinamide (25), pyrazine-2-carboxamide
(
26) and pyrimidine-4-carboxamide (27) derivatives showed IC50
Notes and references
values between 8.4 and 27.4 mM (Table 1). These results indicate
that heterocyclic aromatic systems are not tolerated for this
class of compounds.
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lengths on antiplasmodial activity was also established and it
was observed that derivatives 28 to 36 (Table 1) showed reduced
antiplasmodial activity as compared to metergoline 1. As the
chain length increases, activity also increases and octanamide
derivative 35 was found to be the most active with an IC50 value
of 3.9 mM, which is comparable to metergoline. The effect of
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was also evaluated and found to be detrimental to activity (IC50
,
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