Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-Triazole Derivatives

Article abstract of DOI:10.1002/jhet.2736

Here, we demonstrate on the design and synthesis of novel pyrazine containing 1,2,3-triazole derivatives (7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, and 12a, 12b, 12c, 12d) using various chemicals, bases, and catalysts synthesized with excellent yields (78–92%) as described in the procedures. The development of this methodology is simple, efficient, and easier to handle; milder reaction conditions and higher selectivity under versatile coupling reagent useful for both amide and ester bond formations have also been developed. The synthesis of amide coupling derivatives prepared by (6a, 6b, 6c, 6d) was coupled with N-ethylpiperazine to afford (7a, 7b, 7c, 7d) and morpholine to afford (8a, 8b, 8c, 8d) by using 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in dichloromethane at room temperature for 10 h. The derivatives (6a, 6b, 6c, 6d) were coupled with alcohol (11) by using N,N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane (DCM) at room temperature for 16 h to give final compounds (12a, 12b, 12c, 12d). In silico docking approach has been applied to these compounds to screen their efficacy against selected drug targets of cancer and diabetes. The docking approach may facilitate the prediction of activity profile for future experimental findings.

Full text of DOI:10.1002/jhet.2736

Month 2016 Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing
1,2,3-Triazole Derivatives
a
a
a
b
*
Radhakrishnam Raju Ruddarraju, Adharvana Chari Murugulla, Ravindar Kotla, Muni Chandra Babu Tirumalasetty,
Rajendra Wudayagiri,b Shobha Donthabakthuni,a Ravichandar Maroju,c and Sadhanadham Palled
aDr. MACS Bio-Pharma Pvt. Ltd., Factory: Plot-79/B&C, Pashamylaram, Patancheru, Medak (Dist.) 502 307,
Telangana, India
bBioinformatics Center, Division of Molecular Biology, Department of Zoology, Sri Venkateswara University, Tirupati
517 502, Andhra Pradesh, India
cMahatma Gandhi Institute of Technology, Gandipet, Jawaharlal Nehru Technological University, Hyderabad 500 075,
Telangana, India
dCentre for Chemical Sciences and Technology, IST, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad
500 085, Telangana, India
*
E-mail: drmacs36@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received April 13, 2016
DOI 10.1002/jhet.2736
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Here, we demonstrate on the design and synthesis of novel pyrazine containing 1,2,3-triazole derivatives
(7a–d, 8a–d, and 12a–d) using various chemicals, bases, and catalysts synthesized with excellent yields
(78–92%) as described in the procedures. The development of this methodology is simple, efficient, and
easier to handle; milder reaction conditions and higher selectivity under versatile coupling reagent useful
for both amide and ester bond formations have also been developed. The synthesis of amide coupling
derivatives prepared by (6a–d) was coupled with N-ethylpiperazine to afford (7a–d) and morpholine to
afford (8a–d) by using 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in dichloromethane at room
temperature for 10 h. The derivatives (6a–d) were coupled with alcohol (11) by using N,N′-
dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane (DCM) at room temperature
for 16 h to give final compounds (12a–d). In silico docking approach has been applied to these compounds
to screen their efficacy against selected drug targets of cancer and diabetes. The docking approach may
facilitate the prediction of activity profile for future experimental findings.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
antihypertensive [13], cardiovascular [14], antidiabetic
[15], antioxidant [16], and antimycobacterial [17]
properties. Pyrazines play an important role as intermedi-
ates for perfumes [18], pharmaceuticals [19], and
agrochemicals [20], and they are also present in other
biological active natural products [21].
On the other hand, 1,2,3-triazoles have occupied an
important role not only in organic chemistry but also in
medicinal chemistry because of their easy synthesis by
click chemistry and attractive features as well as numerous
biological activities [22–24] such as antibacterial [25],
antifungal [26], antiallergic [27], antitubercular [28], anti-
inflammatory [29], analgesic [30], anticonvulsant [31],
and antimalarial [32] activities and also in many agrochem-
icals, pharmaceuticals, dyestuffs, and fluorescent whiteners
[33]. They have also found application as herbicides [34],
light stabilizers [35–37], optical brightening agents, and
corrosion retardants [38]. Some 1,2,3-triazole derivatives
Pyrazine nucleus-based pharmaceuticals are rapidly
becoming an important class of therapeutic agents and
are likely to replace many existing pharmaceuticals in the
near future. Pyrazine is less basic in nature than pyridine,
pyridazine, and pyrimidine, and it is a symmetrical
molecule with point group D2h. Pyrazine has been paid
great attention, because the diazine rings form an important
class of compounds presented in several natural and
synthetic compounds [1]. Pyrazine derivatives have been
widely used in the field of medicinal chemistry for the
skeleton of biologically active sites [2,3]. Pyrazine
derivatives are important drugs with two nitrogen atoms
in the para-position of the six-member ring, exhibit a wide
range of biological activities like analgesic [4], antiallergic
[5], antibacterial [6], anti-inflammatory [7], antiviral [8],
diuretic [9], anticancer [10], anti-HIV [11], hepatitis [12],
© 2016 Wiley Periodicals, Inc.

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R. R. Ruddarraju, A. C. Murugulla, R. Kotla, M. C. B. Tirumalasetty, R. Wudayagiri,
S. Donthabakthuni, R. Maroju, and S. Palle
Vol 000
have shown significant antimicrobial, cytostatic, virostatic,
and anti-inflammatory activities [39–42], anticancer agents
[43], antihistamine agents, and muscarinic agonists for the
treatment of Alzheimer’s disease [44–46]. 1,2,3-Triazole
moieties are attractive connecting units because they are
stable to metabolic degradation and improve not only the
binding of bimolecular drugs to the target through hydro-
gen bonding but also their solubility [47]. Although the
1,2,3-triazole moiety does not occur in nature, synthetic
molecules containing these units show diverse biological
activities. The importance of triazole compounds in medic-
inal chemistry is undeniable; based on the importance, we
have exemplified the 1,2,3-triazole molecules according
to their biological activities [48]. 1,2,3-Triazoles are highly
stable under basic and acidic hydrolysis and reductive and
oxidative conditions, indicative of a high aromatic stabili-
zation [49,50]. Recent innovation in click chemistry has
made 1,4-disubstituted-1,2,3-triazoles to be easily accessi-
ble alkynes and azides, through huisgen 1,3-dipolar
cycloaddition [51]. The key benefits involving research in
this area include ease of preparation and high success rate
in clinical trial compared with traditional pharmaceuticals
because of their diverse biological action with less toxicity.
To further explore previous structure–activity relationship,
we planned to couple the triazole ring with a pyrazine ring.
Pyrimidine, being an integral part of DNA and RNA,
imparts diverse biological activities such as antibacterial
[52], antifungal [53], antimalarial [54], antifilarial [55],
anticonvulsant [56], and antihistamine [57] activities.
Fused pyrimidine derivatives have attracted the attention
of numerous researchers over many years, because of
their important biological activities such as antimicrobial
[58–60], antioxidant [60], antitumor [61], analgesic,
anti-inflammatory [62,63], and antipyretic [63] activities.
The metabolism of these pyrimidines is unique and
important to understand both biochemical utilization of
these compounds and drug metabolism of pyrimidine
derivatives [64].
1,2,3-triazole derivatives in the open literature so far. The
computational analysis has been recently shown to an
important complementary tool for the study of biological
activity of these scaffolds. Keeping in view of the relevant
importance and with the aim of future in vitro experimental
study, the computational molecular docking studies on
pyrazine containing 1,2,3-triazole derivatives with various
therapeutic targets involved in cell proliferation and
diabetes will be taken up to screen potent leads.
RESULTS AND DISCUSSION
Initially, we focused our attention on the optimization of
the reaction conditions to synthesize the target compounds
(7a–d), (8a–d), and (12a–d) as described in Schemes 1 and 2.
We investigated some parameters in the procedure, such
as different reagents, bases, catalysts, ligands, copper load-
ing salts, additives and solvents are described in Table 1.
Direct bromination of aromatic compounds using bromine
generates toxic and corrosive HBr, which is hazardous to
the environment and the reaction is also generally non-
selective, forming mixtures of mono and disubstituted
products. N-bromosuccinimide (NBS) is considered a supe-
rior brominating agent due to the ease of its handling and
low cost. For this purpose, we employed commercially
available 2-amino-5 bromopyrazine 1 which was reacted
with NBS in CHCl3 at room temperature to give 3,5-
dibromopyrazin-2-amine 2 in 92% yield. Additionally, we
investigated the reaction behavior in different solvents,
such as dichloromethane (CH2Cl2), acetonitrile (CH3CN),
dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
ethanol (EtOH). Here we observed decreasing yields as
solvent polarities are increasing; (80%–40%) in polar
aprotic solvents such as CH3CN, DMF, DMSO and 20%
in polar protic solvent such as EtOH; however CHCl3
and CH2Cl2 gave the best results because of low dielectric
constants (Table 1, entries 1 and 2).
Therefore, the discovery of novel, stable, cost-effective,
and biologically active molecules for the synthesis of
pyrazine containing 1,2,3-triazole derivatives continues to
attract the attention of researchers. Recently, the synthesis
of novel molecules has been received considerable impor-
tance in organic synthesis because of their biological
activity under mild and convenient conditions to afford
the corresponding products in excellent yields with high
selectivity. In the continuation of our interest on the
synthesis of various novel molecules, herein, we report a
simple, convenient, and efficient method for the synthesis
of biologically active pyrazine containing 1,2,3-triazole
derivatives using various reagents. However, the reports
on the synthesis of these compounds are quite limited. To
the best of our knowledge, there has been no report
available on the synthesis of pyrazine containing
In the next investigation, 3,5-dibromopyrazin-2-amine 2
was reacted with cyclopropylamine with base
triethylamine (TEA) and sodium hydroxide (NaOH) at
80–85°C for 16h, but the product 3a was not observed
by Liquid chromatography-mass spectrometry (LC-MS)
as in the previous cases after completion of the starting ma-
terial (Table 1, entry 7 and 8). Next, we attempted palla-
dium-catalyzed C-N cross-coupling reactions. Compound
2 was reacted under various conditions using sodium
tert-butoxide (NaOtBu)/tripotassium phosphate (K3PO4)
asbases, Pd2(dba)3/Pd(OAc)2 as catalysts and 2,2’-bis
(diphenylphosphino)-1,1’-binaphthyl (BINAP)/Xantphos
as ligands suspended in different solvents like 1,4-dioxane
and toluene at 100°C for 10h [65,66], but the product was
not observed in LC-MS. Instead, we observed
debrominated product. Next, we increased the temperature
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-
Triazole Derivatives
Scheme 1. Synthesis of pyrazine containing 1,2,3-triazole compounds (7a–d) and (8a–d).
Scheme 2. Synthesis of pyrazine containing 1,2,3-triazole compounds (12a–d).
under the conditions such as potassium tert-butoxide
(KOtBu) in DMSO, potassium carbonate (K2CO3) in
DMF, but the product 3a was obtained in trace amounts
(Table 1, entry 9). However, microwave irradiation with
high temperature under pressure without any base and
solvent afforded the desired product 3a in high yield
(82%) (Table 1, entry 13) and is more efficient with shorter
reaction times than the previous reaction conditions. When
compound 2 was treated under microwave irradiation with
four different amines under different temperatures, the
3-bromo was selectively substituted. Compound 3a & 3b
was prepared by substituting with cyclopropylamine at
130°C and cyclopentylamine at 140°C respectively for
1.5 h. 3c & 3d were prepared by heating 2 with
isopropylamine at 110°C for 16h and methyl amine (40%
aqueous solution) at 100°C for 18h in seal tube. The
diamines (3a-d) were reacted with oxalyl chloride in the
presence of TEA in dichloromethane at 0°C to room
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DOI 10.1002/jhet

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R. R. Ruddarraju, A. C. Murugulla, R. Kotla, M. C. B. Tirumalasetty, R. Wudayagiri,
S. Donthabakthuni, R. Maroju, and S. Palle
Vol 000
Table 1
Optimization of solvent, base, catalyst for the synthesis of compounds 2, 3a, 4a, 5b, 6b, and 8b.
Entry
Starting material
Compound
Reagent/catalyst
NBS (1.2 eq.)
Solvent
CH2Cl2
CHCl3
EtOH
CH3CN
DMF
DMSO
CH3CN
EtOH
Conditions
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
rt
rt
rt
rt
rt
rt
6
6
6
6
6
6
16
16
16
16
10
10
1.5
6
88
91
20
82
70
40
—
—
Trace
—
—
—
82
50
93
70
60
85
75
50
—
75
40
20
Trace
30
92
NBS (1.2 eq.)
NBS (1.2 eq.)
NBS (1.2 eq.)
NBS (1.2 eq.)
NBS (1.2 eq.)
TEA (3.0 eq.)
NaOH (3.0 eq.)
K2CO3 (3.0 eq.)
KOtBu (1.2 eq.)
NaOtBu/Pd2(dba)3
K3PO4/Pd(OAc)2
—
3a
3a
3a
3a
3a
3a
3a
4a
4a
5b
5b
5b
5b
5b
5b
6b
6b
6b
6b
6b
8 b
80°C
85°C
120°C
110°C
100°C
100°C
130°C (MW)
rt
9
DMF
10
11*
12*
13*
14
15
16
17
18
19
20
21
22*
23
24*
25
26
27
DMSO
1,4-dioxane
Toluene
—
DCM
DCM
THF
THF
THF
THF
CH3CN
Acetone
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
DCM
2
3a
3a
4b
4b
4b
4b
4b
4b
5b
5b
5b
5b
5b
6b
—
TEA (3.0 eq.)
NaH (2.0 eq.)
DBU (2.0 eq.)
K2CO3 (2.0 eq.)
Cs2CO3 (2.0 eq.)
KOtBu (2.0 eq.)
KOH (2.0 eq.)
CuSO4.5H2O (1.0 eq.)
CuSO4.5H2O (0.5 eq.)
CuI (0.5 eq.)
rt
3
85°C
75°C
80°C
70°C
70°C
80°C
rt
12
12
12
12
12
12
16
20
36
20
20
10
rt
rt
rt
rt
CuI (0.5 eq.)
Cu (OAc)2 (1.5 eq.)
HATU (1.5)
rt
DIPEA (3.0)
PyBOP (1.5)
TEA (2.0)
EDC.HCl (1.5),
HOBt (1.5 eq.)
DIPEA (3.0)
28
29
6b
6b
8 b
8 b
DCM
DCM
rt
rt
10
10
85
81
30
6b
8 b
T3P(2.0)
DCM
rt
10
70
DIPEA (3.0 eq.)
*Ligand: 11 – BINAP; 12 – Xantpos; 13 – MW: microwave; 22 – sodium ascorbate (1.0); 24 – sodium ascorbate (0.5).
Bold entries indicate optimized conditions for better yields.
temperature for 3h to give compounds (4a-d). As shown in
Table 1 (entry 14), product 4a was obtained in only 50%
yield without employing the base. At present, the choice
of base is still empirical and no general rule for their selec-
tion has been established. A variety of bases and solvents
under different conditions were optimized and potassium
carbonate was found to be more suitable.
The dione derivatives (4a–d) was treated with propargyl
bromide and K2CO3 in tetrahydrofuran at 80°C for 12h to
afford compounds (5a–d).
Traditionally, the triazole forming, 1,3-dipolar cycload-
dition reaction between azide and alkyne is performed at
high temperature for long duration that usually results in
a mixture of two isomers-1,4 and 1,5-disubstituted 1,2,3-
triazoles. The reaction is regioselective only in the pres-
ence of Cu(I) catalysts, because Cu(I) as a catalyst,
strongly activates the terminal acetylenes towards 1,3-di-
polar cycloadditions with azide to give the desired 1,4-
disubstituted 1,2,3-triazoles. As described in the literature,
sodium ascorbate is considered to be a convenient additive
for in situ reducing agent to generate catalytically active
Cu(I) [67–69] species from Cu(II). This justifies the results
found with the combination of CuSO4.5H2O and sodium
ascorbate (Table 1, entry 22). We investigated some pa-
rameters in the procedure, regarding the amount of the cop-
per salt; an increase in the amount of CuSO4.5H2O from
0.5 to 1.0 eq increased the yield of the product to 75%
(Table 1, entry 22). Other copper salts were tested, such
as CuI, Cu(OAc)2, however, they are less effective and
the results are summarized in Table 1 (entries 23–26). With
the optimized conditions in hand, 1,2,3-triazole acid deriv-
atives (6a–d) were synthesized from (5a–d) derivatives by
using CuSO4.5H2O (1.0 eq) and sodium ascorbate (1.0 eq)
at room temperature in t-BuOH and H2O (2:1).
We undertook the coupling of four different triazole acid
derivatives (6a-d) with two cyclic amines and an alcohol to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-
Triazole Derivatives
prepare our final analogs. The growing need for new and
more complex peptide structures, particularly for biomedi-
cal studies and very recently, for the large-scale production
of peptides as drugs, required manufacturing peptide
products by efficient synthetic strategies, at reasonably
low prices. The most widely used coupling reagents are
carbodiimides and propane phosphonic cyclic anhydride
(T3P). Optimized conditions for the amide coupling were
achieved using 1-[Bis(dimethylamino)methylene]-1H-
1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
(HATU), PyBOP, EDC.HCl/HOBt and T3P in Dichloro-
methane (DCM) at room temperature; the yields were
summarized in Table 1 (entries 27–30). HATU was found
to be more suitable. The synthesis of amides were per-
formed from (6a–d) with N-ethylpiperazine to afford
(7a–d) and with morpholine to afford (8a–d) by using
HATU, N,N-Diisopropylethylamine (DIPEA) in dichlo-
romethane at room temperature for 10 h as shown in
Scheme 1.
To prepare our ester analog, the required alcohol deriva-
tive was prepared as follows; commercially available
4-chloro-7H-pyrrolo[2,3-d]pyrimidine 9 was alkylated
with ethyl 2-bromopropanoate using NaH in tetrahydrofu-
ran at 80°C for 16 h to gave 10 in 85% yield, which was
reduced with sodiumborohydride in ethanol at 0°C to
room temperature to afford compound 11 in yield 90%.
The derivatives (6a–d) was coupled with the alcohol (11)
using N,N’-dicyclohexylcarbodiimide (DCC) and 4-
dimethylaminopyridine (DMAP) in DCM at room tempera-
ture for 16h to give final ester compounds (12a–d) as shown
in Scheme 2.
MOLECULAR DOCKING STUDIES
In order to explore the potency of pyrazine containing
1,2,3-triazole derivatives (7a–d, 8a–d, and 12a–d) with
reference to anticancer and antidiabetic activities,
Figure 1. Binding of compound 8a (A and B) in the active site of EGFR and compound 7d (C and D) in the active site of aldose reductase. The compound
was represented in ball and stick form with red in color; the surrounding active-site amino acids are represented in stick model. [Color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
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R. R. Ruddarraju, A. C. Murugulla, R. Kotla, M. C. B. Tirumalasetty, R. Wudayagiri,
S. Donthabakthuni, R. Maroju, and S. Palle
Vol 000
Table 2
Synthesis of pyrazine containing 1,2,3-triazole derivatives (7a–d, 8a–d, and 12a–d).
Conditions/
time (h)
Yield
(%)
Entry
1
Acid derivative
Amine/alcohol
Product
rt, 10 h
86
2
rt, 10 h
88
3
rt, 10 h
90
4
rt, 10 h
86
5
rt, 10 h
87
6
rt, 10 h
92
(Continued)
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Month 2016
Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-
Triazole Derivatives
Table 2
(Continued)
Conditions/
time (h)
Yield
(%)
Entry
7
Acid derivative
Amine/alcohol
Product
rt, 10 h
85
8
rt, 10 h
88
9
rt, 16 h
82
10
rt, 16 h
86
11
rt, 16 h
80
12
rt, 16 h
78
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R. R. Ruddarraju, A. C. Murugulla, R. Kotla, M. C. B. Tirumalasetty, R. Wudayagiri,
S. Donthabakthuni, R. Maroju, and S. Palle
Vol 000
molecular docking was carried out with various therapeutic
targets, that is, epidermal growth factor receptor (EGFR),
vascular endothelial growth factor receptor 2 (VEGFR2),
aldose reductase, and 1,6-glucokinase, to enumerate the
accurate binding mode of compounds.
acceptors, which played a significant role in forming
H-bonds with active-site amino acids, which leads to the
inhibition of protein activity.
The docking results showed that all of the compounds
CONCLUSIONS
possessed
significant
and/or
moderate
binding
energy/affinity toward the active site of respective target
protein with protein–ligand interactions, which are summa-
rized in Table S1 of the Supporting Information. However,
anticancer drug target EGFR and antidiabetic drug target
aldose reductase have shown good binding energy and
dock score with all of the compounds.
In summary, we have synthesized novel pyrazine
containing 1,2,3-triazole derivatives (7a–d, 8a–d, and
12a–d) using various chemicals, bases, and catalysts as
described in the procedures. Here, detailed optimized
conditions for the amide coupling reaction were achieved
using HATU, PyBOP, EDC.HCl and HOBt, and for T3P
in DCM at room temperature, the yields were summarized
in Table 2. The synthesis of amide coupling derivatives
prepared by (6a–d) was coupled with N-ethylpiperazine
to afford (7a–d) and morpholine to afford (8a–d) by using
HATU and DIPEA in dichloromethane at room tempera-
ture for 10h in Scheme 1. The derivatives (6a–d) was
coupled with alcohol 11 by using DCC and DMAP in
dichloromethane at room temperature for 16h to give final
compounds (12a–d) in Scheme 2. These excellent methods
of synthesis of these molecules make this process simple
and clean, which promote its use in various multicompo-
nent reactions and create the platform for the development
of various pharmaceutical products. The preliminary
computational investigation demonstrates that all of the
compounds have shown well-binding orientation with the
active site of EGFR and aldose reductase. These studies
open a new vision for the consequent in vitro bioassays
with these scaffolds, which explore the effective modula-
tion of protein function with reference to anticancer and
antidiabetic activities.
For EGFR, compound 8a exhibited a significant dock
score, binding energy, and binding affinity with ꢀ14.6,
ꢀ30.59, and 11.16, respectively. Oxygen atom in the
morpholine group has formed one H-bond with Lys 730
by accepting an electron pair with the bond length of
2.82Å. The oxygen atom of C=O group in between
1,2,3-triazole and morpholine ring has formed one H-bond
with Lys 836 by accepting an electron pair with the bond
length of 2.48Å. Each ring of the pyrazine and
1,2,3-triazole has formed aren–cationic interaction with
Lys 836. The oxygen atom of the second C=O group of
pyrazine ring has formed two H-bonds: one with Val 810
and another one with Arg 812 by accepting an electron pair
with the bond lengths of 2.87 and 3.14 Å, respectively.
Oxygen atom of the third C=O has formed one H-bond
with Asp 812 by accepting an electron pair with the bond
length of 3.01 Å. The nitrogen atom of 1,2,3-triazole ring
has formed one H-bond with Arg 812 by accepting an
electron pair with the bond length of 2.74Å (Fig. 1a,b).
For aldose reductase, compound 7d has shown the
highest dock score, binding energy, and binding affinity
with ꢀ16.72, ꢀ38.9, and 11.42, respectively. The oxygen
atom of the third C=O of pyrazine ring has formed two
H-bonds: one with Lys 21 and another one with Ser 214
by accepting an electron pair with the bond lengths of
2.51 and 2.80Å, respectively. During the conformational
changes of compound in the binding pocket of the protein,
the oxygen atom of the second C=O has protonated and
converted into OH group; the lone pair electron shifted into
nitrogen, and it exhibits cationic form. Oxygen atom of this
OH group has formed one H-bond with Ser 214 by
accepting an electron pair with the bond length of 2.71 Å.
The oxygen atom of C=O group in between 1,2,3-triazole
and piperizine ring has formed one H-bond with Tyr 48
by accepting an electron pair with the bond length of
2.44Å. The nitrogen atom in the n-ethyl piperizine group
has protonated and exhibits cationic form; it has formed
one cationic–aren interaction with Trp 20 (Fig. 1c,d).
From the results of protein–ligand interactions, the
substructures of compound, viz. pyrazine, morpholine,
1,2,3-triazole, and piperizine, have rich source of H-bond
EXPERIMENTAL
Starting materials were obtained from commercial
suppliers and used without further purification. Melting
points were determined in open glass capillaries on a
Fisher–Johns melting point apparatus and are uncorrected.
The 1H NMR and 13C NMR spectra were taken on a
Bruker 400-MHz (Bruker Corporation, Billerica, MA,
USA) spectrometer using the solvent (CDCl3: 7.26 and
77.0 ppm, DMSO-d6: 2.49 and 39.7 ppm) and TMS used
as an internal standard. Chemical shifts are given in δ parts
per million, and coupling constant (J) is given in hertz. IR
spectra were recorded on a Perkin Elmer FTIR 1600
(Perkin Elmer Office, Akron, OH, USA) spectrometer for
samples in KBr disks. Low-resolution MS data were
obtained using ESI, and high-resolution spectra were
recorded on QSTARXL hybrid MS/MS system (Applied
Biosystems, Carlsbad, CA) under ESI. All compounds
were purified by flash chromatography performed using
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-
Triazole Derivatives
silica gel (100–200 mesh). All of the reactions were moni-
tored by thin-layer chromatography on silica gel 60F254
plates (VWR, Darmstadt, Germany); visualization by UV
detection is at 254nm.
1.0eq) at room temperature. The reaction mixture was stirred
at 110°C in a seal tube for 16h to afford 1.0g (74%) as a dark
brown solid. mp: 140–142°C; IR (KBr): υmax/cmꢀ1 =3397,
3335 (NH2), 3244 (NH), 3161, 3090 (Ar CH), 641 (C–Br);
1H NMR (400MHz, CDCl3): δ (ppm) 7.43 (s, 1H),
4.24–4.16 (m, 1H), 4.06 (brs, 3H), 1.25 (d, J=6.8Hz, 6H);
m/z (ES)+: 231.4 [M+1]+, 233.4 [M+3]+.
Synthesis of compound (2).
The NBS (12.3g,
69.38 mmol) was added to a stirred solution of compound
1 (10 g, 57.81 mmol) in 150 mL of chloroform at 0°C.
After 30min, reaction mixture was stirred at room
temperature for 6h. The reaction mixture was poured into
water and extracted with EtOAc, dried over anhydrous
Na2SO4, filtered, and concentrated. The crude product
was purified by chromatography using a gradient of
30–50% ethyl acetate and n-hexane to afford 13.2g
(91%) of compound 2 as a brown solid. mp: 110–112°C;
IR (KBr): υmax/cmꢀ1 = 3451, 3285 (NH2), 3157 (Ar –
6-Bromo-N2-methylpyrazine-2,3-diamine (3d).
Methylamine
in 40% aqueous solution (20 mL) was added to compound
2 (1.2g, 1.0eq) at room temperature. The reaction mixture
was stirred at 100°C in a seal tube for 18h to afford
720 mg (75%) as a brown solid. mp: 139–141°C; IR
(KBr): υmax/cmꢀ1 = 3438, 3390 (NH2), 3245 (NH), 3097,
3093 (Ar CH), 636 (C–Br); 1H NMR (400MHz,
DMSO-d6): δ (ppm) 7.18 (s, 1H), 6.61 (brs, 1H), 6.12 (s, 2H),
2.82 (d, J= 8.0 Hz, 3H); m/z (ES)+: 202.98 [M+1]+, 204.99
[M + 3]+.
1
CH), 637 (C–Br); H NMR (400MHz, CDCl3): δ (ppm)
8.04 (s, 1H), 5.05 (br s, 2 H); m/z Electrospray Ionization
(ES)+: 252.1 [M+ 1]+, 254.0 [M + 3]+.
General procedure for the synthesis of compounds
General procedure for the synthesis of compounds
(4a–d).
Oxalylchloride (5.0–3.0 eq) was added to a
(3a–d).
Cyclopropyl/pentyl amine was added to
stirred solution of appropriate diamines (3a–d) (1.0 eq)
and TEA (3.0 eq) in DCM at 0°C for 1h. The mixture
was stirred at room temperature for 3 h. The reaction
mixture was poured into crushed ice water and extracted
with EtOAc (2 × 30mL), dried with Na2SO4, filtered, and
concentrated to afford solid products.
7-Bromo-1-cyclopropylpyrazino[2,3-b]pyrazine-2,3(1H,4H)-
dione (4a). Prepared by general procedure from compound
3a (5.0 g, 21.92 mmol), (COCl)2 (9.46 mL, 109.64 mmol),
and TEA (9.2mL, 65.78mmol) in 150mL of dichlorometh-
ane to afford 5.8g (93%) as a brown solid. mp: 268–270°C;
IR (KBr): υmax/cmꢀ1 = 3380 (NH), 3084, 3051, 3020 (Ar
CH), 1712, 1699 (C=O), 648 (C–Br); 1H NMR (400MHz,
DMSO-d6): δ (ppm) 12.70 (s, 1H), 8.25 (s, 1H), 2.89–2.83
(m, 1H), 1.12–1.09 (m, 2H), 0.77–0.72 (m, 2H); m/z (ES)+:
282.99 [M+1]+, 284.97 [M+3]+.
7-Bromo-1-cyclopentylpyrazino [2,3-b]pyrazine-2,3(1H,4H)-
dione (4b). Prepared by general procedure from compound
3b (5.0g, 19.53mmol), (COCl)2 (8.4mL, 97.65mmol), and
TEA (8.2mL, 58.59mmol) in 150mL of dichloromethane to
afford 5.4g (90%) as a gray solid. mp: 278–280°C; IR
(KBr): υmax/cmꢀ1 =3426 (NH), 3155, 3123 (Ar CH), 1729,
1687 (C=O), 617 (C–Br); 1H NMR (400MHz, DMSO-d6):
δ (ppm) 12.79 (s, 1H), 8.24 (s, 1H), 5.48–5.44 (m, 1H),
2.10–1.97 (m, 4H), 1.87–1.79 (m, 2H), 1.62–1.58 (m, 2H);
m/z Electrospray Atmospheric Pressure Ionization
(ES-API)ꢀ: 309.0 [M–1]+.
compound 2 (1 eq) at room temperature. The reaction
mixture was stirred at 130°C to 140°C in microwave for
1.5h. Isopropyl amine/methyl amine (40% aqueous
solution) was performed in a seal tube at 100°C to 110°C
for 16–18h. Then, the reaction mixture was poured into
water and extracted twice with ethyl acetate. The
combined organics were dried over Na2SO4, filtered, and
concentrated. The crude product was purified by flash
column chromatography (100–200mesh) using a gradient
of 15–30% ethylacetate and n-hexane to afford solid
products.
6-Bromo-N2-cyclopropylpyrazine-2,3-diamine
(3a).
Cyclopropyl amine (10 mL) was added to compound 2
(1.2 g, 1.0eq) at room temperature. The reaction mixture
was stirred at 130°C in microwave for 1.5 h to afford
900mg (82%) as a brown solid. mp: 128–130°C; IR
(KBr): υmax/cmꢀ1 =3425, 3344 (NH2), 3241 (NH), 3087
1
(Ar CH), 637 (C–Br); H NMR (400 MHz, DMSO-d6): δ
(ppm) 7.20 (s, 1H), 6.71 (d, J= 2.0 Hz, 1H), 6.10 (brs,
2H), 2.71–2.68 (m, 1H), 0.71(q, J = 6.4 Hz, 2H), 0.44 (d,
J =6.8 Hz, 2H); m/z (ES)+: 229.2 [M + 1]+, 231.2 [M + 3]+.
6-Bromo-N2-cyclopentylpyrazine-2,3-diamine
(3b).
Cyclopentyl amine (12mL) was added to compound 2
(1.2 g, 1.0 eq) at room temperature. The reaction mixture
was stirred at 140°C in microwave for 1.5 h to afford
980mg (80%) as a brown solid. mp: 138–140°C; IR (KBr):
υ
max/cmꢀ1 =3401, 3325 (NH2), 3233 (NH), 2955 (Ar CH),
7-Bromo-1-isopropylpyrazino [2,3-b]pyrazine-2,3(1H,4H)-
1
636 (C–Br); H NMR (400MHz, CDCl3): δ (ppm) 7.43 (s,
1H), 4.31–4.24 (m, 1H), 4.18 (brs, 1H), 4.05 (brs, 2H),
2.17–2.09 (m, 2H), 1.75–1.60 (m, 4H), 1.46–1.39 (m, 2H);
m/z Atmospheric Pressure Chemical Ionization (APCI)+:
257.0 [M+1]+, 259.0 [M+ 3]+.
dione (4c).
Prepared by general procedure from com-
pound 3c (5.0 g, 21.73 mmol), (COCl)2 (9.38mL,
108.69mmol), and TEA (9.1 mL, 65.21mmol) in 150mL
of dichloromethane to afford 5.2 g (84%) as a brown solid.
mp: 258–260°C; IR (KBr): υmax/cmꢀ1 = 3418 (NH), 3160
(Ar CH), 1730,1688 (C=O), 635 (C–Br); 1H NMR
(400 MHz, DMSO-d6): δ (ppm) 12.74 (s, 1H), 8.25
6-Bromo-N2-isopropylpyrazine-2,3-diamine
Isopropylamine (20mL) was added to compound 2 (1.5g,
(3c).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

10
R. R. Ruddarraju, A. C. Murugulla, R. Kotla, M. C. B. Tirumalasetty, R. Wudayagiri,
S. Donthabakthuni, R. Maroju, and S. Palle
Vol 000
(s,1H), 5.33–5.26 (m, 1H), 1.48 (d, J= 6.8 Hz, 6H); m/z
(ES)+: 284.99 [M +1]+, 287.01 [M +3]+.
compound 4d (1.4 g, 5.46 mmol), K2CO3 (1.50 g,
10.93mmol), and propargylbromide (0.94mL, 10.93mmol)
in 42mL of THF to afford 1.21g (75%) as an off-white solid.
mp: 175–176°C; IR (KBr): υmax/cmꢀ1 =3371 (≡CH), 3053,
3004 (Ar CH), 1703 (C=O), 626 (C–Br); 1H NMR
(400MHz, CDCl3): δ (ppm) 8.32 (s, 1H), 5.09 (d, J=2.4Hz,
2H), 3.74 (s, 3H), 2.21 (t, J=2.8Hz, 1H); m/z (ES)+: 294.81
[M+1]+, 296.82 [M+3]+.
7-Bromo-1-methylpyrazino[2,3-b]pyrazine-2,3(1H,4H)-dione
(4d). Prepared by general procedure from compound 3d
(1.7 g, 8.41 mmol), (COCl)2 (2.18 mL, 25.24 mmol), and
TEA (2.36 mL, 16.83 mmol) in 51 mL of dichloromethane
to afford 1.82 g (84%) as a brown solid. mp: 288–290°C;
IR (KBr): υmax/cmꢀ1 = 3444 (NH), 3081, 3049 (Ar CH),
1702, 1682 (C=O), 653 (C–Br); 1H NMR (400 MHz,
DMSO-d6): δ (ppm) 12.82 (s, 1H), 8.24 (s, 1H), 3.44 (s,
3H); m/z (ES)+: 257.01 [M + 1]+, 258.97 [M + 3]+.
General procedure for the synthesis of compounds
(6a–d).
Sodium ascorbate (1.0 eq) and CuSO4.5H2O
(1.0 eq) were added subsequently to a solution of
appropriate (prop-2-ynyl)pyrazino[2,3-b]pyrazine (5a–d)
(1.0 eq) and 3-azido propionic acid (1.7 eq) in (2:1)
mixture of tert-butyl alcohol and water at room
temperature and stirred for 16h. From the reaction
mixture, tert-butyl alcohol was concentrated and added
with water, and the mixture was extracted with 10%
MeOH and CH2Cl2. The organic layers were dried with
Na2SO4, filtered, and concentrated to afford solid products.
3-(4-((7-Bromo-1-cyclopropyl-2,3-dihydro-2,3-dioxopyrazino
[2,3-b]pyrazin-4(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl) propanoic
acid (6a). Prepared by general procedure from compound
5a, sodium ascorbate (260mg, 1.31mmol) and
CuSO4.5H2O (327mg, 1.31mmol) were added subse-
quently to a solution of appropriate (prop-2-ynyl)pyrazino
[2,3-b]pyrazine (420mg, 1.31mmol) and 3-azido propionic
acid (256mg, 2.23mmol) in (2:1) mixture of tert-butyl alco-
hol and water to afford 480mg (84%) as a brown solid. mp:
190–192°C; IR (KBr): υmax/cmꢀ1 =3416 (OH), 3068, 3017
(Ar CH), 2099 (N¼N–N), 1712, 1701 (C=O), 629 (C–Br);
1H NMR (400MHz, DMSO-d6): δ (ppm) 12.48 (s, 1H),
8.38 (s, 1H), 7.96 (s, 1H), 5.35 (s, 2H), 4.45 (t, J=6.8Hz,
2H), 2.91–2.88 (m, 1H), 2.82 (t, J=7.2Hz, 2H), 1.14
(q, J=6.8Hz, 2H), 0.80 (brs, 2H); m/z (APCI)+: 438.0
[M+3]+.
General procedure for the synthesis of compounds
(5a–d). K2CO3 (2.0 eq) was added to a stirred solution
of appropriate pyrazine diones (4a–d) (1.0 eq) in THF at
room temperature. After 10 min, propargylbromide
(2.0 eq) was added to the reaction mixture and was
heated to 80°C for 12 h. The reaction mixture was cooled
to room temperature, added with water and extracted with
EtOAc, dried over Na2SO4, filtered, concentrated, and
purified by chromatography using a gradient of 10–50%
ethyl acetate and n-hexane to afford solid products.
6-Bromo-4-cyclopropyl-1-(prop-2-ynyl)pyrazino[2,3-b]pyrazine-2,3
(1H,4H)-dione (5a). Prepared by general procedure from com-
pound 4a (4.6 g, 16.31 mmol), K2CO3 (4.5g, 32.62 mmol), and
propargylbromide (2.81mL, 32.62 mmol) in 92mL of THF to
afford 4.0 g (76%) as an off-white solid. mp: 143–145°C; IR
(KBr): υmax/cmꢀ1 =3417 (≡CH), 3091, 3018 (Ar CH), 1713
1
(C=O), 645 (C–Br); H NMR (400MHz, CDCl3): δ (ppm)
8.31 (s, 1H), 5.06 (d, J=2.4Hz, 2H), 3.08–3.04 (m, 1H), 2.21
(t, J=2.0Hz, 1H), 1.35 (q, J=7.2Hz, 2H), 0.92 (q, J=7.2Hz,
2H); m/z (ES)+: 320.80 [M+ 1]+.
6-Bromo-4-cyclopentyl-1-(prop-2-ynyl)pyrazino[2,3-b]pyrazine-2,3
(1H,4H)-dione (5b). Prepared by general procedure from com-
pound 4b (1.4 g, 4.51 mmol), K2CO3 (1.24g, 9.03 mmol), and
propargylbromide (0.77mL, 9.03mmol) in 42mL of THF to af-
ford 1.35 g (85%) as a light brown solid. mp: 156–158°C; IR
(KBr): υmax/cmꢀ1 =3424 (≡CH), 2125 (C≡C), 1707 (C=O),
3-(4-((7-Bromo-1-cyclopentyl-2,3-dihydro-2,3-dioxopyrazino
[2,3-b]pyrazin-4(1H)-yl) methyl)-1H-1,2,3-triazol-1-yl)propanoic
acid (6b). Prepared by general procedure from 5b, sodium
ascorbate (227mg, 1.14mmol) and CuSO4.5H2O (286mg,
1.14mmol) were added subsequently to a solution of appro-
1
631 (C–Br); H NMR (400MHz, CDCl3): δ (ppm) 8.28 (s,
1H), 5.69–5.65 (m, 1H), 5.07 (d, J=2.4Hz, 2H), 2.22–2.10
(m, 5H), 2.01–1.95 (m, 2H), 1.70–1.67 (m, 2H); m/z (ES)+:
348.81 [M+1]+, 350.79 [M + 3]+.
priate
(prop-2-ynyl)pyrazino[2,3-b]pyrazine
(400mg,
6-Bromo-4-isopropyl-1-(prop-2-ynyl)
pyrazino
[2,3-b]
1.14mmol) and 3-azido propionic acid (224mg, 1.95mmol)
in (2:1) mixture of tert-butyl alcohol and water to afford
400mg (75%) as a gray solid. mp: 220–222°C; IR (KBr):
pyrazine-2,3(1H,4H)-dione (5c). Prepared by general pro-
cedure from compound 4c (1.4 g, 4.92mmol), K2CO3
(1.36g, 9.85 mmol), and propargylbromide (0.84 mL,
9.85mmol) in 42 mL of THF to afford 1.15g (72%) as a
υ
max/cmꢀ1 =3440 (OH), 2100 (N¼N–N), 1704 (C=O), 621
(C–Br); 1H NMR (400MHz, DMSO-d6): δ (ppm) 12.49 (s,
1H), 8.38 (s, 1H), 7.98 (s, 1H), 5.52–5.46 (m, 1H), 5.36 (s,
2H), 4.46 (brs, 2H), 2.83 (brs, 2H), 2.11–1.93 (m, 4H),
1.87–1.85 (m, 2H), 1.68–1.49 (m, 2H); m/z (Multimode
Electrospray Ionization (MM-ES) +APCI)+: 465.9 [M +3]+.
3-(4-((7-Bromo-2,3-dihydro-1-isopropyl-2,3-dioxopyrazino[2,3-b]
brown solid. mp: 140–142°C; IR (KBr): υmax
/
cmꢀ1 = 3398 (≡CH), 3081 (Ar CH), 2152 (C≡C), 1713
(C=O), 621 (C–Br); 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.29 (s, 1H), 5.58–5.53 (m, 1H), 5.07 (d,
J =2.4 Hz, 2H), 2.22 (t, J =2.0 Hz, 1H), 1.61 (d,
J =6.8 Hz, 6H); m/z (ES)+: 322.85 [M + 1]+.
pyrazin-4(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoic
(6c).
acid
6-Bromo-4-methyl-1-(prop-2-ynyl)pyrazino[2,3-b]pyrazine-2,3
(1H,4H)-dione (5d). Prepared by general procedure from
Prepared by general procedure from 5c, sodium
ascorbate (196mg, 0.99 mmol) and CuSO4.5H2O (248mg,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-
Triazole Derivatives
0.99 mmol) were added subsequently to a solution of appropri-
ate (prop-2-ynyl)pyrazino[2,3-b]pyrazine (320mg, 0.99mmol)
and 3-azido propionic acid (194mg, 1.68mmol) in (2:1) mix-
ture of tert-butyl alcohol and water to afford 330mg (76%)
6-Bromo-4-cyclopentyl-1-((1-(3-(4-ethylpiperazin-1-yl)-3-
oxopropyl)-1H-1,2,3-triazol-4-yl)methyl)pyrazino[2,3-b]pyrazine-2,3
(1H,4H)-dione (7b).
Yellow solid; yield 88%; mp:
190–192°C; IR (KBr): υmax/cmꢀ1 =2959, 2870 (CH2,
as an off-white solid. mp: 218–220°C; IR (KBr): υmax
/
CH3), 1703, 1643 (C=O), 1538, 1460 (C=C, C=N), 1301,
1219 (C–N), 557 (C–Br); H NMR (400MHz, CDCl3): δ
cmꢀ1 =3444 (OH), 3064, 3025 (Ar CH), 2102 (N¼N–N),
1740, 1700 (C=O), 621 (C–Br); 1H NMR (400MHz,
DMSO-d6): δ (ppm) 12.47 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H),
5.36 (s, 2H), 4.46 (t, J= 7.2 Hz, 2H), 2.83 (t, J=6.8Hz,
2H), 1.49 (d, J=7.2Hz, 6H); m/z (MM-ES+ APCI)+: 437.9
[M+1]+, 439.9 [M+ 3]+.
1
(ppm) 8.29 (s, 1H), 7.81 (s, 1H), 5.62 (s, 2H), 4.65 (t,
J=6.8Hz, 2H), 3.60 (brs, 2H), 3.38 (brs, 2H), 3.03–3.01
(m, 1H), 2.92 (t, J=6.8Hz, 2H), 2.42–2.38 (m, 6H), 2.21–
2.08 (m, 4H), 1.95 (brs, 2H), 1.68 (brs, 2H), 1.08 (t,
J=7.2Hz, 3H); 13C NMR (400MHz, CDCl3): δ (ppm)
167.70, 154.0, 153.78, 141.11, 138.17, 135.70, 134.38,
130.29, 125.14, 52.88, 52.14, 51.81, 48.29, 46.02, 44.13,
40.53, 36.98, 32.99, 18.88, 10.97; HRMS (ESI): calculated
for C23H31BrN9O3 [M+H]+: 560.1727, found: 560.1722.
6-Bromo-1-((1-(3-(4-ethylpiperazin-1-yl)-3-oxopropyl)-1H-
1,2,3-triazol-4-yl)methyl)-4-isopropylpyrazino[2,3-b]pyrazine-
3-(4-((7-Bromo-2,3-dihydro-1-methyl-2,3-dioxopyrazino[2,3-b]
pyrazin-4(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoic acid
(6d). Prepared by general procedure from 5d, sodium
ascorbate (357 mg, 1.80 mmol) and CuSO4.5H2O
(450 mg, 1.80 mmol) were added subsequently to a solu-
tion of appropriate (prop-2-ynyl)pyrazino[2,3-b]pyr-
azine (530 mg, 1.80 mmol) and 3-azido propionic acid
(414 mg, 3.60 mmol) in (2:1) mixture of tert-butyl alco-
hol and water to afford 580 mg (79%) as an off-white
solid. mp: 257–259°C; IR (KBr): υmax/cmꢀ1 = 3443
(OH), 3084 (Ar CH), 2100 (N¼N–N), 1700, 1693
2,3(1H,4H)-dione (7c).
Pale yellow solid; yield 90%;
mp: 185–187°C; IR (KBr): υmax/cmꢀ1 = 2971, 2934
(CH2, CH3), 1703, 1643 (C=O), 1538, 1460 (C=C,
C=N), 1300, 1218 (C–N), 557 (C–Br); 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.29 (s, 1H), 7.82 (s, 1H),
5.61 (s, 2H), 4.65 (t, J=6.4Hz, 2H), 3.60 (t, J=4.8Hz,
2H), 3.39 (t, J=4.8Hz, 2H), 3.0–2.99 (m, 1H), 2.92 (t,
J=6.8Hz, 2H), 2.44–2.38 (m, 6H), 1.59 (d, J=6.8Hz,
6H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (400 MHz,
CDCl3): δ (ppm) 167.53, 154.09, 153.87, 141.08,
138.17, 135.69, 134.33, 130.27, 125.34, 52.58, 52.22,
52.16, 48.26, 45.99, 45.08, 41.62, 36.83, 33.29, 18.84,
11.83; HRMS (ESI): calculated for C21H29BrN9O3 [M
+ H]+: 534.1571, found: 534.1561.
1
(C=O), 695 (C–Br); H NMR (400 MHz, DMSO-d6): δ
(ppm) 12.41 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 5.39 (s,
2H), 4.45 (t, J = 6.8 Hz, 2H), 3.49 (s, 3H), 2.82 (t,
J = 6.8 Hz, 2H); m/z (MM-ES + APCI)+: 409.8 [M + 1]+,
411.9 [M + 3]+.
General procedure for the synthesis of compounds (7a–d
and 8a–d).
To a solution of 6a–d (1.0 equiv) and N-
ethylpiperazine or morpholine (1.5 equiv) in CH2Cl2
(10 mL) were added HATU (1.5 equiv) and DIPEA
(3.0 equiv) at room temperature, and the reaction mixture
was stirred at room temperature for 10 h. Then, the
reaction mixture was poured into water and extracted
with dichloromethane (20 mL) and washed with brine
solution, dried with anhydrous Na2SO4, filtered, and
concentrated. The crude products were purified by silica
gel short-column chromatography using a gradient of 2–
5% MeOH in CH2Cl2.
6-Bromo-1-((1-(3-(4-ethylpiperazin-1-yl)-3-oxopropyl)-1H-
1,2,3-triazol-4-yl)methyl)-4-methylpyrazino[2,3-b]pyrazine-2,3
(1H,4H)-dione (7d).
Brown solid; yield 86%; mp:
180–182°C; IR (KBr): υmax/cmꢀ1 = 2980, 2966 (CH2,
CH3), 1703, 1696 (C=O), 1538, 1470 (C=C, C=N), 1274,
1
1260 (C–N), 567 (C–Br); H NMR (400MHz, CDCl3): δ
(ppm) 8.31 (s, 1H), 7.80 (s, 1H), 5.64 (s, 2H), 4.65 (t,
J =6.4 Hz, 2H), 3.71 (s, 3H), 3.62 (brs, 2H), 3.43 (brs,
2H), 2.91 (t, J =6.0 Hz, 2H), 2.41 (brs, 6H), 1.10 (brs,
3H); 13C NMR (400MHz, CDCl3): δ (ppm) 167.57,
153.99, 153.43, 141.05, 138.51, 136.06, 134.52, 131.05,
125.08, 52.19, 51.82, 48.20, 45.99, 45.07, 41.60, 36.83,
33.06, 28.97, 12.10; m/z (MM-ES+ APCI)+: 506.0 [M
+ 1]+, 508.0 [M +3]+.
6-Bromo-4-cyclopropyl-1-((1-(3-morpholino-3-oxopropyl)-1H-
1,2,3-triazol-4-yl)methyl)pyrazino[2,3-b]pyrazine-2,3(1H,4H)-
dione (8a). Off-white solid; yield 87%; mp: 180–182°C; IR
(KBr): υmax/cmꢀ1 =3041 (Ar CH), 2921, 2857 (CH2), 1714,
1696, 1632 (C=O), 1534, 1456 (C=C, C=N), 1225, 1214
(C–N), 1143, 1113 (C–O–C), 685 (C–Br); 1H NMR
(400MHz, CDCl3): δ (ppm) 8.31 (s, 1H), 7.81 (s, 1H), 5.60
(s, 2H), 4.65 (t, J= 6.8 Hz, 2H), 3.64–3.57 (m, 6H), 3.37
(J=4.8Hz, 2H), 3.18–3.04 (m, 1H), 2.92 (t, J=6.8Hz, 2H),
6-Bromo-4-cyclopropyl-1-((1-(3-(4-ethylpiperazin-1-yl)-3-
oxopropyl)-1H-1,2,3-triazol-4-yl)methyl)pyrazino[2,3-b]pyrazine-
2,3(1H,4H)-dione (7a).
Yellow solid; yield 86%; mp:
170–172°C; IR (KBr): υmax/cmꢀ1 =2969, 2921 (CH2,
CH3), 1716, 1696,1633 (C=O), 1536, 1455 (C=C, C=N),
1225, 1215 (C–N), 618 (C–Br); 1H NMR (400MHz,
CDCl3): δ (ppm) 8.30 (s, 1H), 7.80 (s, 1H), 5.60 (s, 2H),
4.65 (t, J=6.0Hz, 2H), 3.61 (brs, 2H), 3.41 (brs, 2H),
3.04–3.02 (m, 1H), 2.92 (t, J= 6.0 Hz, 2H), 2.40 (brs, 6H),
1.32 (q, J= 7.2 Hz, 2H), 1.09 (brs, 3H), 0.91 (brs, 2H); 13C
NMR (400MHz, CDCl3): δ (ppm) 167.60, 154.64, 153.75,
141.13, 138.56, 137.10, 134.38, 130.94, 125.06, 52.18,
51.88, 51.62, 45.99, 44.26, 40.82, 36.85, 32.86, 11.01,
9.03; HRMS (ESI): calculated for C21H27BrN9O3 [M
+ H]+: 532.1414, found: 532.1406.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

12
R. R. Ruddarraju, A. C. Murugulla, R. Kotla, M. C. B. Tirumalasetty, R. Wudayagiri,
S. Donthabakthuni, R. Maroju, and S. Palle
Vol 000
1.32 (q, J= 7.2 Hz, 2H), 0.90 (q, J= 4.0 Hz, 2H); 13C NMR
(400MHz, CDCl3): δ (ppm) 167.77, 154.61, 153.76,
141.09, 138.53, 137.14, 134.38, 130.93, 125.42, 66.68,
66.35, 46.12, 45.65, 42.07, 36.70, 33.09, 9.02; HRMS
(ESI): calculated for C19H22BrN8O4 [M+H]+: 505.0941,
found: 505.0950.
(2 × 30mL), dried with Na2SO4, filtered, and
concentrated. The crude product was purified by column
chromatography using a gradient of 2% MeOH in
CH2Cl2 to afford as a colorless liquid 1.7 g (85%) of
1
compound 10. H NMR (400MHz, CDCl3): δ 8.63 (s,
1H), 7.43 (d, J =3.6 Hz, 1H), 6.68 (d, J = 3.2 Hz, 1H),
5.67 (q, J = 7.6 Hz, 1H), 4.21 (q, J= 7.2 Hz, 2H), 1.81 (d,
J = 7.6 Hz, 3H), 1.25 (t, J= 7.2 Hz, 3H); m/z (ES
+ APCI)+: 254.1 [M+ 1]+, 256.1 [M + 3]+.
6-Bromo-4-cyclopentyl-1-((1-(3-morpholino-3-oxopropyl)-
1H-1,2,3-triazol-4-yl)methyl) [2,3-b]pyrazine-2,3(1H,4H)-dione
(8b).
Off-white solid; yield 92%; mp: 217–219°C; IR
(KBr): υmax/cmꢀ1 =3073 (Ar CH), 2958, 2919 (CH2),
1703, 1636 (C=O), 1537, 1457 (C=C, C=N), 1295, 1224
(C–N), 1146, 1114 (C–O–C), 550 (C–Br); 1H NMR
(400MHz, CDCl3): δ (ppm) 8.29 (s, 1H), 7.82 (s, 1H),
5.67–5.62 (m, 3H), 4.66 (t, J=6.4Hz, 2H), 3.64–3.58 (m,
6H), 3.37 (t, J=4.8Hz, 2H), 2.92 (t, J=6.4Hz, 2H), 2.17–
2.10 (m, 4H), 1.96 (brs, 2H), 1.68 (brs, 2H); m/z (ES)+:
533.48 [M+1]+.
2-(4-Chloro-7H-pyrrolo [2,3-d]pyrimidin-7-yl)propan-1-ol
(11). NaBH4 (470mg, 12.64 mmol) was added to a 0°C
solution of compound 10 (1.6 g, 6.32mmol) in EtOH
(24 mL). The mixture was stirred at room temperature for
6 h. The reaction mixture was quenched with crushed ice
water and extracted with EtOAc (2× 30mL), dried with
Na2SO4, filtered, and concentrated to afford white solid
1.2 g (90%) of compound 11. mp: 206–208°C; IR (KBr):
6-Bromo-4-isopropyl-1-((1-(3-morpholino-3-oxopropyl)-1H-
1,2,3-triazol-4-yl)methyl) pyrazino [2,3-b]pyrazine-2,3(1H,4H)-
dione (8c). Off-white solid; yield 85%; mp: 200–202°C;
IR (KBr): υmax/cmꢀ1 =3063 (Ar CH), 2975, 2923 (CH2),
1707, 1699, 1633 (C=O), 1535, 1456 (C=C, C=N), 1290,
υ
max/cmꢀ1 = 3288 (OH), 3080 (Ar CH), 2986, 2950,
2929, 2875 (CH2, CH3), 1588, 1543, 1505, 1459, 1429
(C=C, C=N), 1360 (C–N), 1077, 1052 (C–O), 747
1
(C–Cl); H NMR (400MHz, CDCl3): δ 8.61 (s, 1H), 7.36
(d, J =3.6 Hz, 1H), 6.64 (d, J =3.6 Hz, 1H), 4.92–4.90
(m, 1H), 3.99 (qd, J = 3.2 Hz, J= 11.6 Hz, 2H), 1.59 (d,
J = 7.2 Hz, 3H); m/z (ES + APCI)+: 212.0 [M + 1]+, 214.0
[M + 3]+.
1
1227 (C–N), 1148, 1116 (C–O–C), 562 (C–Br); H NMR
(400MHz, CDCl3): δ (ppm) 8.29 (s, 1H), 7.82 (s, 1H),
5.62 (s, 2H), 5.56–5.53 (m, 1H), 4.66 (t, J=6.4Hz, 2H),
3.65–3.57 (m, 6H), 3.37 (t, J= 4.8 Hz, 2H), 2.92 (t,
J=6.0Hz, 2H), 1.59 (d, J=6.8Hz, 6H); 13C NMR
(400MHz, CDCl3): δ (ppm) 167.79, 153.77, 153.60,
141.07, 138.15, 135.68, 134.36, 130.21, 125.21, 66.92,
66.35, 48.21, 45.60, 42.02, 36.77, 33.09, 18.89; HRMS
(ESI): calculated for C19H24BrN8O4 [M+H]+: 507.10984,
found: 507.10983.
General procedure for the synthesis of compounds
(12a–d).
The DCC (1.5 equiv) was added to a 0°C
solution of 6a–d (1.0 equiv) and corresponding alcohol
11 (1.1 equiv) in 10mL of CH2Cl2. After 2 min, DMAP
(0.4 equiv) was added, and the solution was allowed to be
stirred at room temperature for 16h. The reaction mixture
was filtered and washed with dichloromethane. The
filtrate was washed with water and brine solution, dried
with anhydrous Na2SO4, filtered, and concentrated. The
crude products were purified by silica gel column
chromatography using a gradient of 2–5% MeOH in
CH2Cl2.
6-Bromo-4-methyl-1-((1-(3-morpholino-3-oxopropyl)-1H-
1,2,3-triazol-4-yl)methyl)pyrazino [2,3-b]pyrazine-2,3(1H,4H)-
dione (8d). Off-white solid; yield 88%; mp: 206–208°C;
IR (KBr): υmax/cmꢀ1 =2960, 2925 (CH2), 1707, 1642
(C=O), 1536, 1465 (C=C, C=N), 1227, 1217 (C–N),
1
1153, 1115 (C–O–C), 533 (C–Br); H NMR (400MHz,
2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl 3-(4-((6-
bromo-4-cyclopropyl-2,3-dioxo-3,4-dihydropyrazino[2,3-b]
pyrazin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoate
(12a). Yellow solid; yield 82%; mp: 167–169°C; IR
(KBr): υmax/cmꢀ1 = 2930, 2855 (CH2, CH3), 1706,
1651 (C=O), 1588, 1539, 1456 (C=C, C=N), 1354,
1322, 1215, 1148 (C–O, C–N), 733 (C–Cl), 619
CDCl3): δ (ppm) 8.34 (s, 1H), 7.84 (s, 1H), 5.66 (s, 2H),
4.67 (t, J = 6.8 Hz, 2H), 3.73 (s, 3H), 3.66–3.60 (m,
6H), 3.39 (t, J = 4.8 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H);
13C NMR (400 MHz, CDCl3): δ (ppm) 167.78, 153.93,
153.36, 141.06, 138.53, 136.04, 134.51, 131.02,
125.19, 66.69, 66.34, 45.91, 45.60, 42.03, 36.78, 33.14,
28.96; m/z (MM-ES + APCI)+: 479.0 [M + 1]+, 481.0
[M + 3]+.
1
(C–Br); H NMR (400MHz, DMSO-d6): δ (ppm) 8.55
(s, 1H), 8.35 (d, J=6.4Hz, 1H), 7.92 (s, 1H), 7.86 (d,
J =4.0Hz, 1H), 6.66 (d, J= 3.6Hz, 1H), 5.35 (s, 2H),
5.13–5.08 (m, 1H), 4.49–4.36 (m, 4H), 2.90–2.86 (m,
1H), 2.81–2.73 (m, 2H), 1.50 (d, J = 6.8 Hz, 3H),
1.15–1.14 (m, 2H), 0.77–0.73 (m, 2H); 13C NMR
(400 MHz, CDCl3): δ (ppm) 169.85, 154.60, 153.76,
152.24, 151.02, 150.46, 141.15, 138.63, 137.03,
134.29, 130.97, 126.46, 125.07, 117.71, 100.16,
67.06, 49.75, 45.30, 36.64, 34.15, 26.26, 16.71, 9.01;
Ethyl-2-(4-chloro-7H-pyrrolo
[2,3-d]pyrimidin-7-yl)
propanoate (10). NaH (560 mg, 23.52 mmol) was added
to a 0°C solution of compound 9 (1.2 g, 7.84 mmol) in
THF (18 mL). After 30 min, ethyl 2-bromopropanoate
(2.28 mL, 15.68 mmol) was added at 0°C, and the
resulting stirring mixture was warmed to 80°C for 16h.
The reaction mixture was cooled to 0°C and quenched
with crushed ice water and extracted with EtOAc
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3-
Triazole Derivatives
HRMS (ESI): calculated for C24H23BrClN10O4 [M
+ H]+: 629.0770, found: 629.0778.
34.19, 28.88, 16.68; m/z (ES)+: 603.19 [M + 1]+, 605.18
[M + 3]+.
2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl 3-(4-((6-
bromo-4-cyclopentyl-2,3-dioxo-3,4-dihydropyrazino[2,3-b]pyrazin-
Molecular Docking and Binding Energy/Affinity
Calculations.
Protein–ligand docking studies were
1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoate (12b).
Pale
yellow solid; yield 86%; mp: 180–182°C; IR (KBr):
max/cmꢀ1 = 3084 (Ar CH), 2934, 2852 (CH2, CH3),
performed with compounds 7a–d, 8a–d, and 12a–d
against selective drug targets of cancer and diabetes, viz.
EGFR, VEGFR2, aldose reductase, and 1,6-glucokinase,
using docking module implemented in Molecular
Operating Environment (MOE) [70]. All of the cocrystal
structures were retrieved from the protein data bank
(www.rcsb.org). Initially, all crystal structures were
protonated with the addition of polar hydrogen followed
by energy minimization with MMFF94x force field in
order to obtain stable conformer of the proteins. The
inhibitor-binding site residues were collected from the
literature, which is selected and highlighted through “Site
Finder” module implemented in MOE software, and
docking was carried out with default parameters, that is,
placement: triangle matcher, recording 1: London dG,
and refinement: force field, and a maximum of 10
conformations of each compound was allowed to save in
a separate database file in .mdb format.
υ
1705, 1626 (C=O), 1587, 1539, 1456 (C=C, C=N), 1354,
1344, 1295, 1214, 1147 (C–O, C–N), 730 (C–Cl), 552
1
(C–Br); H NMR (400 MHz, CDCl3): δ (ppm) 8.51 (s,
1H), 8.30 (s, 1H), 7.75 (s, 1H), 7.29 (d, J = 3.6 Hz, 1H),
6.62 (d, J = 4.0 Hz, 1H), 5.62 (d, J = 3.6 Hz, 3H), 5.18–
5.17 (m, 1H), 4.49–4.38 (m, 4H), 2.79 (t, J = 6.4 Hz, 2H),
2.15–2.07 (m, 4H), 1.94–1.92 (m, 2H), 1.68–1.66 (m,
2H), 1.60 (d, J = 7.2 Hz, 3H); 13C NMR (400 MHz,
CDCl3): δ (ppm) 169.84, 153.65, 153.61, 152.23, 151.0,
150.47, 141.36, 138.16, 135.71, 134.40, 130.21, 126.44,
125.05, 117.70, 100.13, 67.03, 55.05, 49.74, 45.27,
36.66, 34.16, 33.94, 32.45, 26.00, 25.92, 16.72; HRMS
(ESI): calculated for C26H26BrClN10O4Na [M + Na]+:
679.09026, found: 679.09021.
2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl 3-(4-
((6-bromo-4-isopropyl-2,3-dioxo-3,4-dihydropyrazino[2,3-b]
pyrazin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoate (12c).
Off-white solid; yield 80%; mp: 158–160°C; IR (KBr):
The binding energy and binding affinity of protein–
ligand complexes were calculated using molecular
mechanics generalized Born interactions/volume integral
implicit solvent method in LigX of MOE [71].
υ
max/cmꢀ1 =3078 (Ar CH), 2934, 2856 (CH2, CH3),
1705, 1638 (C=O), 1587, 1538, 1457 (C=C, C=N),
Acknowledgment. The authors are thankful to the Director,
1354, 1323, 1296, 1214, 1149 (C–O, C–N), 732 (C–Cl),
553 (C–Br); H NMR (400MHz, CDCl3): δ (ppm) 8.25
Dr. MACS Bio-Pharma Pvt. Ltd., for providing facilities.
1
(s, 1H), 8.31 (s, 1H), 7.76 (s, 1H), 7.29 (d, J=3.6Hz,
1H), 6.61 (d, J=3.6Hz, 1H), 5.61 (s, 2H), 5.59–5.49
(m, 1H), 5.42–5.31 (m, 1H), 4.49–4.38 (m, 4H), 2.79 (t,
J=6.4 Hz, 2H), 1.61–1.54 (m, 9H); 13C NMR (400MHz,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet