Antiplasmodial, β-haematin inhibition, antitrypanosomal and cytotoxic activity in vitro of novel 4-aminoquinoline 2-imidazolines

Article abstract of DOI:10.1039/b813007h

A novel series of 4-aminoquinoline-containing 2-imidazolines were synthesized via a one-pot 3-component condensation reaction of amine, aldehyde and isocyanoacetate. The products were obtained in high yield as well as purity and were evaluated directly against two strains of Plasmodium falciparum and Trypanosoma brucei. Compound 21 was the most active across all parasites with ED₅₀ = 3.3 nM against a chloroquine (CQ)-sensitive 3D7 strain, ED₅₀ = 33 nM against a CQ-resistant K1 strain and ED₅₀ = 70 nM against T. brucei. Several compounds were able to inhibit formation of β-haematin in vitro, suggesting haemozoin formation in the malaria parasite as a possible target. On the other hand, evaluation against a human KB cell line revealed that the compounds were generally non-cytotoxic to the host cells.

Full text of DOI:10.1039/b813007h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Antiplasmodial, b-haematin inhibition, antitrypanosomal and cytotoxic
activity in vitro of novel 4-aminoquinoline 2-imidazolines†
Chitalu C. Musonda,a Vanessa Yardley,b Renata C. Carvalho de Souza,c Kanyile Ncokazi,a Timothy J. Egana
and Kelly Chibale*a,d
Received 28th July 2008, Accepted 19th September 2008
First published as an Advance Article on the web 24th October 2008
DOI: 10.1039/b813007h
A novel series of 4-aminoquinoline-containing 2-imidazolines were synthesized via a one-pot
3-component condensation reaction of amine, aldehyde and isocyanoacetate. The products were
obtained in high yield as well as purity and were evaluated directly against two strains of Plasmodium
falciparum and Trypanosoma brucei. Compound 21 was the most active across all parasites with ED50
3.3 nM against a chloroquine (CQ)-sensitive 3D7 strain, ED50 = 33 nM against a CQ-resistant K1
strain and ED50 = 70 nM against T. brucei. Several compounds were able to inhibit formation of
=
b-haematin in vitro, suggesting haemozoin formation in the malaria parasite as a possible target. On the
other hand, evaluation against a human KB cell line revealed that the compounds were generally
non-cytotoxic to the host cells.
the global significance of malaria cannot be overemphasized.
Introduction
On the other hand, African trypanosomiasis (sleeping sickness)
affects both humans as human African trypanosomiasis (HAT)
and livestock as nagana in cattle. The causal agent is a parasite
within the Trypanosoma brucei complex2 that is spread to humans
through the bite of a tsetse fly and is believed to infect 300 000–
500 000 people in Africa, mostly in the sub-Saharan regions. If
it remains untreated the disease can be fatal. Unfortunately, the
chemotherapies employed for the treatment of HAT are usually
administered in large doses and are associated with high levels
of toxicity or are expensive (e.g. DL-a-difluoromethylornithine,
DFMO).
Contemporary drug discovery is faced with the challenge of
having to design chemical reactions that are highly efficient.
To this end, reactions that can provide maximum structural
complexity and diversity with minimal synthetic steps to assemble
molecules with therapeutic properties would be attractive.3 One of
the most versatile tools that has emerged as a means to rapidly
identify, generate and optimize lead compounds in the drug
discovery process is combinatorial chemistry.4,5 A survey of the
literature reveals that most drugs on the market are small organic
compounds that contain heterocyclic rings.6,7 However, easy access
and availability of suitably functionalized heterocyclic building
blocks for the synthesis of diverse libraries is rather limited.
Consequently the development of new, efficient and clean synthetic
reactions remains a vital challenge to organic and medicinal
chemists.8
Sub-Saharan Africa remains the most affected global region in
terms of the major parasitic diseases afflicting humanity. For
instance, malaria, a parasitic disease transmitted by the female
species of the Anopheles mosquito, afflicts an estimated 300–
500 million people on an annual basis. Approximately 1–2 million
of these cases result in death.1 Plasmodium falciparum is the causal
agent of malaria, and of the four species that are responsible for
transmission of human malaria, P. falciparum is the most virulent,
accounting for 95% of malaria-related deaths. The problem of
endemic malaria has been exacerbated by the emergence of
widespread resistance to the once first line treatment drugs such
as chloroquine, (CQ) 1, Fig. 1 and others.
Fig. 1
This new dimension to the malaria problem created by the
emergence of multiple drug resistance has prompted the need to
discover new chemotherapeutic agents against the parasite. Thus,
aDepartment of Chemistry, University of Cape Town, Rondebosch 7701,
South Africa. E-mail: Kelly.Chibale@uct.ac.za; Fax: +27 21 689 7499;
Tel: +27 21 650 2553
The multicomponent reaction (MCR)9,10 strategy has sparked
widespread interest in the recent past as a means to discover-
ing biologically interesting entities.11 Multicomponent reactions
(MCRs) involve at least three starting materials in a one-
pot reaction and by far remain the most efficient method of
rapidly introducing molecular diversity. As such they have found
widespread use in organic and diversity-oriented synthesis by
their ability to access highly functionalized molecules in simple
and straightforward one-step transformations.12 Of the many
bDepartment of Infectious & Tropical Diseases, London School of Hygiene
and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
cCentro de Pesquisas Rene´ Rachou, FIOCRUZ, 30190-002 Belo Horizonte,
Brazil
dInstitute of Infectious Disease and Molecular Medicine, University of Cape
Town Medical School, Observatory, 7925, South Africa
† Electronic supplementary information (ESI) available: Experimental
details for the synthesis of all compounds and biological evaluation. See
DOI: 10.1039/b813007h
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MCRs known to date, the most valuable ones are those based on
isocyanides, also known as isocyanide-based MCRs (IMCRs).11
One such very early reaction is the Ugi 4-component condensation
(4CC) reaction10 that combines an amine, aldehyde (or ketone),
carboxylic acid and isocyanide in a single-stage reaction to afford
a-acylamino amides. Various expressions of the Ugi MCR have
been documented,11 with those delivering heterocyclic scaffolds
such as 2-imidazolines being particularly attractive.
Our interest in the 2-imidazoline scaffold stemmed from the
array of biological properties exhibited by compounds containing
this sub-structure. Indeed, imidazoline derivatives exhibit a wide
variety of biological activities including potent antidiabetic13 and
antihypertensive14 properties. Despite the great potential of 2-
imidazolines in chemotherapy, however to our knowledge, they
have not been previously investigated as antimalarial compounds,
or indeed as antiparasitic agents in general. We were thus
interested in exploring the potential of the 2-imidazoline scaffold
as an antiplasmodial as well as an antitrypanosomal entity.
In our15 continued efforts to discover new antiplasmodial and
antitrypanosomal agents by way of established MCRs and known
antiprotozoal pharmacophores, we elected to generate novel 4-
aminoquinoline-containing 2-imidazolines via MCR chemistry.
To this end we set out to explore the potential of hybridizing the
2-imidazoline sub-structure and the 4,7-diaminoquinoline sub-
structure (a well known antimalarial pharmacophore) via the
recently disclosed 3-component condensation of amine, aldehyde
and isocyanoacetate.16
The free base was then formylated by the method described
by Orru et al.,16 whereby a suspension of the amino ester 10 was
refluxed in DCM in the presence of the preformed mixed anhydride
of Ac2O and HCOOH. The resultant formamide 11 was isolated
by repeated dilution of the mixture with water and continued
evaporation without the need to perform any extractive processes.
Using this method of isolation, 11 was obtained in quantitative
yield and with high purity. Finally, dehydration of the formamide
11 to the isocyanide 12 was achieved by treatment of the former
with POCl3 in anhydrous DCM in the presence of 5 equivalents
of Et3N. The low product yield (20%) of 12 was attributed to
the decomposition of the product during column chromatography
of the crude material on the (SiO2) gel column. Unfortunately,
neither use of Et3N-deactivated SiO2 gel nor basic alumina could
improve the yield of 12. Having synthesized 12, we attempted the
multicomponent reaction to generate a modest exploratory library
of the 4-aminoquinoline-containing 2-imidazolines. Deliberately,
we restricted ourselves to the use of amines 3–5 and randomly
chose five aldehydes (13a–e, Scheme 3) and carried out the
multicomponent reactions as described, Scheme 3. The multicom-
ponent reaction to 2-imidazolines was previously optimized as
reported by Orru et al.16 and accordingly, MeOH was found to be
one of the better solvents for the reaction. Thus, our synthesis of
the 2-imidazolines was conducted in MeOH. Orru and co-workers
conducted their synthesis at room temperature in the presence of
a drying agent (Na2SO4) to remove the water produced during the
condensation of amine and aldehyde. Perhaps the low temperature
at which the reactions were performed was responsible for the
prolonged reaction times that were seen with these reactions (up
to 18 h). In our laboratories we found that performing the reactions
at elevated temperatures greatly accelerated the forward reactions
towards formation of the 2-imidazoline heterocycle.
Chemistry
The design of the target 4-aminoquinoline-containing 2-
imidazolines was such that the 4-aminoquinoline substructure
was incorporated in the amine input of the MCR while using
commercially available aldehydes. Thus, the synthesis of the req-
uisite 4-aminoquinoline amines followed the approach reported
previously (Scheme 1)17 in which commercially available 4,7-
dichloroquinoline 2 was treated with a 5-fold excess of terminal
alkyldiamines 3–5 in the absence of solvent, initially at 80 ◦C for
1 h followed by temperature elevation to 135 ◦C for a further 3 h.
In all three cases, the yields were excellent.
Scheme 3 Reagents and conditions i) MeOH, 45 ◦C, 2 h.
Typically, all reactions were allowed to proceed for 20 min
prior to addition of isocyanoacetate 12 and were deemed complete
within a space of 2 h (TLC) after addition of 12. A temperature of
45 ◦C was established to be optimal, although higher temperatures
were tolerated. The preclusion of a drying agent from the reaction
mixtures was found to have no effect on the isolated yields of
the products. The average diastereoselectivity reported by Orru
et al. was 1 : 3 syn vs. anti diastereomer, whereas in our cases
the diastereoselectivites were comparable and in some cases as
high as 1 : 5. Thus on this basis our chosen high temperature of
Scheme 1 Reagents and conditions i) 3–5, 80 ◦C, 1 h then 135 ◦C, 3 h.
Next, commercially available racemic phenylglycine 9 was
esterified via the acid chloride using SOCl2/MeOH at ambient
temperature (Scheme 2).18
Scheme 2 Reagents and conditions i) (a) SOCl2, MeOH, rt, 2 h, (b) K2CO3, MeOH, 15 min, rt, 100%; ii) HCOOH, Ac2O, DCM, reflux, 2 h, 100%;
iii) POCl3, DCM, -25 ◦C, 3 h, 20%.
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Table 1 Isolated yields and structures of 14–28
different strains of the malaria parasite, namely CQ-sensitive
3D7 and CQ-resistant K1, while the determination of compound
cytotoxicity was done on a human KB cell line. The results of these
screens are tabulated in Table 2.
From the results shown in Table 2, it is apparent that most
compounds indeed show great promise as antiplasmodial agents
as most have activities comparable to chloroquine or even better.
In two separate independent experiments, the chloroquine ED50
was determined to be 0.02 mM and 1.03 mM, whereas in a third
experiment (compounds marked ‘b’), the ED50 of chloroquine was
0.16 mM. When the compounds were tested against 3D7, it was
found that 7 out of 15 compounds possessed greater potencies in
comparison to chloroquine (ED50 chloroquine = 0.02 mM). With
an ED50 of 0.34 mM, 14 was the least active, exhibiting 17 times
less efficacy than chloroquine and was the only compound whose
activity did not approach that of the standard drug. As can also
General structure of 4-aminoquinoline-containing 2-imidazolines 14–28
Compound
n
R
% Yield
dr
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1
1
1
1
1
2
2
2
2
2
3
3
3
3
3
H
CH3
84
82
76
86
95
78
55
77
56
96
67
43
74
52
99
—
1 : 3
1 : 3
1 : 3
1 : 4
—
1 : 4
1 : 4
1 : 5
1 : 5
—
1 : 3
1 : 3
1 : 3
1 : 4
Fc
iBu
2¢¢-Furfuryl
H
CH3
Fc
iBu
be seen from the table, the next least active compound, 19 (ED50
=
2¢¢-Furfuryl
H
CH3
0.095 mM) was 5 times less active than chloroquine. On the other
hand, the most potent compound in this assay, 26 (ED50 = 0.00048
mM), showed a 42-fold improvement in activity over chloroquine
in the (CQS) 3D7 strain. In terms of SAR, compounds with the
shortest ethylene spacer 14, 15, 16, 17, and 18 were generally
less efficacious than those with the longer carbon spacers (in the
chloroquine-sensitive strain); in fact the former were all less active
than chloroquine (including 19 and 28). Furthermore, compounds
possessing a substituent at the 5¢-position were generally more
active than unsubstituted compounds except for 28; notably,
compounds with the ferrocenyl (16, 21 and 26) and isobutyl groups
(17, 22 and 27) were the most active among their respective groups.
Another general trend that was seen was that compounds with
Fc
iBu
2¢¢-Furfuryl
45 ◦C did not appear to compromise the diastereoselectivity of
the reaction. Table 1 shows the isolated yields and diastereomeric
ratios of compounds 14–28.
Biological evaluation
In vitro antiplasmodial activity 14–28. The in vitro antiplas-
modial activity of compounds 14–28 were determined on two
Table 2 In vitro antiplasmodial activities of compounds 14–28a
Therapeutic index
Compound
3D7 ED50 (mM)
K1 ED50 (mM)
Cytotoxicity (mM)
a
b
Chloroquine
0.02
1.03
nd
—
1722
2106
808
1889
1326
1182
2283
2550
7435
4297
48246
636
—
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0.34
0.49b
0.54
587.8
99.0
41.2
81.2
111.4
112.3
52.5
8.4
46.8
17.6
111.0
14.0
2.6
1200
183
142
541
293
116
76
255
557
46
241
—
163
305
57
0.047
0.051
0.043
0.084
0.095
0.023
0.0033
0.0063
0.0041
0.0023
0.022
0.00048
0.0020
0.04
0.29
0.15
0.38b
0.97b
0.69b
0.033
0.084
0.38b
0.46b
nd
0.016
0.020
0.44
5375
3047
622
6.1
24.9
a All compounds were screened as diastereomers. b Chloroquine (diphosphate salt of) ED50 was determined as 0.16 mM; nd = not determined; therapeutic
index a = cytotoxicity/3D7 ED50; therapeutic index b = cytotoxicity/K1 ED50.
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Table 3 In vitro inhibition of b-haematin formation by 14–28
the longer 4-carbon spacer 24, 25, 26 and 27 were the more
active within their respective groups. As can be seen from the
table, all compounds show favourable therapeutic indices, with
the most active compound 26 being 5375 times more cytotoxic
to the parasite (3D7) than the mammalian KB cells used in the
cytotoxicity assays. Even more notable was compound 24 whose
cytotoxicity towards the parasite over the mammalian cells was
over 48 000.
Compound
Phib equiv IC50
CQ
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1.91 0.3
5.60 0.1
4.50 0.2
2.68 0.08
3.45 0.3
> 5
4.98 0.07
2.42 0.2
> 5
1.53 0.2
1.41 0.08
3.09 0.4
1.32 0.2
> 5
1.26 0.2
1.35 0.1
Against the chloroquine-resistant K1 strain, the results show
that most compounds had activities comparable to those of
chloroquine except 14, 16, 18, 19, 20 and 28. Ferrocenic compound
26 (ED50 = 0.016 mM) and isobutyl compound 27 (ED50
=
0.02 mM) were again the most potent in the resistant strain within
the modest library.
A similar trend in activity in K1 as seen in 3D7 with regard
to the size of the carbon spacer between the side chain nitrogens
was only observed for compounds 16 vs. 21 vs. 26 and 17 vs.
22 vs. 27. Among these compounds, 26 and 27 showed the
best activities. These two compounds were >100 and >80 times
more active in the chloroquine-resistant strain than the standard
drug chloroquine respectively. Despite their lower antiplasmodial
activities, compounds 15, 16 and 17 all exhibited several hundred-
fold greater efficacy than chloroquine (IC50 = 1.03 mM). The
therapeutic indices reveal that the compounds were generally
nontoxic to the mammalian KB cell line used in the assay. The
low toxicities associated with the compounds are manifest in the
high therapeutic indices obtained, from which it can be seen that
the majority of compounds are over 100 times more cytotoxic to
the parasite than the human cell line. Considering the more active
ferrocenyl and isobutyl-substituted compounds, it is noted that
the former (16, 21 and 26) are generally more cytotoxic than the
latter (17, 22 and 27).
compounds 23 and 24 against the CQ-resistant K1 strain where the
compounds are weaker inhibitors than CQ, it does hold true in the
CQ-sensitive 3D7 strain. However, it must be noted that biological
activity is likely to depend on both b-haematin inhibition and the
degree of accumulation in the food vacuole as a result of pH
trapping. The pH trapping effect is determined by the pKa of the
compounds, which are unknown. Thus a quantitative correlation
is not expected. Overall the strong b-haematin inhibition activity
of these compounds indicates that this is their mode of action.
In vitro antitrypanosomal activity
Determination of the ED50s identified the ferrocenyl compound
21 as the most potent (ED50 = 0.070 mM, Table 4), which besides
this encouraging activity remains far inferior to the efficacy of
the control drug pentamidine. Encouragingly though, 21 exhibits
good selectivity of parasite cytotoxicity over the mammalian KB
cell line used in this assay as is revealed by its high therapeutic index
of 120. Since T. brucei exists in the bloodstream as extracellular
trypomastigotes, the problems that are usually associated with
drug penetration of the macrophage are absent and the compound
is more likely to reach its site of action. In this regard 21 is a
potential valid lead compound.
In vitro inhibition of b-haematin formation
The inhibition of b-haematin formation was determined using
the recently disclosed method called the pyridine hemichrome
inhibition of b-haematin (Phib) assay.19 This high throughput
method was chosen over other assays given its low cost, accuracy
and short assay time. Using the method, compounds are screened
for inhibitory activity below a cut-off point of 5 equivalents
prior to determination of IC50 values. Compounds with values
higher than this cut-off point are not examined further for IC50
determination.
Results for the screen are given in Table 3 and, for comparative
purposes, the Phib IC50 of CQ (the standard) is also given in
the table. It was determined that six of these compounds (22–28,
except 26) were stronger inhibitors of b-haematin formation in
vitro than CQ (IC50 = 1.91 0.3). Among the compounds, 27 was
the strongest inhibitor with an IC50 of 1.26 equivalents. It was also
established that compounds bearing the ferrocenyl subunit (16, 21
and 26) did not inhibit the formation of b-haematin at or below
the desirable cut-off point, suggesting that the compounds are
inhibiting plasmodial growth by other means other than inhibition
of haemozoin formation. Considering the more active inhibitors,
the data suggest that generally there is a correlation between the
antiplasmodial activity and inhibition of b-haematin formation.
This is most clearly evident with compounds 22 and 27 against
both strains. Whilst the same generalization does not hold for
Discussion
The improved activities of the novel 4-aminoquinoline-2-
imidazolines may be speculated to be a result of several factors.
It is known that the 4-amino-7-chloroquinoline subunit is an
antimalarial pharmacophore that inhibits haem dimerization and
crystallization (biomineralization) into nontoxic haemozoin.20
Therefore, the primary antiplasmodial activities associated with
these compounds may be arising from inhibition of haem biomin-
eralization causing a build up of toxic haem, which may result
in parasite death. It is also possible that the increase in basicity
caused by the two nitrogens of the imidazoline ring may be
improving the accumulation of the compounds in the acidic food
vacuole of the parasite via pH trapping.21 The presence of the
heterocycle in the lateral chain may also be resulting in secondary
interactions with other targets apart from haem, resulting in
the observed antiplasmodial activities. Considering the ferrocenyl
compounds 16, 21 and 26, whose antiplasmodial activities seem to
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Table 4 In vitro activity against T. brucei
Compound
ED50 (mg ml-1)
ED50 (mM)
Cytotoxicity ED50 (mg ml-1)
Cytotoxicity ED50 (mM)
Therapeutic index
Pentamidine
Podophyllotoxin
> 0.0001
0.002
13.94
1.83
1.19
1.12
2.25
4.88
1.40
0.43
0.61
1.81
3.93
1.06
0.43
0.38
2.48
> 0.0003
—
34.2
4.3
2.0
2.7
4.7
11.6
3.2
0.07
1.3
3.7
—
—
—
—
—
17
23
21
30
24
10
16
120
36
5
12
6
4
8
5
0.00024
239.9
41.8
24.4
37.7
52.8
47.7
22.9
5.1
22.4
8.6
48.4
6.3
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
587.8
99.0
41.2
81.2
111.4
112.3
52.5
8.4
46.8
17.6
111.0
14.0
2.6
9.0
2.4
0.7
0.8
1.6
3.0
12.5
6.1
4.9
24.9
be superior to those of their counterparts, but did not necessarily
show the strongest inhibition of b-haematin formation, this result
may be explained on the basis of the influence of the ferrocenyl
moiety on the pharmacodynamic behaviour of these compounds.
Previous studies have shown that the ferrocenyl moiety alters
the shape, volume, lipophilicity, basicity and electronic profile of
the parent molecule, and by implication its pharmacodynamic
behaviour.22,23 Ferroquine, the ferrocenyl analogue of chloroquine,
which has been partially studied suggests haemozoin formation to
be the target.24 The aforementioned studies also pointed to the
importance of physico-chemical properties of ferroquine as being
important in the significant antiplasmodial activity displayed by
ferroquine. It may also be possible that the increased lipophilici-
ties of ferrocenic 4-aminoquinoline 2-imidazolines compared to
chloroquine and the other 4-aminoquinoline 2-imidazolines is
favouring their transport across the parasitic cell membrane,
causing much increased concentrations within the parasite. The
lipophilicity may also be important in circumventing chloroquine
resistance for a number of the described 2-imidazolines found
to be more potent than chloroquine against resistant strains. It
is known that the chloroquine resistance mechanism is much
less effective for certain classes of aminoquinolines as already
mentioned. Within the context of lipophilicity, the chloroquine
resistance mechanism does not seem to recognize lipophilic
compounds.25,26 For example, quinolines such as mefloquine are
more lipophilic than 4-aminoquinolines such as chloroquine. It
may be suggested that mutations in the pfcrt gene, the gene
implicated in chloroquine resistance, may not favour or recognize
more lipophilic chloroquine-based 4-aminoquinolines such as the
4-aminoquiniline 2-imidazolines described herein.
of-action studies suggest haemozoin formation to be the target.
Finally, while we acknowledge the inherently high lipophilicities
of the compounds described herein, it must be stressed that the
outlined 3CC strategy can be employed to discover compounds
with improved physicochemical properties. Work to generate other
longer chain-linkers between the aminoquinoline ring and the
imidazoline subunits, as well as new functional groups on the latter
is currently under way in our laboratories and will be reported in
due course elsewhere.
Acknowledgements
This work was supported by the South African National Research
Foundation under grant number 2053362 (KC). The investigation
also received support from UNDP/World Bank/WHO Special
Programme for Research and Training in Tropical Diseases
(TDR) (VY).
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The multicomponent reaction strategy has been exploited to
synthesize novel 4-aminoquinoline-containing 2-imidazolines in
which diversity is introduced in a single step. The compounds
have shown great promise both as antiplasmodial and antitry-
panosomal agents and form the basis of extensive SAR studies in
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