Close the ring to break the cycle: Tandem quinolone-alkyne-cyclisation gives access to tricyclic pyrrolo[1,2-: A] quinolin-5-ones with potent anti-protozoal activity

Article abstract of DOI:10.1039/c9cc01689a

Expanding the chemical space of quinolones led to a tandem quinolone-alkyne-cyclisation reaction allowing chemoselective control of the synthesis of tricyclic pyrrolo[1,2-a]quinolin-5-ones. Importantly, we discovered anti-protozoal activity against Plasmodium and Toxoplasma with specific potency of one of the compounds against the liver stage of the malaria parasite in the nanomolar range.

Full text of DOI:10.1039/c9cc01689a

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DOI: 10.1039/C9CC01689A
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Close the ring to break the cycle: Tandem quinolone-alkyne-
cyclisation gives access to tricyclic pyrrolo[1,2-a]quinolin-5-ones
with potent anti-protozoal activity
Received 00th January 20xx,
Accepted 00th January 20xx
Dávid Szamosvári,a Kayla Sylvester,b Philipp Schmid,a Kuan-Yi Lu,b Emily R. Derbyshire *bc and
Thomas Böttcher *a
DOI: 10.1039/x0xx00000x
quinolines and 4(1H)-quinolones have been described as anti-
plasmodial agents. These include natural products like aurachine E15
or furoquinolines16 as well as the quinolone related, synthetic
tricyclic acridinediones and acridones.17 Hereby the fusion side of the
ring on the quinolone seems to be a critical factor for antiplasmodial
activity. While ortho-ring fusion b sides are common and enable
activity, c side fused-4(1H)-quinolones that lock the 4-position, such
Expanding the chemical space of quinolones led to a tandem
quinolone-alkyne-cyclisation reaction allowing chemoselective
control of the synthesis of tricyclic pyrrolo[1,2-a]quinolin-5-ones.
Importantly, we discovered anti-protozoal activity against
Plasmodium and Toxoplasma with specific potency of one of the
compounds against the liver stage of the malaria parasite in the
nanomolar range.
as aurachines
A
and H, were inactive against protozoa.15
Quinolines and quinolones are privileged structures that are
common features in a large variety of medically valuable natural
products and artificial drugs.1-3 Many of them exhibit antibiotic4, 5
Interestingly, a side fused 4(1H)-quinolones including position 1
nitrogen have so far not been investigated for their antiprotozoal
potential. We thus envisioned a simple synthesis giving access to new
tricyclic 4-quinolone compounds to study their activity against
protozoal pathogens. Here, we report synthetic access to previously
undescribed pyrrolo[1,2-a]quinolin-5-ones by a tandem cyclization
reaction involving a Camps reaction and the nucleophilic addition on
an alkyne moiety. In addition, we show that these tricyclic
quinolinones display antiprotozoal activity and are especially potent
against the liver stage of Plasmodium. Our pyrrolo[1,2-a]quinolin-5-
ones represent the first examples of antiprotozoan compounds
based on this tricyclic core which may be useful for future drug
development efforts. In particular new scaffolds with antiplasmodial
activity are desirable to address parasite resistance to existing
quinolone-based drugs.
7
and antiprotozoal activities.6, While 3-carboxy-4(1H)-quinolones
inhibit topoisomerases and thus replication, 2-alkyl-4(1H)-
quinolones (AQs) and their N-oxides (AQNOs) are known to target
proteins of the electron transport chain in Gram-positive bacteria,
mycobacteria and protozoa.1 We have recently demonstrated that
one of the various naturally produced AQNOs of the human
pathogen P. aeruginosa
– a trans-unsaturated 2-nonenyl-4-
quinolone N-oxide (trans-Δ1-NQNO) – is particularly potent against S.
aureus.8 While the saturated AQNO congeners were considerably
less active or inactive against S. aureus,8 saturated AQNOs such as 2-
dodecyl-4-quinolone N-oxide (DQNO) are potent anti-protozoal
agents with activity against Plasmodium falciparum and Toxoplasma
gondii parasites.9-12 These 4(1H)-quinolones and their N-oxides are
dual inhibitors of the electron transport chain of protozoa via type II
NADH:ubiquinone oxidoreductase (PfNDH2 and TgNDH2) and the
cytochrome bc1 complex.11-13 In Mycobacterium tuberculosis
structurally related 4(1H)-quinolones inhibited NADH:menaquinone
oxidoreductase (Ndh).14 In addition, ortho- and peri-fused tricyclic
We started by comparing the activities of the native saturated and
unsaturated AQs and AQNOs of P. aeruginosa against the blood and
liver stage of the Plasmodium parasite that causes malaria, and
against Toxoplasma gondii, the causative agent of toxoplasmosis.
The synthesis of the saturated AQs (1-4) and AQNOs (5-8) was
described previously.8 At concentrations of 5 µg/mL all tested AQs
and AQNOs were highly potent against Plasmodium and Toxoplasma,
demonstrating the general activity of the 4-quinolone scaffold is
largely independent of its alkyl side chain length (Fig. 1). Most
notably, infection of human red blood cells by Plasmodium
falciparum was fully abrogated by all compounds at 5 µg/mL.
a. Department of Chemistry, Konstanz Research School Chemical Biology,
Zukunftskolleg, University of Konstanz, 78457 Konstanz, Germany. E-mail:
Thomas.Boettcher@uni-konstanz.de
b. Department of Molecular Genetics and Microbiology, School of Medicine, Duke
University, Durham, North Carolina 27708 USA.
c. Department of Chemistry, Duke University, Durham, North Carolina 27708 USA.
E-mail: Emily.Derbyshire@duke.edu.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C9CC01689A
Scheme 1. Synthesis of furo[2,3-b]quinolones 11 and 13.
The more polar solvent tert-butanol seemed to facilitate
lactam-lactim tautomerization of the 2- quinolone amide group
to its 2-hydroxyquinoline that reacts in an intramolecular
nucleophilic addition with the sp1-carbon of the triple bond to
perform a second, consecutive ring closure after the alkyne-
zipper-induced Camps cyclization. The reaction mechanism via
the 3-alkynyl-2(1H)-quinolone was confirmed by base
treatment of the isolated 2-quinolone 10 bypassing the alkyne
zipper to receive 11 in 64% yield which proofed to be the
limiting factor for the synthesis of the furo[2,3-b]quinolones
during the tandem reaction. When oct-3-ynamide 12a was used
as substrate under the same conditions, yield of the
furoquinoline 13 in the tandem reaction could be increased to
32% (Scheme 1). Cyclization reactions of similar 2-quinolones
and 2-pyridones that depend on iodide or copper(I) iodide
catalysts are known.22, 23 While our tandem mechanism allows
a new rapid synthesis of furo[2,3-b]quinolones, this compound
Fig. 1 (A) Synthetic route for the generation of natural saturated and
unsaturated AQs (1-4) and AQNOs (5-8). (B) Activity of compounds 1-
8 against protozoa.
Parasite loads of Plasmodium berghei in liver HuH7 cells decreased
by one to three orders of magnitude and T. gondii parasite load
decreased by two orders of magnitude. No major differences were
found in the activity between AQs and AQNOs, and saturated and
unsaturated compounds, in all three protozoan infection models.
This result was particularly interesting since AQs were virtually
inactive against S. aureus, suggesting that a greater diversity of
substitutions at the nitrogen could be tolerated for compounds
against protozoa. We next aimed to expand the chemical space
by the synthesis of novel tricyclic quinolone-derived scaffolds.
Since alkynes are known to engage in diverse rearrangement
class itself is already known for its antiprotozoal activity 16, 24
We
.
speculated that Δ2-2-alkynyl-4(1H)-quinolones could give access
to new tricyclic cores when the α-position of the amide was
blocked and hence obstructed 2-quinolone formation.
and annulation reactions 18, 19
quinolones could give access to the corresponding tricycles
,
we explored if alkynylated 4(1H)-
We
.
We synthesized 2,2-dimethyl-oct-3-ynamide 14d and subjected
it to the same conditions that enabled the tandem reaction
leading to furoquinolones. As expected, Camps cyclization to
the 2(1H)-quinolone product was prevented and the 4(1H)-
quinolone 14 was isolated as a minor reaction product. The
major product was isolated and identified as 1-butyl-3,3-
first focused on the synthesis of Δ1-2-pentynyl-4(1H)-quinolone
(9) with an alkyne group directly at the position 2. The only
method for the synthesis of similar 2-alkynyl-4-quinolone was
described by Wube et al.20 who reacted N-alkyl isatoic acid
anhydride with 3-alkynyl-2-ones to obtain N-alkyl-2-alkynyl-4-
quinolones after the procedure of Coppola.21 This method could
not be applied for our non-N-alkylated target compound
therefore we used previous Camps cyclization conditions for
amide 9a to give the desired compound 9. Interestingly, we
could also isolate the 2-quinolone 10 as the main product of the
reaction which required a 1,2 shift of the triple bond. Activation
by the electron withdrawing carbonyl of the amide group next
to the triple bond likely facilitated deprotonation and thereby
induction of an alkyne-zipper reaction that enabled the ring
closure to the 3,4-disubstituted-2(1H)-quinolone product by
Camps cyclization (Scheme S1A). Since the chemoselectivity of
this alkyne-zipper-induced Camps cyclization was surprising, we
screened different reaction conditions (Table S1). The 4-
quinolone product was obtained only in low yields under all
conditions and always as byproduct with its 2-quinolone isomer.
The ring closure to the 2-quinolone was generally preferred in
presence of weak (CsCO3) or bulky base (tert-BuOK). These
conditions may have favored induction of the alkyne shift over
α-deprotonation of the acetophenone. When using tert-butanol
as solvent instead of 1,4-dioxane with either CsCO3 or tert-BuOK
under reflux conditions (83°C), we could surprisingly observe
the formation of a third product identified as 2-ethyl-4-
methylfuro[2,3-b]quinoline 11.
dimethylpyrrolo[1,2-a]quinolin-5(3H)-one 15,
a
tricyclic
compound with a previously undescribed scaffold which
presumably was formed by addition of the quinolone-nitrogen
on the alkyne. To investigate the synthesis of this
pyrroloquinolin-5-one structure, we screened the reaction for
chemoselectivity under identical reaction conditions as for the
furoquinolones.
4(1H)-Quinolone (14) formation was generally facilitated by
strong bases like NaOH and tert-BuOK independent of
temperature and whether a protic (tert-butanol) or aprotic
solvent (1,4-dioxane) was used. Only in combination with the
more polar solvent tert-butanol, CsCO3 induced Camps
cyclization in very low yields. In 1,4-dioxane at 75 °C with tert-
BuOK as base, trace amounts of the endocyclic unsaturated
pyrrolo[1,2-a]quinolin-5-one (15) were observed, while under
reflux traces of only an exocyclic unsaturated product, 3,3-
dimethyl-2,3-dihydropyrrolo[1,2-a]quinolin-5-one (16) were
obtained. With the protic solvent tert-butanol, cyclization of 14
to the endocyclic unsaturated tricycle 15 increased drastically
with either NaOH (yield 35%) or tert-BuOK (yield 57%). In order
to mechanistically dissect these reactions, we used an up-scaled
preparation of 2-alkynyl-4(1H)-quinolone 14 which was
subsequently investigated in cyclisation reactions to the
pyrrolo[1,2-a]quinolin-5-ones 15 and 16. In tert-butanol under
2 | J. Name., 2012, 00, 1-3
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reflux with tert-BuOK, 15 was obtained in 55% yield, confirming
that the reaction proceeded via the 4(1H)-quinolone. However,
under these conditions the constitutional isomer 16 was not
detectable. This phenomenon suggests that 15 was the kinetic
product whereas the thermodynamically more favorable
product 16 with lower strain in the fused pyrrolidine ring would
form at higher temperature (Table 1A). Motivated by the
perspective of chemoselective synthesis of the unprecedented
scaffold of 16, we tested solvents with higher boiling points.
While Ph2O and DMSO gave no product or a complex mixture of
products, DMF at 100°C selectively facilitated the cyclization of
14 to 16 in yields of 27% without formation of 15. Temperature
increase or longer reaction times had no or rather adverse
effects on the yield of 16 (Table 1B). Interestingly, from the
same reaction we could also identify the dienylquinolones 17
and 18 (Scheme S1B), suggesting the formation of 16 via the
allene as the initial step of an alkyne-zipper reaction similar to
the reaction towards furoquinolines (Scheme S1C). Previously
reported syntheses of pyrrolo[1,2-a]quinoline-5-ones were
dependent on pyrrolidine or pyrrolidine-2-one precursors and
View Article Online
DOI: 10.1039/C9CC01689A
Fig. 2 (A) Activity of tricyclic compounds 11, 15 and 16 against
protozoa. Potency reported as IC50s in g/mL. P. berghei and T. gondii
loads were evaluated in human liver HuH7 cells while P. falciparum
load was evaluated in human red blood cells. (B) Dose-dependent
activity of 15 against various parasites. (C) Visualization of P. berghei
growth in liver HuH7 cells in the presence of 15 (0.37 M) and
atovaquone (1 nM). Representative images were shown. Scale bar is
10 m. (D) Quantification of parasite size in the presence of 15 and
atovaquone (ATV). p-value <0.0001 (****).
therefore contained only fully saturated pyrrolo-units 25-28
here provide the first example of chemoselectiv ly synthesized
.
We
e
unsaturated pyrrolo[1,2-a]quinolin-5-ones 15 and 16 that extend
Table 1 Optimization of reaction conditions.
O
N
O
N
A
the chemical space of this so far rather unexplored class of
pyrrolo[1,2-a]quinolin-5-ones. To determine if these new
scaffolds have biological activities similar to quinolines and
O
O
base (3 eq.)
+
+
N
solvent, temp., 2h
H
N
H
O
quinolones, their antiparasitic activity was profiled
.
14d
14
15
16
We hereby investigated the anti-protozoal activity of novel
tricyclic compounds. All compounds exhibited only moderate
activity against the blood stage of P. falciparum (Fig. 2A). While
the furo[2,3-b]quinolone was generally the least active
compound, the pyrrolo[1,2-a]quinolin-5-ones 15 and 16 gave
IC50 values of 3.2 µg/mL and 7.0 µg/mL against T. gondii. The
compounds were particularly active against the liver stage of P.
berghei. Here, 15 and 16 exhibited IC50 values of 0.038 µg/mL
and 0.25 µg/mL corresponding to activity in the nanomolar
range (142 nM and 935 nM, respectively). Importantly, 15 did
not affect human liver cell (HuH7) viability up to 50 µg/mL,
indicating a favorable selectivity index (Fig. 2B, Fig S3). While
the scaffold structure of 15 and 16 differs only in the endo- and
exocyclic double bond of the fused pyrrole-unit, it caused a
pronounced difference in activity with 15 being over six-times
more active than 16 against the liver stage of P. berghei. This
strict dependence on the position of just one double bond
indicates that even minor structural modification of the
pyrrolo[1,2-a]quinolin-5-one scaffold may be exploited to
customize anti-protozoal activity. Compound 15 reduced P.
berghei parasite size similar to the atovaquone positive control
(Fig. 2C, 2D), further demonstrating the anti-Plasmodium
activity of the compound. Yet unlike atovaquone and other
cytochrome bc1 complex inhibitors,29-31 15 exhibits greater
inhibition of liver stage Plasmodium parasites when compared
to the blood stage (Table S2, Fig. S4). This unique selectivity
profile suggests that 15 reduces parasite load by a mechanism
yield 14
(%)a
yield 15
yield 16
base
solvent
temp.
(%)a
-
(%)a
-
NaOH
tert-BuOK
CsCO3
NaOH
tert-BuOK
CsCO3
NaOH
tert-BuOK
CsCO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
tert-BuOH
75 °C
75 °C
75 °C
reflux
reflux
reflux
reflux
reflux
reflux
76
68
-
72
60
-
64
26
8
tracesb
-
-
-
-
35
57
-
-
-
-
tracesb
-
-
-
-
tert-BuOH
tert-BuOH
O
N
O
N
B
O
base (3 eq.)
solvent, temp., 2h
+
N
H
16
14
15
base
solvent
temp.
reflux
100 °C
100 °C
100 °C
125 °C
100 °C
time (h)
yield 15 (%)a
yield 16 (%)a
tert-BuOK
tert-BuOK
tert-BuOK
tert-BuOK
tert-BuOK
tert-BuOK
tert-BuOH
DMSO
DMF
4
2
75
-
-
c
-
2
-
27d
15e
DMF
4
-
c
DMF
o/n
2
-
-
f
Ph2O
-
-
aisolated yields. bidentification based on NMR from impure
c
d
chromatography fractions. complex mixture of products. 48% of 14
was recovered. e35% of 14 was recovered. f93% of 14 was recovered.
This journal is © The Royal Society of Chemistry 20xx
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distinct from well-characterized electron transport chain
disruption. While currently unknown, this additional mode(s) of
action makes the scaffold desirable for further development to
target drug resistant Plasmodium parasites.
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DOI: 10.1039/C9CC01689A
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Conflicts of interest
There are no conflicts to declare.
18
19
20
Acknowledgements
We are grateful to Prof. Dr. Andreas Marx and his group for their
generous support. This work was funded by the Emmy Noether
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DOI: 10.1039/C9CC01689A
We describe a tandem reaction leading to tricyclic pyrrolo[1,2-a]quinolin-5-ones with unique
selectivity against the liver stage of the malaria parasite.