A novel and easy two-step, microwave-assisted method for the synthesis of halophenyl pyrrolo[2,3-b]quinoxalines via their pyrrolo precursors. Evaluation of their bioactivity

Article abstract of DOI:10.1016/j.tetlet.2014.01.106

A novel, two-step, facile route for the synthesis of pyrrolo[2,3-b] quinoxalines via 2,3-dioxopyrroles, enhanced by microwave irradiation, is presented. The newly synthesized 2,3-dioxo-5-halophenyl pyrrolo precursors 4a-c as well as the non-aromatized ethyl 2-(4-halophenyl)-1-methyl-2,4-dihydro-1H- pyrrolo[2,3-b]quinoxaline-3-carboxylates 6a-c and the aromatized ethyl 2-(4-halophenyl)-1-methyl-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 7a-c were evaluated for their antioxidant, cytostatic, and antiviral properties. Most of them proved to be potent hydroxyl radical scavengers and inhibited in vitro lipid peroxidation. The compounds showed moderate antiproliferative activity, while 6a inhibited vaccinia virus at an EC₅₀ value of 2 μM, and 4c and 6c inhibited Sindbis virus at EC₅₀ values of 4 μM.

Full text of DOI:10.1016/j.tetlet.2014.01.106

Tetrahedron Letters 55 (2014) 1873–1876
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel and easy two-step, microwave-assisted method
for the synthesis of halophenyl pyrrolo[2,3-b]quinoxalines
via their pyrrolo precursors. Evaluation of their bioactivity
Stella Manta a, Dimitra-Niki Gkaragkouni a, Eleni Kaffesaki a, Petros Gkizis b, Dimitra Hadjipavlou-Litina c,
Eleni Pontiki c, Jan Balzarini d, Wim Dehaen e, , Dimitri Komiotis a,
⇑
⇑
a Department of Biochemistry and Biotechnology, Laboratory of Bio-Organic Chemistry, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece
b Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
c Aristotle University of Thessaloniki, Department of Pharmaceutical Chemistry, School of Pharmacy, 54124 Thessaloniki, Greece
d Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium
e Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, two-step, facile route for the synthesis of pyrrolo[2,3-b]quinoxalines via 2,3-dioxopyrroles,
enhanced by microwave irradiation, is presented. The newly synthesized 2,3-dioxo-5-halophenyl pyrrolo
precursors 4a–c as well as the non-aromatized ethyl 2-(4-halophenyl)-1-methyl-2,4-dihydro-1H-pyrrol-
o[2,3-b]quinoxaline-3-carboxylates 6a–c and the aromatized ethyl 2-(4-halophenyl)-1-methyl-1H-pyr-
rolo[2,3-b]quinoxaline-3-carboxylates 7a–c were evaluated for their antioxidant, cytostatic, and
antiviral properties. Most of them proved to be potent hydroxyl radical scavengers and inhibited
in vitro lipid peroxidation. The compounds showed moderate antiproliferative activity, while 6a inhibited
Received 16 October 2013
Revised 12 December 2013
Accepted 22 January 2014
Available online 31 January 2014
Keywords:
Pyrroloquinoxaline
Pyrrolidine
Multicomponent reaction
Antioxidant activity
Antiviral activity
Cytostatic activity
vaccinia virus at an EC50 value of 2
lM, and 4c and 6c inhibited Sindbis virus at EC50 values of 4
lM.
Ó 2014 Elsevier Ltd. All rights reserved.
Microwave (MW) technology and multicomponent reactions
(MCRs) have attracted significant attention from synthetic organic
chemists as they accelerate a wide variety of chemical transforma-
tions. MWs impart many chemical reactions with attributes such
as enhanced reaction rates, higher yields of pure products, better
selectivity, improved ease of manipulation, rapid optimization of
reactions, and several ecofriendly advantages,1,2 while MCRs are
extremely useful tools for the synthesis of diverse and complex
compounds, as well as small and drug-like heterocycles.3,4 Accord-
ing to current synthetic requirements, environmentally benign
multicomponent procedures employing microwave methodology
are particularly welcome.
is present in many pharmaceutical agents exhibiting a broad spec-
trum of biological activities, such as antitumor, antiviral, antiglau-
coma, antitubercular, and anti-inflammatory.10–13 2-Oxopyrroles
are important substructures in a variety of drugs, including those
active against viral infections (HIV,14 influenza,15 cytomegalovi-
rus16), microbiological diseases17,18 (bacterial or fungal), and can-
cer.19 Finally, pyrroloquinoxaline derivatives20 are also known as
anti-HIV,21 antimalarial,22 antagonist,23 anticancer,24–26 and anti-
oxidant27agents, as well as PARP-128 and Akt kinase29 inhibitors.
Based on the pharmacological interest in compounds that be-
long to the pyrrolo and quinoxaline families, and considering that
only a few methods have been reported for the synthesis of pyrrol-
o[2,3-b]quinoxalines,27,30–32 we present herein a novel two-step
process for the synthesis of 4-chloro, 4-fluoro, and 4-iodophenyl
pyrrolo[2,3-b]quinoxalines via 2,3-dioxo-pyrroles using micro-
wave irradiation, and a comparison of this methodology with con-
ventional heating.
Among various classes of heterocyclic compounds, pyrrolyl5–7
and quinoxalinyl8,9 derivatives are well known as antioxidants,
presenting potent lipid peroxidation inhibition in vitro and signif-
icant hydroxyl radical scavenging activity. The quinoxaline nucleus
Our approach to the key intermediates, 2,3-dioxo-5-(4-hal-
ophenyl) pyrroles 4a–c, involved the operationally simple, practi-
cal, and economical, three-component condensation of sodium
⇑
Corresponding authors. Tel.: +32 16 32 74 39; fax: +32 16 32 79 90 (W.D.); tel.:
+30 2410 565285; fax: +30 2410 565290 (D.K.).
E-mail addresses: dkom@bio.uth.gr (W. Dehaen), wim.dehaen@chem.
kuleuven.be (D. Komiotis).
http://dx.doi.org/10.1016/j.tetlet.2014.01.106
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1874
S. Manta et al. / Tetrahedron Letters 55 (2014) 1873–1876
diethyl oxalacetate (3) with an equimolar amount of an aromatic
aldehyde (1a–c) and methylamine (2), in refluxing ethanol.33 This
reaction provided the desired pyrroles 4a–c in a one-pot reaction
and in moderate yields (36–48%), depending on the halogen on
the aromatic aldehyde used (Scheme 1). All the products could
be easily filtered from the reaction mixture and could be prepared
on multigram scale.
all the reactions were also conducted under MW conditions. Thus,
the three-component reaction between aldehydes 1a–c and
methylamine (2) with sodium diethyl oxalacetate (3) under MW
irradiation (100 W) at 110 °C for 20 min produced pyrroles4a–c,
which were condensed upon irradiation (200 W) with o-phenyl-
enediamine (5), to afford solely after 3 min at 40 °C the non-aro-
matized quinoxalines 6a–c and the aromatized isomers 7a–c
after 10 min at 180 °C (Table 1). When compared to conventional
heating, the MW technology completed the two-step synthesis
much faster, while the yields of the products were slightly in-
creased (by 4–11%).
These substituted pyrroles are useful intermediates for the syn-
thesis of pyrrolo[2,3-b]quinoxalines 6a–c and 7a–c. Therefore, pyr-
roles 4a–c were condensed with o-phenylenediamine (5) in
refluxing glacial acetic acid for one hour to give a mixture of two
products, which were separable by thin-layer chromatography.
The slower moving derivatives were isolated in 39–46% yields
and were identified as the non-aromatized ethyl 2-(4-halophe-
nyl)-1-methyl-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-3-car-
boxylates 6a–c, while the less polar analogues corresponding to
the aromatized ethyl 2-(4-halophenyl)-1-methyl-1H-pyrrolo[2,3-
b]quinoxaline-3-carboxylates 7a–c, were obtained in slightly high-
er yields (50–58%) (Scheme 1). When the condensation reaction
was performed for two hours, the aromatized isomers 7a–c were
afforded exclusively (65–72%). When oxygen or 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) was used, the starting materials
were recovered together with some degradation products. It
should be noted that the nature of the halogen on the aromatic ring
at position 5 of the heterocycle, in compounds 4a–c, did not affect
the reaction course.
All new compounds were characterized by NMR and IR spec-
troscopy, mass spectrometry, and elemental analysis. Regarding
the structures of products 4, 6, and 7, their IR spectra showed
the typical absorptions of an a,b-unsaturated ethyl carboxylate at
1625–1698 cmꢀ1. Their 1H NMR spectra showed signals that could
be attributed to the carboethoxy group at 1.00–1.22 ppm (t, 3H)
and at 3.97–4.30 ppm (q, 2H). In the 1H NMR spectra of dihydro
analogues 6a–c, prominent 3-proton methyl signals appeared,
which were ascribed to the N-methylamino group (6a: d 2.76,
6b: d 1.25, 6c: d 1.25), while following aromatization the same pro-
tons were remarkably deshielded (7a: d 3.78, 7b: d 3.78, 7c: d 3.77).
The 1H NMR spectra of compounds 6a–c exhibited signals for the
H-20 protons of the pyrrole ring at 4.85–5.02 ppm as characteristic
singlets, contrary to compounds 7a–c, whose 1H NMR spectra re-
vealed the absence of such signals.
A possible reaction mechanism probably includes an imine–en-
amine exchange (intermediate A, Scheme 1), which may lead to a
favorable situation for the second step (cyclization) to operate; this
can directly result from the hydrogen atom on the nitrogen leading
to compounds 6, or from the hydrogen atom on the carbon after
cyclic hemiaminal formation leading to compounds 7.
All the products were evaluated for their antioxidant, cytostatic,
and antiviral properties. The interactions of the examined com-
pounds with the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free
radical34 are listed in Table 2, in comparison to the well-known anti-
oxidant agent, nordihydroguaiaretic acid (NDGA). The best DPPH
radical scavenging activity was presented by 6b (at 20 min) and
6a (at 60 min), while the results for all the analogues at a concentra-
Since thermally driven organic transformations take place
either by conventional heating or microwave accelerated heating,
tion of 100
lM were time-dependent with the exception of 4c. A
H
O
O
O
O
HO
O
EtOH
reflux
CH3NH2
O
R
N
O
O
O
R
2
4a-c
1a-c
3
H2N
AcOH
reflux
H2N
5
O
O
H
N
R
N
N
O
O
N
6a-c
R
a: R = Cl, b: R = F, c: R = I
N
O
H2N
A
O
O
N
N
R
N
7a-c
Scheme 1. Synthesis of the novel 2,3-dioxo-5-(4-halophenyl) pyrroles 4a–c, ethyl 2-(4-halophenyl)-1-methyl-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates
6a–c, and ethyl 2-(4-halophenyl)-1-methyl-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 7a–c.

S. Manta et al. / Tetrahedron Letters 55 (2014) 1873–1876
1875
Table 1
Comparison of conventional and microwave synthetic procedures for the synthesis of compounds 4a–c, 6a–c, and 7a–c
Product
Conventional
Microwave
Time (h)
Yield (%)
Time (min)
Yield (%)
Temp (°C)
Power (W)
4a
4b
4c
6a/7a
6b/7b
6c/7c
7a
7b
7c
4
6
5
1
1
1
2
2
2
45
36
48
46/50
42/56
39/58
70
72
65
20
20
20
3
3
3
10
10
10
51
46
52
110
110
110
40
40
40
180
180
180
100
100
100
200
200
200
200
200
200
56 (only 6a)
53 (only 6b)
50 (only 6c)
74
76
70
Table 2
Interaction-reducing activity % with DPPH (RA %); scavenging activity for hydroxyl radicals OH %; % inhibition of lipid peroxidation (AAPH %)
Product
ClogP36
RA % 100
lM 20 min
RA % 100
lM 60 min
OH % 100
l
M
AAPH % 100 lM
4a
4b
4c
6a
6b
6c
7a
7b
3.15
2.58
3.56
5.86
4.32
6.27
4.29
3.72
4.70
—
13 0.01
22 0.2
42 1.1
41 1.8
57 1.2
23 1.1
23 0.8
15 0.8
41 1.4
21 1.1
65 1.9
59 0.8
32 1.0
26 0.6
22 0.2
17 0.3
83 2.3
—
No
No
No
92 2.3
91 3.3
97 2.7
No
95 3.7
No
88 2.1
72 1.7
94 2.9
90 3.4
73 2.4
39 1.9
18 0.5
59 2.1
No
6
9
0.8
0.5
7c
NDGAa
Trolox
81 1.9
—
—
—
—
73 1.4
63 1.7
a
NDGA = nordihydroguaiaretic acid; no results under the reported experimental conditions; each experiment was performed at least in triplicate and the standard
deviation of absorbance was less than 10% of the mean.
Table 3
slight increase was observed with 4a, 6b, and 7a after 60 min. When
evaluated for their hydroxyl radical scavenging activity generated
by the Fe3+/ascorbic acid system, only analogues 6a, 6b, 6c, and 7b
Cytostatic activity of the test compounds
a
Product
CC50 (lM)
exhibited remarkable activity at 100 lM (being higher than the
L1210b
CEMb
HeLab
well-known anti-oxidant, trolox, 73%, Table 2). Among the members
of series 7 only 7b, the F-substituted derivative seemed to be a po-
tent scavenger of hydroxyl radicals, whereas 7a (Cl-substituted) and
7c (I-substituted) did not exhibit any activity under the reported
experimental conditions. The majority of the studied compounds
inhibited effectively 2,20-azobis(2-amidinopropane) dihydrochlo-
4a
4b
4c
6a
6b
6c
7a
7b
274
119
21 11
43
93
51
216
176 42
34
2.8 1.1
8
1
175
>250
6
118 26
98
5.8 0.7
35
72 14
5
146 25
35
101 11
37
93 28
117 51
30 19
2.8 1.3
1.1 0.3
1
2
9
2
1
1
18
54
4
9
1
ride (AAPH)35-induced lipid peroxidation at 100
lM, showing high-
126 44
32
er activity than the reference compound trolox. The results
indicated that 4c with a lipophilicity clogP value (calculated-theo-
retical logP) of 3.56 presents the highest anti-LPO (lipid peroxida-
tion) ability, whereas 7c with a higher clogP value (4.70) shows
no activity. Among the derivatives of subgroup 4a–c, an increase
of the overall lipophilicity enhances anti-lipid peroxidation, and
7c
9
9
6-Mercaptopurine
6-Thioguanine
1.1 0.1
0.38 0.17
0.94 0.04
a
50% Cytostatic concentration.
L1210: murine leukemia cells, CEM: human lymphocyte cells, HeLa: human
cervix carcinoma cells.
b
particularly enhancement of the lipophilic contribution (p values)
of the halogen leads to an increase in the antioxidant activity.
Compounds 4, 6, and 7 were also evaluated for their cytostatic
activity against murine leukemia L1210, human lymphocyte CEM,
and human cervix carcinoma HeLa cells. None of the compounds
inhibitory at subtoxic concentrations, except 6a, which inhibited
vaccinia virus-induced cytopathicity at an EC50 value of 2
lM
(MIC: 100 M) in HEL cell cultures. This compound may be consid-
l
ered as a potential lead compound for poxvirus inhibition. Com-
pounds 4c and 6c showed inhibitory activity against Sindbis
virus (EC50: 4 lM).
showed pronounced antiproliferative activity (CC50
with 4c being an exception that showed cytostatic activity
(CC50: 5.8 M) against HeLa cells, but this compound was mark-
edly less inhibitory against CEM cell proliferation (CC50: 146 M).
The reason for this phenomenon is unclear since the other
compounds inhibited tumor cell proliferation at similar potencies
irrespective of the nature of the tumor cell-type. The known anti-
cancer compounds, 6-mercaptopurine (6MP) and 6-thioguanine
(6TG) were by far superior in their cytostatic activity
: P20 lM)
l
In conclusion, a novel, two-step, facile synthesis of halophenyl
pyrrolo[2,3-b]quinoxalines enhanced by microwave irradiation
has been accomplished via their 2,3-dioxopyrrolo precursors. The
reactions occurred remarkably fast under mild conditions using
inexpensive reagents, and two types of pyrroloquinoxaline prod-
ucts were isolated based on the amount of time the reactions were
heated. Most of the compounds proved to be potent hydroxyl
radical scavengers and inhibited in vitro lipid peroxidation. Com-
pounds 6a and 7b presented high anti-lipid peroxidation and
l
(CC50: 0.38–2.8 lM) (Table 3) than the test compounds.
When the 4, 6, and 7 analogue series were evaluated against a
variety of DNA and RNA viruses, none of the compounds proved

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S. Manta et al. / Tetrahedron Letters 55 (2014) 1873–1876
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This work was supported in part by the Postgraduate
Programmes ‘Biotechnology-Quality assessment in Nutrition and
the Environment’, ‘Application of Molecular Biology-Molecular
Genetics-Molecular Markers’, Department of Biochemistry and
Biotechnology, University of Thessaly, and KU Leuven (GOA 10/
14). We thank Lizette van Berckelaer, Leen Ingels, Leentje Persoons
and Frieda De Meyer for excellent technical assistance in the
biological assays. The authors are grateful to Biobyte Corp. 201
West 4th St. Suite 204, Claremont CA 91711, USA and Dr. Leo for
their support and free access to the C-QSAR program.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
106.
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