Ligand-free MCR for linking quinoxaline framework with a benzimidazole nucleus: A new strategy for the identification of novel hybrid molecules as potential inducers of apoptosis

Article abstract of DOI:10.1039/c4ob01268b

We report a true MCR involving the reaction of N-(prop-2-ynyl)quinoxalin-2- amine derivatives with 2-iodoanilines and tosyl azide in the presence of 10 mol% of CuI and Et₃N in DMSO to afford the pre-designed hybrid molecules containing quinoxaline framework linked with a benzimidazole nucleus. The MCR proceeds in the absence of any ligand and/or lateral addition of the catalyst/base affording products within 30 min in good yields, some of which showed encouraging apoptosis inducing properties in zebrafish. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01268b

Organic &
Biomolecular Chemistry
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Ligand-free MCR for linking quinoxaline
framework with a benzimidazole nucleus: a new
strategy for the identification of novel hybrid
molecules as potential inducers of apoptosis†
Cite this: Org. Biomol. Chem., 2014,
12, 6800
Received 18th June 2014,
Accepted 10th July 2014
Rajnikanth Sunke,a P. Vijaya Babu,a,b Swapna Yellanki,a,c Raghavender Medishetti,a,c
DOI: 10.1039/c4ob01268b
www.rsc.org/obc
Pushkar Kulkarnic and Manojit Pal*a
We report a true MCR involving the reaction of N-(prop-2-ynyl)-
quinoxalin-2-amine derivatives with 2-iodoanilines and tosyl azide
in the presence of 10 mol% of CuI and Et3N in DMSO to afford the
pre-designed hybrid molecules containing quinoxaline framework
linked with a benzimidazole nucleus. The MCR proceeds in the
absence of any ligand and/or lateral addition of the catalyst/base
affording products within 30 min in good yields, some of which
showed encouraging apoptosis inducing properties in zebrafish.
Apoptosis, also termed as programmed cell death, is a series
of genetically controlled events that result in the elimination
of damaged or abnormal cells. Being an important method of
cellular control, any disruption of apoptosis leads to abnormal
growth of cells e.g. cancer. Thus, the induction of apoptosis in
tumor cells is considered as an effective approach in the
management and therapy of cancer as well as its prevention.1
Indeed, many of the known anticancer agents and drugs work
by inducing apoptosis in cancer cells. While various natural
products and small molecules have been explored as inducers
of apoptosis earlier, there is still a continued need for a new
Fig. 1 The strategy of hybrid molecule A and B in the design and dis-
covery of potential new drugs.
framework or scaffold for the design and discovery of potential been enhanced by tethering it with the known antitumor com-
novel apoptotic agents.
pounds or simple active moieties of known antitumor
The hybrid molecules are generally defined as agents with agents.2b,c Prompted by this idea we adopted a similar strategy
two (or more) structural frameworks having different biological to design our target hybrid molecules as potential apoptotic
functions and dual activity (e.g., A, Fig. 1), and can act as two agents.
distinct pharmacophores.2a However, the strategy of a hybrid
The quinoxaline framework has been reported to be an
molecule is also used to enhance the pharmacological activi- integral part of several anticancer agents.3 The benzimidazole
ties of the individual pharmacophore (e.g. B, Fig. 1). For nucleus on the other hand has also found to be present
example, the weak cytotoxicity of distamycin A (Fig. 1) has in various antitumor/anticancer agents.4 Thus we anticipated
aDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally,
Hyderabad 500072, India
cZephase Therapeutics (an incubated company at the DRILS), University of
Hyderabad Campus, Gachibowli, Hyderabad 500046, India
†Electronic supplementary information (ESI) available: Experimental pro-
Fig. 2 New hybrid framework (C) for the design and identification of
cedures, spectral data for all new compounds. See DOI: 10.1039/c4ob01268b
novel inducers of apoptosis.
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Table 2 Synthesis of N-substituted 3-chloro-N-(2-(1-tosyl-1H-benzo[d]-
imidazol-2-yl)ethyl)quinoxalin-2-amines (7)a
Scheme 1 Synthesis of hybrid molecules 7 based on C via a ligand-free
MCR.
Yieldb
Entry Alkyne (5); R1 = Aniline (6); R2 = Product (7); R1, R2 = (%)
1
2
3
4
5
6
7
8
5a-C6H4OMe-p 6a H
7a-C6H4OMe-p, H
7b-C6H4OMe-p, Me 89
94
5a
5a
6b Me
6c Cl
6a
7c-C6H4OMe-p, Cl
7d-C6H4Me-p, H
7e-C6H4Me-p, Me
7f-C6H4Me-p, Cl
7g-C6H4Cl-p, Me
7h-C6H4Br-p, H
7i-C6H4Br-p, Me
7j-C6H4Br-p, Cl
7k-C6H4F-p, H
7l-C6H4F-p, Me
7m-CH2Ph, H
90
92
86
90
89
95
91
89
93
86
73
81
5b-C6H4Me-p
Scheme 2 Synthesis of compound 5.
5b
5b
6b
6c
5c-C6H4Cl-p
5d-C6H4Br-p
5d
6b
6a
6b
6c
Table 1 Optimization of reaction conditionsa
9
10
11
12
13
14
5d
5e-C6H4F-p
5e
6a
6b
5f-CH2Ph
5f-CH2Ph
6a
6b
7n-CH2Ph, Me
a All the reactions are carried out using compound 5 (0.30 mmol),
6
(0.34 mmol), TsN3 (0.36 mmol), TEA (0.36 mmol) and CuI
(0.03 mmol) in DMSO (2 mL), rt, N2, 30 min. b Isolated yield.
target molecules based on C. A literature search revealed that
the 2-substituted benzimidazole synthesized via the reaction
of 1,2-phenylenediamines with the corresponding carboxylic
acids or with aldehydes followed by oxidation5 can be functio-
nalized further, for example, by sulfonylation using an alkyl or
aryl sulfonyl chloride.6 However, this method appeared to be
less attractive for the synthesis of molecules based on C as the
introduction of quinoxaline moiety seemed to be difficult.
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
THF
CH3CN
DCM
32
57
65
66
48
94
88
94c
10
70
DCE
Toluene
DMSO
DMF
DMSO
DMSO
DMSO
Cu(OTf)2
CuI
10
a All the reactions are carried out using compound 5a (0.30 mmol), 6a
(0.34 mmol), TsN3 (0.36 mmol), in the presence of a Cu catalyst
(0.03 mmol) and base (0.36 mmol) in a solvent (2 mL) at room temp
for 30 min under nitrogen. b Isolated yield. c The reaction was carried
using 30 mol% CuI and completed within 10 min.
that the combination of these two moieties connected through
an appropriate linker in a single molecule may provide a new
framework (C, Fig. 2) suitable for the design and identification
of novel inducers of apoptosis. Indeed, the strategy was found
to be operative in our case. Herein, we report our preliminary
findings on the synthesis and pharmacological evaluation of
compounds based on C as potential inducers of apoptosis. To
the best of our knowledge, pharmacological evaluation of this
class of compounds, especially as apoptotic agents, has not
been explored earlier.
To achieve our project goal, we required a direct and
straightforward synthetic method for the rapid supply of our
Scheme 3 Proposed reaction mechanism.
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component reaction11). Moreover, the methodology involved
the overall use of 20 mol% of Cu catalyst and required a total
reaction time of 6 h to complete the reaction. The yields of the
products obtained were also not particularly high being in the
range of 43%–78%. In contrast, we have observed that the reac-
tion of N-(prop-2-ynyl)quinoxalin-2-amine derivative (5) (pre-
pared via selective amination12 of 2,3-dichloroquinoxaline 1
followed by propargylation, Scheme 2) with 2-iodoanilines (6)
and tosyl azide in the presence of 10 mol% of CuI and Et3N in
DMSO afforded the desired target compound 7 (Scheme 1)
within 30 min in the absence of any ligand and/or lateral
addition of the catalyst/base. The methodology was used to
prepare a range of target compounds in good to excellent
yields, the details of which are presented here.
Fig. 3 Results of apoptosis assay: the percentage induction of apopto-
sis caused by compounds 7k, 7e and 7i at different concentrations along
with methotrexate (*p < 0.05, ***p < 0.001). All the statistical analysis
was performed using GraphPad Prism® software.
The reaction of 3-chloro-N-(4-methoxyphenyl)-N-(prop-2-
ynyl)quinoxalin-2-amine (5a) with 2-iodoaniline (6a) and tosyl
azide was used to establish the optimized reaction conditions.
The reaction was initially performed in the presence of CuI
(10 mol%) and Et3N at room temperature in the absence of
any ligand in a number of solvents, such as THF, MeCN, DCM,
toluene, DMSO and DMF (entries 1–7, Table 1). While the reac-
tion proceeded well in all these solvents affording the desired
product 7a in variable yields, the best result was obtained
when the reaction was performed in DMSO (entry 6, Table 1)
affording 7a in 94% yield. We were delighted with this obser-
vation as the reaction proceeded in the absence of any ligand
and was completed within 30 min. Moreover, the use of
10 mol% of CuI was found to be enough to catalyze this MCR
though the use of higher quantity of catalyst e.g., 30 mol% of
CuI completed the reaction within 10 min (entry 8, Table 1).
Since the yield of 7a was not improved further in this case, the
conditions in entry 6 were identified as the best reaction
This problem was found to be common with the other
methods of constructing 1,2-disubstituted benzimidazole7
moieties possessing the required quinoxaline8 substituent.9
Nevertheless, during the literature search a recent report on
Cu-catalyzed 3-component cascade reaction of sulfonyl azides,
alkynes and 2-bromoaniline leading to the functionalized ben-
zimidazoles10 attracted our attention. The substitution pattern
on the benzimidazole ring was very similar to that we were
looking for. Indeed, we envisioned that the incorporation of
quinoxaline moiety into the alkyne reactant may afford our
desired product in a single step. However, a closer look at the
reported reaction10 revealed that the methodology required
the use of a ligand and lateral addition of an extra quantity of
Cu catalyst as well as a base to facilitate the second step of
the cascade sequence making it not truly an MCR (multi-
Fig. 4 Representative images of the embryos treated with compounds assayed for apoptosis.
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terminal alkyne 5 reacts with the tosyl azide in the presence of
CuI and Et3N to form the ketenimine species E-1 via a copper-
catalyzed azide–alkyne cycloaddition (CuAAC) process13 fol-
lowed by the release of nitrogen gas from the resulting tri-
azolo-Cu intermediate. E-1 then undergoes nucleophilic attack
at the sp-carbon by the 2-iodoaniline derivative (6), which trig-
gers several changes including the tautomerism of N-tosylamid-
ine intermediate E-2 to the tosylamide E-3. The Cu-catalyzed
intramolecular C–N bond formation of E-3 then shifts the tau-
tomerism equilibrium from towards E-3 and affords product 7.
Thus, the organo-copper(III) species generated from E-3 and
CuI undergoes intramolecular cyclization, involving the initial
formation of N–Cu(III) bond followed by the reductive elimin-
ation of CuI to give 7.
While the reason for the (i) rapid reaction, (ii) low catalyst
loading, (iii) non-requirement of any ligand and/or lateral
addition of the catalyst/base and (iv) good to high yields of pro-
ducts in the present case in compared to the earlier protocol10
is not clear if the use of the 2-iodoaniline derivative in place of
2-bromo analog could be a possible reason. It is well known
Fig. 5 Results of teratogenicity assay: each embryo was scored based
on their level of toxicity from 5 being non toxic and 0.5 being highly
toxic (*p < 0.05, ***p < 0.001). Statistical analysis for scoring was done
using GraphPad Prism® software using two-way ANOVA. The graph rep-
resents the teratogenic scoring given compared to the positive control
Phenobarbital.
conditions for further studies. We also examined the use of
another catalyst Cu(OTf)2 (entry 9, Table 1) and base K2CO3
(entry 10, Table 1), but these were found to be less efficient in
terms of product yield. Nevertheless, being truly an MCR, the
present method seemed to have advantages over the earlier
method that was more of a cascade reaction.
The ligand-free MCR was further explored to expand its
scope and generality. Thus a range of alkynes (5) along with a
number of 2-iodoaniline derivatives were employed in the
present MCR, and the results are summarized in Table 2 (see
also Table S1 in ESI†). The reaction proceeded well in all these
cases affording a variety of N-substituted 3-chloro-N-(2-(1-tosyl-
1H-benzo[d]imidazol-2-yl)ethyl)quinoxalin-2-amines (7) in
good to excellent yield (73%–95%).
From the view point of the reaction mechanism, the
present MCR seems to proceed via a number of steps, includ-
ing the formation of (i) ketenimine, (ii) tosylamide and finally
(iii) intramolecular C–N bond as shown in Scheme 3. The
Fig. 7 The EC50 (apoptosis) and NOAEL of test compound 7k (EC50
=
14.76 µM & NOAEL = 30 µM), 7e (EC50 = 6.94 µM & NOAEL = 10 µM),
and 7i (EC50 = 2.23 µM & NOAEL = 3 µM) (*p < 0.05). The overall thera-
peutic index (ratio of NOAEL/EC50) of 7k is 2.032, 7e is 1.44, and 7i
is 1.34.
Fig. 6 Representative zebrafish images from the teratogenicity assay of compounds tested at 30 µM.
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Table 3 Summary of the pharmacological evaluations of compounds 7k, 7e, and 7i
Pharmacological evaluations
Test compounds data
Tests
Endpoint
Positive control
Parameters
7k
7e
7i
Apoptosis
Teratogenicity
Overall therapeutic index
Acridine Orange staining of apoptotic cells
Morphological assessment of phenotypic changes
Ratio of NOAEL/EC50
Methotrexate
Phenobarbital
—
EC50
NOAEL
Therapeutic index
14.76
30
2.032
6.94
10
1.44
2.23
3
1.34
that the reactivity order of the halogen substituent towards the addition to the reference compound gemcitabine20 were also
transition metal catalyst is I > Br > Cl and therefore 10 mol% included in this assay to test the concept presented in Fig. 1
Cu catalyst alone in the presence of Et3N was found to be (e.g. B). While 7i and 7k showed 61% and 46% growth inhi-
enough to facilitate the overall transformation efficiently. The bition of CAL 27, respectively, the compound 8 and 9 showed
other reason could be the nature of terminal alkynes used. The only 20%–25% inhibition, indicating the usefulness of this
alkynes (5) used in the present MCR contain a tertiary amino concept.
group, which because of its bulkiness, could force the orien-
In conclusion, an efficient MCR has been developed invol-
tation of the tosylamide moiety of E-3 to a position favorable ving the reactions of N-(prop-2-ynyl)quinoxalin-2-amine deriva-
for intramolecular cyclization thereby accelerating the Cu-cata- tives with 2-iodoanilines and tosyl azide in the presence of
lyzed C–N bond forming step.
10 mol% of CuI and Et3N in DMSO to afford the pre-designed
In order to assess their potential to induce apoptosis, the target compounds containing the quinoxaline framework
synthesized compounds were tested in zebrafish embryos14 linked with a benzimidazole nucleus. In contrast to the pre-
along with a known drug methotrexate15 at 30 µM. Based on viously reported cascade reaction for the synthesis of a similar
their considerable effects in the present assay of apoptosis class of compounds, the present MCR seemed to have the fol-
compounds 7k, 7e and 7i were further tested at 1, 3, 10 and 30 lowing favorable features e.g., (i) rapid reaction (30 min), (ii)
µM along with methotrexate (Fig. 3 and 4). While the com- low catalyst loading (10 mol%), (iii) non-requirement of any
pound 7k showed an increase in its apoptotic activities up to ligand and/or lateral addition of the catalyst/base and (iv) good
3 µM, a decrease in activity was observed at 10 and 30 µM. The to high yields of products (73%–95%). A range of novel hybrid
embryos were found to be safe at all concentrations. In the molecules originally designed as potential inducers of apopto-
case of compound 7e, the increase in apoptotic activities was sis were prepared using this methodology and tested for apop-
observed with the increase of concentration from 1 to 10 µM, tosis, and teratogenicity in zebrafish embryos. Furthermore,
but the activity was decreased at 30 µM. Compound 7i showed some of these compounds showed encouraging apoptosis
significant apoptotic activity at 10 µM; however, the embryos inducing properties and therefore seem to have potential med-
were dead when the concentration was increased to 30 µM.
icinal value. MCR presented here could be useful in building a
These compounds were also evaluated for their potential library of hybrid molecules that are helpful for medicinal/
toxicities16 e.g. teratogenicity in the zebrafish embryo at a pharmaceutical chemistry and drug discovery efforts.
range of 1.0–30 µM. The toxicological evaluation was carried
RS thank CSIR for a research fellowship. The authors thank
out in a blind fashion. All the embryos in the control group the management of DRILS and CSIR [Grant 02(0127)/13/
were found to be normal. Phenobarbital (3 mM) was used as a EMR-II] for support.
positive control in this assay (Fig. 5 and 6). The compound 7k
was found to be non-toxic in all the tested concentrations.
While the compound 7e showed mild toxicity at 30 µM, it was
found to be safe at lower concentrations e.g., 1, 3 and 10 µM.
Notes and references
Compound 7i was found to be safe at 1 and 3 µM but showed
toxicity at 10 and 30 µM.
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Org. Biomol. Chem., 2014, 12, 6800–6805 | 6805