Synthesis and anti-toxoplasmosis activity of 4-arylquinoline-2-carboxylate derivatives

Article abstract of DOI:10.1039/c3ob41539b

A one-step synthesis of 4-arylquinoline-2-carboxylates along with their antiprotozoal activity against the pathogenic parasite Toxoplasma gondii is reported. Mechanistic insights into the role of Lewis acid (silver triflate) versus Bronsted acid (triflic

Full text of DOI:10.1039/c3ob41539b

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Synthesis and anti-toxoplasmosis activity of
4-arylquinoline-2-carboxylate derivatives†
Cite this: DOI: 10.1039/c3ob41539b
James McNulty,*a Ramesh Vemula,a Claudia Bordón,b Robert Yolkenb and
Received 26th July 2013,
Accepted 16th November 2013
Lorraine Jones-Brandob
DOI: 10.1039/c3ob41539b
www.rsc.org/obc
A one-step synthesis of 4-arylquinoline-2-carboxylates along with prior to the advent of multidrug resistance. The quinolone
their antiprotozoal activity against the pathogenic parasite Toxo- derivative endochin (Scheme 1) was reported to possess anti-
plasma gondii is reported. Mechanistic insights into the role of malarial activity as early as 1948,1b and has led to the recent
Lewis acid (silver triflate) versus Bronsted acid (triflic acid) catalysis emergence of the synthetic quinolone-3-diarylether ELQ-300 as
are revealed clarifying aspects of the mechanism of the quinoline a potent antimalarial agent, active against multidrug resistant
synthesis.
strains of Plasmodium sp.1c Related quinolone-3-diarylethers
have also demonstrated potent activity to Toxoplasma gondii,
the parasite responsible for toxoplasmosis.
Quinoline alkaloids and synthetic small-molecule analogues
have been well documented to possess important antiproto-
zoal biological activities,1 particularly antimalarial activity. In
addition, quinolines demonstrate activity against a wider
range of targets including use as antibacterial, anticancer,
antiviral and antiasthmatic agents.2 Classic antiprotozoal
quinolines include the cinchona alkaloid quinine, one of the
longest serving, continuously used pharmaceuticals (over 300
years) and the synthetic derivatives chloroquine and meflo-
quine (Scheme 1). These compounds were utilised as standard
therapeutics in the treatment of malaria for many decades
Functionalised 4-quinoline-2-carboxylate derivatives substi-
tuted with either a 4-arylether (Scheme 1, A) or 4-aryl substitu-
ent alone (Scheme 1, B) have long been known to possess
antiprotozoal activity1e although, to our knowledge, their
activity against T. gondii has not been specifically assessed. In
addition quinoline-2-carboxylate derivatives have proven their
value as important ligands in various transition metal cata-
lyzed reactions.3 Literature methods to access quinolines
through classical approaches generally involve harsh con-
ditions, such as treatment with Lewis or Bronsted acids and/or
high temperatures.4 As a means of developing a mild, catalytic
entry to functionalised quinoline-2-carboxylates (Scheme 1, B),
we became attracted to recent developments involving
the
three-component
condensation–cyclization–oxidation
sequence of an aldehyde, terminal alkyne and functionalised
aniline (Scheme 2, general reaction).
This overall quinoline synthesis has previously been shown
to be catalyzed by a wide range of electrophilic species includ-
ing acid-modified clay,5d iodine,5f as well as heterogeneous
copper,5a,b,e,g gold,5b iron,5c,j and, very recently, silver salts
under thermal conditions.5h,i The three-component coupling
process may mechanistically be viewed to proceed via sub-
sequent cyclisation of the A3 Mannich-type condensation
product, Scheme 3, path A.5b The A3 reaction was originally
Scheme 1 Biologically active quinolines and quinolones.
aDepartment of Chemistry and Chemical Biology, McMaster University, Hamilton,
Ontario, Canada L8S 4M1. E-mail: jmcnult@mcmaster.ca; Fax: (+1)-905-5222509;
Tel: (+1)-905-525-9140, Ext. 27393
bStanley Division of Developmental Neurovirology, Department of Pediatrics,
Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore,
Maryland 21287, USA
†Electronic supplementary information (ESI) available: General experimental
details, procedures, NMR and MS data for new compounds. See DOI: 10.1039/
c3ob41539b
Scheme 2 Three component condensation leading to 4-arylquinoline-
2-carboxylate derivatives.
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Table 1 Screening of various silver salts to effect the three-component
condensation reactiona
Entry
Catalyst
Yield (%)
1
2
3
4
5
6
7
8
Ag2O
0
0
25
0
89
29
27
0
AgNO2
AgNO3
AgOAc
AgOTf
Ag2SO4
AgOTs
Ag2CO3
Scheme 3 Possible mechanistic pathways leading to 4-arylquinoline-
2-carboxylate derivatives.
a Reaction conditions: phenyl acetylene (0.09 mmol, 1.0 eq.),
ethylglyoxalate (0.19 mmol, 1.0 eq.), p-anisidine (0.19 mmol, 2.0 eq.),
catalyst (20 mol%), CH2Cl2 (0.5 mL), 50 °C, 48 h.
described by Ishii and co-workers using an iridium catalyst,6a
and subsequently shown to be effected by silver species by the
groups of Li6b and Navarro.6c Alternatively, the quinoline may
arise as the inverse-electron demand cycloadduct of the imine
(A2 adduct) and alkyne via a Povarov reaction, path B. In fact,
several proposals have been made for these cyclization and oxi-
dation steps, including the order of these steps, involving
either concerted (Povarov and Doebner–Miller types) or various
stepwise cycloadditions as well as the involvement of direct
aryl CH-activation,5h a process that requires an aryl silver inter-
mediate. Our group has recently demonstrated the use of silver
salts and homogeneous catalysts of type L2AgX in alkyne acti-
vation, describing the first examples of the silver catalyzed
Husigen cycloaddition.7 As all steps in the above 3-component
quinoline synthesis appear amenable to silver catalysis, we
decided to investigate the use of ethyl glyoxylate5f,g in the reac-
tion under mild silver-catalyzed conditions (not previously
investigated) in order to access 4-arylquinoline-2-carboxylates.
Herein we report the first, surprisingly mild, silver promoted
three-component coupling to produce 4-arylquinoline-2-car-
boxylates and the anti-toxoplasmosis structure activity relation-
ship within the library of derivatives prepared. The mild
conditions employed provided a unique opportunity to probe
and clarify aspects of the mechanism uncovering a previously
unknown distinction between the Lewis acid and Bronsted
acid catalysed variants of the process, and development of a
coherent mechanistic view on two divergent reaction
sequences.
to 50 °C in a sealed tube (teflon-capped microwave vial)
to achieve high conversion, for example proceeding to
only 37% conversion over 48 h when performed at room
temperature.
We next investigated the generality of the reaction using a
variety of substituted phenyl acetylenes which gratifyingly
provided the corresponding quinolines in excellent yields
(Table 2, entries 1–8). We further investigated the scope of the
reaction by using a small selection of substituted anilines
(Table 2, entries 9–12) which provided the desired 4-arylquino-
lone-2-carboxylates in good to excellent isolated yields. We
note that Li and co-workers6b and subsequently Chan and co-
workers8 have reported the synthesis of only A3-type adducts,
not quinolines, employing silver iodide and silver triflate as
catalyst respectively. We were able to repeat this work, however
we noted the slow formation of quinolines, which could
readily be detected in the reaction under Chan’s conditions
(3–4% quinoline after 1 h).
Returning to the mechanism of this quinoline synthesis, we
noted immediately that in all cases investigated (Table 1)
metallic silver slowly precipitates during the reaction, in contrast
to our previous studies employing stable ligated silver(I) com-
plexes.7 In addition, given the low solubility of such silver salts
in organic solvents, we felt it necessary to distinguish a direct
heterogeneous silver(I) catalyzed process from a possible
Bronsted-acid catalyzed possibility. To probe the mechanism
of the reaction, we conducted the two initial control experi-
ments shown in Scheme 4. Imine 5 was prepared in 75% yield
through condensation of p-anisidine with ethyl glyoxylate.
Treatment of the imine 5 under the conditions of the quino-
line synthesis in the presence of deuterium oxide but absence
of phenylacetylene led to no detectable incorporation of deu-
terium at the ortho-position (Scheme 4, i). This result is in con-
trast to the results of Zhu et al.,5h who under more forcing
conditions, including the use of triflic acid, reported 57% deu-
terium incorporation.
We initially screened a series of the silver salts AgO, AgNO2,
AgNO3, AgOAc, AgOTf, Ag2SO4, AgOTs and Ag2CO3 as hetero-
geneous catalysts for this reaction using phenylacetylene,
ethylglyoxylate and p-anisidine as standard substrates in
dichloromethane at 50 °C for 48 h (Table 1). Most of these
silver sources provided little or no product formation with the
exception of silver triflate which yielded the quinoline product
in 89% yield (Table 1, entry 5). We next investigated standard
solvents (toluene, acetonitrile, tetrahydrofuran etc.) for the
silver triflate catalysed process, however dichloromethane
proved most suitable. The optimal reaction required heating
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Table 2 Scope of the AgOTf catalysed process leading to 4-arylquino-
line-2-carboxylates
Yield
(%)
Yield
(%)
Entry
1
Product
Entry
7
Product
89
91
Scheme 5 Quinolines are formed from both silver and proton catalysed
processes in both the three component and two component cyclisa-
tion/oxidation cascades.
2
97
8
83
mild conditions and that C–H activation plays no role in this
present process (Table 2). We also performed the quinoline
synthesis under our standard reaction conditions (Scheme 4,
ii) but using deuterated phenylacetylene prepared from phenyl-
acetylene with n-BuLi and D2O.9 The quinoline was isolated
with no detectable trace of deuterium incorporation, a result
fully in accord with the intermediacy of a silver acetylide inter-
mediate in this reaction.
We now focussed attempts on differentiating a silver(I)
mediated pathway from the alternative proton catalysed
process. First of all, we determined that the quinoline syn-
thesis was readily achieved using either silver triflate as cata-
lyst or a catalytic amount of triflic acid alone; that is in the
complete absence of the π-acidic silver salt (Scheme 5, i).
Either two distinct pathways are operative for the three-com-
ponent coupling/cycloaddition/oxidation leading to the quino-
line, or else a similar process is amenable to both Lewis acid
and Bronsted acid catalysis. We next determined that the
imine 5 also reacts with phenylacetylene using triflic acid
alone, under the standard reaction conditions or even at room
temperature to give the quinoline product in good yield
(Scheme 5, ii). This second result indicates the quinoline may
be the product of either a Povarov inverse electron demand
[4 + 2]-cycloaddition or may be derived from the Mannich type
addition product through subsequent electrophilic cyclization,
among other possibilities.
3
4
97
82
9
23
66
10
5
6
97
90
11
12
18
55
4ha – mixture of regioisomers in the ratio of 75 : 25.
To our delight, we were now able to successfully differen-
tiate these pathways as described in Scheme 6. Following the
procedure of Chan et al.8 we prepared the α-amino alkyne 6
from imine 5 and phenyl acetylene (silver triflate, CH2Cl2, r.t.,
60 min). Compound 6 readily entered into reaction with silver
triflate to slowly generate the quinoline, even at room tempera-
ture. Addition of phenyl acetylene to imine 5 yielding 6 is not
a reversible process and so this result firmly places the
Scheme 4 Control experiments demonstrating the non-involvement of
silver mediated aryl C–H activation and involvement of silver acetylide in
the quinoline synthesis.
This result was taken as evidence of the involvement of an
aryl–silver species in the actual reaction. We conclude from
Scheme 6 Differentiation of the silver(I) versus proton catalysed quino-
the present results that quinoline formation occurs under lone synthesis from the amino-alkyne 6.
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α-amino alkyne 6 on a late pathway leading to the quinoline in and median cytotoxic dose (TD50) were calculated using Calcu-
the silver- mediated sequence. However, we now discovered Syn software (Biosoft, Cambridge, U.K.). For each compound, a
that compound 6 does not cyclise to the quinoline under the therapeutic index (TI) was calculated with the formula TI =
standard reaction conditions when treated with catalytic quan- TD50/IC50. This number reflects the specific activity of a com-
tities of triflic acid. Given the successful quinoline syntheses pound against Toxoplasma. Trimethoprim, a folate antagonist
achieved with triflic acid catalysis outline in Scheme 5, the commonly employed for toxoplasmosis therapy in humans
overall results demonstrate that the α-amino alkyne 6 is not an was used as the assay positive control. Of the 12 4-aryl-quino-
intermediate towards the quinolines in the proton catalysed line derivatives tested, the chloro and methyl-substituted-4-aryl
pathway. Given that C–H activation is not an option under analogues 4a, 4b and 4f analogs displayed good efficacy rela-
these metal free conditions, the only reasonable possibility is tive to control trimethoprim as did two of the ring-A methyl
that the quinoline is the product of a Povarov inverse electron and methylenedioxy-derivatives 4h and 4k. These derivatives
demand cycloaddition in the proton-mediated pathway. were similar in potency, inhibiting T. gondii growth with IC50
The overall process leading to the quinoline from the ranging from 34 to 85 µM.
α-amino alkyne 6 involves both a cyclization and oxidation
In addition, as shown in Table 3, three of these potent
process, although the order of these steps is not known. Many derivatives, compounds 4b, 4h and 4k proved to be relatively
other attempts were made to prepare the quinoline from com- noncytotoxic (TD50 ≥ 320 µM) thus improving their potential
pound 6 under silver-free conditions. For example reaction as valuable hits towards the development of a potent and selec-
with various organic or inorganic bases (Hunig’s base, cesium tive agent against T. gondii.
carbonate etc.) or electrophilic oxidants (DDQ, iodine and
The red/green invasion assay10b allowed us to evaluate the
NBS) failed to deliver any detectable quinoline from com- compounds for inhibition of host cell invasion by the tachy-
pound 6. This result echos conclusions draw by Wang and co- zoites using fluorescent labels to distinguish tachyzoites that
workers on a related AuCl/CuBr mediated process.5b It appears had actively penetrated the cells from those that were attached
that the silver(I) catalyst is effectual in promoting cyclization but unable to enter the host cells. A decrease in the number of
from the π-activation of 6, similar to AuCl3, followed by oxi- penetrated parasites (Fig. 1, green bars) relative to the vehicle
dation leading to the quinoline. In contrast, the proton cata- [DMSO (VHL)] is indicative of invasion inhibition. Of the com-
lysed 2 or 3 component quinoline synthesis described in pounds tested, only 4a significantly inhibited invasion (P =
Scheme 5, proceeds via a distinct pathway in accord with the 0.05, two-tailed Students’ t-test). An overall decrease in both
classical Povarov reaction. The overall pathways operative for attached and invaded parasites strongly indicates an inhibitory
both the silver (path A) and proton (path B) catalysed routes to effect on parasite attachment, an essential prerequisite for
the quinolines are summarised in Scheme 3.
invasion. Compound 4a was the only derivative that
Returning to the antiprotozoal activity of the quinoline approached significance (P = 0.06, one-tailed Students’ t-test)
derivatives, 4-arylquinoline-2-carboxylate derivatives have long in inhibition of tachyzoite attachment. Finally, these same
been known to possess antiprotozoal activity.1e We employed a derivatives were examined for the ability to inhibit intracellular
published colorimetric assay10 to screen the synthesized 4-aryl- replication of tachyzoites in an established infection of host
quinoline derivatives for the ability to inhibit the in vitro cells using a fluorescence based replication assay.10b None of
growth of a closely related protozoan, T. gondii RH-2F (50839; the compounds showed inhibitory activity in this assay (data
ATCC, VA) using human foreskin fibroblasts (HFF; ATCC) for not shown).
host cells. Briefly, diluted compounds were added to HFF cells
In conclusion, we report the synthesis and selective anti-
growing in 96-well tissue culture plates. Beginning at 320 µM, protozoal activity of a series of 4-arylquinoline-2-carboxylate
drugs were serially diluted across the plate by dilutions of 0.5 derivatives. The synthesis of these compounds involved a silver(I)
log10. T. gondii tachyzoites that constitutively express β-galacto- mediated three-component coupling, cyclization, oxidation
sidase (β-gal) were added to most wells, leaving 2 wells in each sequence. The sequence takes place under mild conditions
column parasite-free for cytotoxicity testing. The substrate for through a process that does not require aryl C–H activation.
β-gal, chlorophenol red-β-D-galactopyranoside (CPRG), was Furthermore, independent synthesis and reaction of various
added to the Toxoplasma wells after 4 days of incubation at intermediates in the reaction sequence allowed clear differen-
37 °C/5% CO2. Further incubation for 20 h was followed by tiation the silver(I) mediated cascade from a different route to
addition of the cell viability reagent, CellTiter 96Aqueous One the same quinolines that is solely Bronsted acid catalysed. Bio-
Solution Reagent (Promega Corp., WI) to the uninfected cyto- logical screening allowed us to identify five 4-arylquinoline
toxicity wells. Color reactions in all wells were then read in a derivatives demonstrating selective anti-toxoplasmosis activity.
Vmax microplate reader (Molecular Devices, CA) after 3 h of The most potent derivative, i.e., with the lowest IC50, com-
incubation. The amount of absorbance (570–650 nm) in wells pound 4a, was shown to inhibit host cell invasion but not the
containing drug, Toxoplasma, and CPRG was compared to that replication of tachyzoites that had already invaded cells and
in parasite control wells. In the cytotoxicity wells, the bioreduc- established an infection. While the target and mechanism are
tion of the cell viability reagent by viable cells into a soluble, not clear, these results are consistent with the inability of the
colored formazan product was captured by reading the plates quinoline to cross the host cell membrane or being subject to
at 490–650 nm. The median inhibitory concentration (IC50) active efflux from the host cell. In either case, these results
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Table 3 Anti-toxoplasmosis activity of 4-arylquinolines
IC50
(μM)
IC90
(μM)
TD50
(μM)
Entry
1
Compound
TIa
4
4a
34.0
148
125
2
3
4b
4c
63.0
178
>320
>320
9
>320
NDb
ND
Fig. 1 Quantification of invasion inhibition by 4-arylquinolines using
red/green assay. Compounds (10 µM) were tested for activity directly on
extracellular tachyzoites using an established method.10b Green bars
represent invaded/intracellular parasites; red bars depict attached/extra-
cellular parasites. Data are mean values
SEM of three independent
experiments. * Tachyzoite invasion was significantly lower (P = 0.05,
two-tailed Student’s t-test) than the VHL control.
4
5
4d
4e
104
187
230
279
123
212
1
1
suggest immediate strategies for modulating the activity
through modifying lipophilicity or co-administering the
quinolines with efflux inhibitors. Further developments of
the process and optimization of the current hit compounds
through formation of 4-arylether and other analogues
in pursuit of a potent, selective anti toxoplasmosis agent are
currently under investigation.
6
7
4f
42.0
141
ND
99
2
4g
>320
>320
ND
Acknowledgements
We thank NSERC, Cytec Canada Inc. (JMcN, RV) and the
Stanley Medical Research Institute (CB, RY, LJB) for financial
support of this work.
8
4h
4i
4j
4k
4
85.0
>320
124
200
ND
625
162
ND
>320
>320
>320
>320
>320
7
ND
5
Notes and references
9
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