Design, synthesis,: In silico docking studies and biological evaluation of novel quinoxaline-hydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase inhibitors and antioxidants

Article abstract of DOI:10.1039/c9nj02580d

A new series of quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids, 14a-j, 15a-j and 16a-e, was designed, synthesized and screened for in vitro α-glucosidase and antioxidant activities. For the synthesis of the target compounds, quinoxaline hydrazides were condensed with benzaldehyde triazoles in the presence of AcOH (cat) in ethanol. The key step in the preparation of compounds 8a-j was the Cu(i)-catalyzed [3+2] cycloaddition reaction (CuAAC) with appropriate alkynes (6, 7) and azides, and 13a-j were prepared from simple aldehydes utilizing the same click reaction as the final step. Quinoxaline hydrazides (3, 3a) were synthesized from o-phenylenediamine and pyruvic acid via three-step reactions comprising cyclization, alkylation and hydrazidation. Among these hybrids, 14a (IC₅₀ = 21.92 μg mL^-1), 14b (IC₅₀ = 22.32 μg mL^-1), 14c (IC₅₀ = 23.58 μg mL^-1) and 15a (IC₅₀ = 24.50 μg mL^-1) showed good α-glucosidase inhibition compared with the standard acarbose (IC₅₀ = 22.32 μg mL^-1). Further, the scavenging abilities of the synthesized compounds as antioxidants were studied using the DPPH, H₂O₂, and NO methods; as per the obtained results, compounds 14a, 14b, 14c and 15a displayed good antioxidant activity. Docking studies of the active compounds and acarbose as a standard with α-glucosidase (PDB ID: 2ZEO) were performed to determine the molecular interactions between the inhibitors and the active site of the enzyme. Better binding energies of the active compounds than of the standard acarbose were observed. Therefore, our new hybrid molecules may be useful for further optimization in developing new lead molecules with both α-glucosidase inhibition and antioxidant activities.

Full text of DOI:10.1039/c9nj02580d

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Design, Synthesis, in silico docking studies and biological evaluation of novel
quinoxaline-hydrazide hydrazone-1,2,3-triazole hybrids as α-glucosidase
inhibitors, antioxidants
Settypalli Triloknadh,a Chunduri Venkata Rao,*a Maddineni Aruna Kumaria, Begari
Nagarajua, Allagadda Rajasekhar,b Kotha Peddannab and Chippada Appa Raob
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b
aDepartment of Chemistry, Biochemistry, Sri Venkateswara University, Tirupati-517502,
Andhra Pradesh, India.
*a Corresponding author E-Mail: cvrsvu@gmail.com, Tel: +91 9849605140, Fax:
+918772289555.
Abstract:
A new series of quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids 14a-j, 15a-j & 16a-e has
been designed, synthesized and screened for in vitro α-glucosidase and antioxidant activities. For
the synthesis of target compounds, quinoxalinehydrazides were condensed with
benzaldehydetriazoles in presence of AcOH (cat) in ethanol. The key step in the preparation of
compounds 8a-j is done by the use of Cu(I) catalyzed [3+2] cycloaddition reaction (CuAAC)
with appropriate alkynes (6, 7) and azides and 13a-j were prepared from simple aldehydes
utilizing same click reaction as final step. Quinoxalinehydrazides (3, 3a) were synthesized from
o-phenylenediamine and pyruvic acid via three-step reaction comprising cyclization, alkylation
and hydrazidation. Among these hybrids, 14a (IC50 = 21.92 µg/mL), 14b (IC50 = 22.32 µg/mL),
14c (IC50 = 23.58 µg/mL) and 15a (IC50 = 24.50 µg/mL) showed good α-glucosidase inhibition
as compared with standard acarbose (IC50 = 22.32 µg/mL). Further, scavenging ability of
synthesized compounds as antioxidants was studied by using DPPH, H2O2, NO methods and as
per the obtained results, compounds 14a, 14b, 14c & 15a displayed good antioxidant activity.
The docking studies were performed with α-glucosidase (PDB ID:2ZEO) over the active
compounds to know the molecular interactions between the inhibitors and the active site of
enzyme and acarbose as standard. The good binding energies of active compounds than that of
standard acarbose have been observed. Therefore, our new hybrid molecules would useful for
further optimization in developing of new lead molecules having both α-glucosidase inhibition
and antioxidant activity.
Keywords: Quinoxalines, Hydrazide-hydrazones, 1,2,3-Triazoles, Click chemistry, α-
Glucosidase inhibition, Antioxidant activity, Docking studies

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Introduction
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α-Glucosidase is an enzyme, located in the brush border of small intestine and is
responsible for breakdown of α(1→4) bonds in carbohydrates such as starch, disaccharides and
dextrins to absorbable monosaccharides.1 Thus, inhibition of α-glucosidase activity could reduce
postprandial plasma glucose levels and suppression of postprandial hyperglycemia. Hence, α-
glucosidase has been considered as an important target for type 2 diabetes treatments. Acarbose,
miglitol, voglibose are the important drugs widely used in clinics for the treatment of patients
suffering with type 2 diabetes.2,3 Furthermore, oxidative stress and the overproduction of free
radicals have been implicated in diabetic complications4 and hence the molecules exhibiting both
α-glucosidase inhibition and antioxidant properties are desirable in present market.
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Quinoxaline, also called as benzopyrazine or benzo[b][1,4]diazine, is one of the
important core unit in medicinal chemistry because of broad spectrum of biological activities. It
is used as fungicides, insecticides and herbicides in agricultural field,5 also found applications in
dyes, organic-light emitting diodes,6,7 electroluminescent materials,8 cavitands, organic
semiconductors,9 photovoltaics. Some antibiotics like echinomycin, levomycin, carbadox and
actinoleutin comprised the quinoxaline ring in their structures, which are known to inhibit the
growth of bacteria. Furthermore, quinoxaline derivatives have shown antimalarial,10
antiplasmodial,11 antithrombotic,12 anti-tubercular,13 antitumor,14 antiviral,15,16 AMPA receptor
antagonist,17 antiprotozoal18 activities in the literature. Hydrazide-hydrazone derivatives are vital
class of organic compounds attracting numerous medicinal chemists in drug development,
because they contain azomethine group connected to a carbonyl group (-CONH-N=CH-), which
is responsible for a variety of pharmacological activities19,20; viz., anticancer,21 analgesic and
anti-inflammatory,22 kinase A inhibitor,23 anticonvulsant,24 HIV-1 integrase inhibitor,25
antileishmanial,26 antimalarial,27 cytotoxic28 activities.
1,2,3-Triazole derivatives are important class of bioactive compounds in the field of
pharmaceuticals and drugs. The classical Huisgen’s dipolar (3+2) cycloaddition reaction is one
of the important synthetic approach for synthesis of 1,2,3-triazoles, leading to a mixture of 1,4
and 1,5-disubstituted triazoles.29 However, Sharpless and Meldal developed independently a
significant method to achieve regioselectivity in Huisgen’s dipolar (3+2) cycloaddition using
Cu(I) catalyst in the formation of high yields of 1,4-disubstituted 1,2,3-triazoles with good
reaction rates30 and shorter reaction times31,32 which are stable to metabolic degradation and

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capable to form hydrogen bonding with biomolecular targets.33 They possess wide range of
biological activities such as antitubercular,34 anti-inflammatory and anticancer,35 antifungal,36,37
HIV-RT inhibitor,38 antiviral,39 insecticidal40 etc. The bioactive compounds bearing quinoxaline,
hydrazide-hydrazone, 1,2,3-triazole pharmacophoric units were shown in Figure 1 (I-X).41-49
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Figure 1. Reported α-glucosidase inhibitors and antioxidant compounds containing
Quinoxaline, Hydrazide-hydrazone, 1,2,3-Triazole pharmacophores.
Enthused by above discussed biological significance and reported bioactive molecules
shown in Figure 1, using molecular hybridization technique, we herein designed a strategy
(Figure 2) to club the all three pharmacophoric units into a single molecule and the resulted ones
may have chance to exhibit the good biological activities. Here in this work we have synthesized,
characterized (See Supporting information) and screened twenty novel quinoxaline-

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hydrazidehydrazone-1,2,3-triazole hybrids for their α-glucosidase inhibition and antioxidant
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activities.
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Figure 2. Design strategy for target compounds
Results and discussion
Synthesis and characterization
Synthetic route of compound 3 and 3a was depicted in Scheme 1. The key starting
compound 3-methylquinoxalin-2(1H)-one 1 was easily prepared according to the reported
methods.50 Reaction of 1 with ethyl bromo acetate in acetone in the presence of K2CO3 gives
ethyl 2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetate 2 (Major) and ethyl 2-((3-methylquinoxalin-
2-yl)oxy)acetate 2a (Minor) as two products. Compounds 2 and 2a further reacted with
hydrazine hydrate in ethanol under reflux conditions at 90 ºC for 5 h to afford corresponding
quinoxaline N-alkyl acid hydrazide 3, quinoxaline O-alkyl acid hydrazide 3a in good yields.
Compound 1 was confirmed by appearance of additional –CONH (δ 12.28 ppm), –Me (δ 2.40
1
13
ppm) signals and C2 (δ 154.88 ppm), C3 (159.15 ppm) carbon signals in the H-NMR and C-
NMR spectra respectively. (M+H)+ Peak appeared at m/z = 161 confirm the molecular weight of
compound 1. Compounds 2 and 2a are regioisomers and showed same molecular ion peak in
their MS and the N, O-alkyl linkages were distinguished by the presence of 13C-NMR signals at
43.60, 62.86 ppm for –NCH2CO– (N-alkylation) and –OCH2CO– (O-alkylation) respectively
(See Supporting information). The chemical shifts of 3 and 3a at the δ 9.37, 9.34; and δ 4.29,
4.32; are due to –CONHNH2 and –CONHNH2 confirm the hydrazinolysis of ester group in 2 and
2a.

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O
O
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O
H
O
H2N
H2N
O
N
N
O
N
a
b
O
N
N
O
OH
+
N
O
1
2a
2
Minor
Major
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c
c
O
O
NH2
N
H
H2N
O
N
N
N
O
N
N
H
3
3a
Scheme 1. Synthesis of compounds 3 and 3a. Reagents and conditions: a) H2O, rt 1 h; b) Ethyl
bromoacetate, K2CO3, Acetone, reflux 6 h; c) NH2NH2.H2O, EtOH, reflux 5 h.
Compounds 8a-j were synthesized as per the synthetic route described in Scheme 2.
Compounds 4 and 5 on treatment with propargyl bromide in DMF and K2CO3 at rt for 8-10 h
formed 6 and 7. Next 6 and 7 were treated at rt with various aryl azides in the presence of
CuSO4.5H2O and Na-ascorbate in THF: H2O (1:1) to yield various triazole derivatives 8a-j. The
signals appeared for H-C≡C-CH2-O- between δ 2.54-2.55 and δ 4.84-4.86 respectively for alkyne
and oxymethylene groups in 6 and 7. Triazole –CH signal and substituted phenyl signals of 8c,
1
8d, 8f, 8g, 8h and 8j H-NMR confirmed their formation and 8a, 8b, 8e, 8i were further
established by the appearance of appropriate molecular ion peaks in their mass spectra.
R
O
OHC
R
O
R1
OHC
OHC
R
c
a
N
N
OH
N
4 R= -H
6 R= -H
8a-e
8f-j
R= -H
5 R= -OMe
7 R= -OMe
R= -OMe
R1 = 4-Me, 4-OMe, 3-F, 3-CF3, 4-Cl
8f-j
R= -OMe
8a-e
R= -H
NH2
N3
8a R1 = 4-Me
8b R1 = 4-OMe 8g R1 = 4-OMe
8c R1 = 3-F 8h R1 = 3-F
8d R1 = 3-CF3 8i R1 = 3-CF3
8e R1 = 4-Cl 8j R1 = 4-Cl
8f R1 = 4-Me
b
R1
R1
A1-A10

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Scheme 2. Synthesis of compounds 8a-j. Reagents and conditions: a) Propargyl bromide,
K2CO3, Dry DMF, rt, 8-10 h; b) dil HCl, NaNO2, NaN3, 0 ºC, 30 min; c) ArN3, Sodium
ascorbate, CuSO4.5H2O, THF:H2O (1:1), rt, 2-5 h.
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Treatment of 4 and 5 with 1,2-dibromoethane in K2CO3 & DMF at rt yielded 9, 9a and
10, 10a, however, considerable dimers were formed during the O-alkylation (See Supporting
Information). Substitution of bromo group in 9, 10 with NaN3 in the presence of K2CO3
afforded compounds 11, 12 and further they undergo click reaction with various in situ generated
alkynes in the presence of CuSO4.5H2O, Na-ascorbate gave 13a-j in good yields (Scheme 3).
1H-NMR showed two triplets at δ 4.35, 3.65 and δ 4.38, 3.67 for –OCH2CH2Br group for 9 and
9a respectively. 13d, 13j gave signals at δ 2.13 and δ 1.06, 2.53 due to ˗N(CH3)2, [-
N(CH2CH3)2] protons respectively in addition to the triazole -CH, –CH2N protons. Further the
molecular ion peaks were corroborated with the molecular masses of 13a-j.
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OHC
R
OHC
R
O
c
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a
b
N3
X
OH
9 R = -H, X = Br
9a R = H, X =
10 R = -OMe X = Br
10a R = -OMe, X =
4 R = -H
5 R = -OMe
11 R = -H
12 R = -OMe
O C6H4CHO
O C6H3(3-OMe)CHO
O
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OHC
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13e, 13j
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13a, 13f
13 a-e R= -H
13 f-j R = -OMe
Scheme 3. Synthesis of compounds 13a-j. Reagents and conditions: a) 1,2 dibromo ethane
K2CO3, Dry DMF, rt, 8-12 h; b) K2CO3, NaN3, Dry DMF, 50 ºC, 4-5 h; c) in situ generated
different propargyl alkylamines, Sodium ascorbate, CuSO4.5H2O, THF:H2O (1:1), rt, 2-5 h.
The synthetic pathway for quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids 14a-j,
15a-j and 16a-e is outlined in Scheme 4. Compounds 3 and 3a was treated with various 1,2,3-
triazole liked benzaldehydes (8a-j, 13a-j) in the presence catalytic amount of AcOH in ethanol at
reflux conditions to afford the final analogues 14a-j, 15a-j, 16a-e.
1
The formation of 14a-j was confirmed by H-NMR singlet at δ 7.96-8.13 for –CH=N–
group and corroboration of molecular ion peaks with the molecular mass of 14a-j confirms the

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structures [eg. (m/z = 531 (M+H)+ (14a)]. Moreover molecular weight of 15a was confirmed by
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appearance of molecular ion peak at m/z 508 (M+H)+ in the mass spectrum. C-NMR of 16a-e
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revealed two signals at the range δ 63.23-63.24 and δ 168.05-168.06 due to –OCH2C=O and –
OCH2C=O carbons, respectively. The chlorine presence in compounds 15e (m/z = 526, 528), 16e
(m/z = 556, 558) was confirmed by appearance of (M–H)–, (M+2–H)– ion peaks in 3:1 ratio (See
Supporting Information).
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R2 =
N
N
O
N
N
N
14c, 14h
14d, 14i
14e, 14j
14b, 14g
14a, 14f
N
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a-j
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H
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a
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R2
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N
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NH2
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O
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a
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H
N
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O
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O
N
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15b R1= 4-OMe
15c R1= 3-F
15d R1= 3-CF3
15e R1= 4-Cl
N
N
15 a-e R = -H
N
N
N
R1
O
R
O
O
NH2
N
N
O
N
O
8 f-j
N
N
H
H
a
N
N
16 a-e R = -OMe
16a R1 = 4-Me; 16b R1 = 4-OMe; 16c R1 = 3-F
16d R1 = 3-CF3; 16e R1 = 4-Cl
3a
Scheme 4. Synthesis of quinoxaline-hydrazidehydrazone-1,2,3-triazole hybrids 14a-j, 15a-j and
16a-e. Reagents and conditions: a) EtOH, CH3COOH (cat), reflux 12 h.
α-Glucosidase activity

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All of the synthesized compounds 14a-j, 15a-e and 16a-e were evaluated for their in vitro
α-glucosidase inhibitory activity and the results were summarized in Table 1. Various percent of
inhibitions were observed at different concentrations and the results are proportional to the
concentration. Only 14a-f, 15a-e displayed inhibitory activity at the IC50 range of 21.92−208.33
µg/mL and rest did not show α-glucosidase inhibition. At 25-100 µg/mL range 14a (57-70%),
14b (56-68%), 14c (53-69%) and 15a (51-73%) exhibited potent inhibition as compared to the
standard acarbose (56-86%) and IC50 values of 14a (IC50 = 21.92 µg/mL), 14b (IC50 = 22.32
µg/mL), 14c (IC50 = 23.58 µg/mL) and 15a (IC50 = 24.50 µg/mL) are comparable to the standard
(IC50 = 22.32 µg/mL). Compounds 14d-f and 15b-e also displayed good inhibition at the higher
IC50 values 208.33, 111.11, 135.13 and 125, 142.85, 156.25, 166.66 µg/mL respectively. The
results of α-glucosidase inhibition studies reveal that the structure-activity relationship (SAR,
Figure 4) played a vital role in exhibiting good activity which was found in 14a, 14b, 14c due to
the presence of R2 = Morpholino, Piperidino, Pyrrolidino rings on the 1,2,3-triazole methylene
group. Replacement of those rings by other groups R2 = –N(CH3)2, –N(CH2CH3)2 as in 14d, 14e
showed less activity than 14a-c; by R= –OMe, R2 = Morpholino groups as in 14f showed good
activity than 14d; by R1 = 4–Me substitution on the phenyl ring in 15a displayed potent activity
than 15b-e and in 15c-e with R1 = 3-F, 3-CF3, 4-Cl groups are less active and 14g-j, 16a-e are
inactive may be due to the R = –OMe group and quinoxaline-O linkage respectively.
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Table-1: α-glucosidase inhibitory activity of compounds 14a-j, 15a-e and 16a-e.
% of Inhibition at
Substituents
R1
different concentrations
(µg/mL)
IC50
µg/mL
Compounds
R
25
50
75
100
N
O
14a
14b
14c
14d
14e
14f
-H
57
63
66
70
21.92
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N
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N
-H
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53
15
32
28
60
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41
35
68
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45
37
22.32
-H
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-H
208.33
111.11
135.13
-H
O
-OCH3

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N
N
N
N
14g
14h
14i
-OCH3
-OCH3
-OCH3
-OCH3
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
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14j
15a
15b
15c
15d
15e
16a
16b
16c
-H
-H
-H
-H
-H
4-Me
4-OMe
3-F
3-CF3
4-Cl
51
32
27
23
22
−
−
−
−
−
62
34
30
26
25
−
−
−
−
−
68
37
33
30
28
−
−
−
−
−
73
40
35
32
30
−
−
−
−
−
24.50
125
142.85
156.25
166.66
−
−
−
−
−
-OCH3 4-Me
-OCH3 4-OMe
-OCH3 3-F
-OCH3 3-CF3
-OCH3 4-Cl
16d
16e
Acarbose
56
65
75
86
22.32
Antioxidant Activity
DPPH, NO and H2O2 radical scavenging ability of some synthesized compounds was
evaluated and compared with standard antioxidant ascorbic acid. The graphical representation of
antioxidant activity inhibition concentrations (IC50) of compounds 14a-j, 15a-e and 16a-e was
shown in Figure 3. The perusal of Table 2 revealed that compounds 14a-e, 15a and 15c, 15d
possessed moderate to good antioxidant activity (Figure 3). But most of the compounds (14f-j,
15b, 15e and 16a-e) showed inactivity in all three methods, this result could be due to various
groups like R = –OMe in 14f-j, 4-OMe in 15b, 4-Cl in 15e and quinoxaline-O linkage, R = –
OMe in 16a-e. Although 14a IC50 = 25.00 µg/mL (DDPH), IC50 = 49.01 µg/mL (H2O2), 47.16
µg/mL (NO); 14b IC50 = 28.24 µg/mL (DPPH), IC50 = 54.34 µg/mL (H2O2), IC50 = 52.08 µg/mL
(NO); 14c IC50 = 27.17 µg/mL (DPPH), IC50 = 56.81 µg/mL (H2O2), IC50 = 53.19 µg/mL (NO)
and 15a IC50 = 26.04 µg/mL (DPPH), IC50 = 52.08 µg/mL (H2O2), IC50 = 48.07 µg/mL (NO)
showed good antioxidant activity. Similarly the active compounds 14a (68–73%), 14b (60–
68%), 14c (58-64%) and 15a (65-75%) exhibited good radical scavenging ability in all three
methods at the concentration of 100 µg/mL which may result due to the presence of Morpholino,
Piperidino, Pyrrolidino and electron releasing 4-Me groups respectively in that compounds. 14d
(IC50 = 156.25–166.00 µg/mL) and 14e (IC50=131.57–142.85 µg/mL) are less active than 14a-c

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may be due to the presence of –N(CH3)2 and –N(CH2CH3)2 amino groups respectively (See
SARs in Figure 4). Electron withdrawing group analogues 15d and 15e showed lower activity
than electron donating one 15a.
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Table 2: Antioxidant activity of 14a-j, 15a-e and 16a-e.
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DPPH Method
H2O2 Method
NO Method
% RSA
% RSA
IC50
% RSA
IC50
Compounds
IC50
100
µg/mL
100
µg/mL
100
µg/mL
µg/mL
µg/mL
µg/mL
14a
14b
14c
14d
14e
14f
14g
14h
14i
73
68
64
32
38
−
25
28.24
27.17
156.25 33
131.57 38
−
70
60
58
49.01
54.34
56.81
151.51 30
131.57 35
−
−
−
−
−
52.08
−
138.88 33
185.18 25
−
−
−
68
47.16
63
62
52.08
53.19
166
142.85
−
−
−
−
−
68
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
14j
−
−
15a
15b
15c
15d
15e
16a
16b
16c
16d
16e
75
−
26.04
−
65
−
48.07
−
35
28
−
142.85 36
178.57 27
−
151.51
200
−
−
−
−
−
−
89
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
25.51
−
−
−
−
−
−
−
−
Ascorbic acid 92
21.55
87
24.50
RSA: Relative Scavenging Ability

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Figure 3. Antioxidant activity (DPPH, H2O2 and NO assay IC50s) of 14a-j, 15a-e and 16a-e.
Figure 4. Structure-Activity relationships (SARs) of 14a-j, 15a-e and 16a-e.
Molecular Docking Studies
In order to explore the binding interactions between inhibitors and Geobacillus sp. strain
HTA-462 α-glucosidase, docking studies were performed on the selected active compounds
using 1-Click docking online server tool (http://mcule.com). The crystal structure of GH13 α-
glucosidase (GSJ; PDB ID: 2ZE0)51 was chosen as template for modeling. The resultant binding
energies due to the interaction between the active ligands and the enzyme were shown in Table 3
and the 3D dock poses were represented in Figure 5-7.

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Table 3: Binding site amino acids & Binding energies of compounds 14a-c & 15a
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Binding
energy
(Kcal/J)
-6.8
Active
Ligands
S.No
Binding pocket amino acids
1.
2.
14a
14b
Trp:408, Ile:402, Ser:332, Gly:286, Thr:333, Lys:404
Thr:333, Gly:286, Glu:289, Arg:338, Lys:404
Glu:289, Thr:333, Arg:338, Lys:404, Ile:401, Trp:403,
Asn:371
Leu:287, Lys:404, Arg:338, Arg:373, Glu:289, Trp:403
Thr:333, Arg:338, Ser:295
-6.5
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3.
14c
-6.8
4.
5.
15a
Acarbose
-6.7
-5.4
Inhibitors showed good binding interactions with the active site of the α-glucosidase
enzyme by interacting with the amino acids through conventional hydrogen bonds, carbon
hydrogen bonds, -cation, -anion, van der Walls, -alkyl, - stacked and much more.
However, binding energy of acarbose is −5.4 kcal/J but inhibitors 14a, 14b, 14c and 15a showed
better binding energies when compared to acarbose ranging from −6.5 to −6.8 kcal/J. 14a
connected with the active site of enzyme by forming a - stacked and -sigma interactions with
TRP403 and LYS404 residues through the two phenyl rings, and other interactions involved like
-alkyl interactions with ILE402, van der Walls with ASN371, ARG373 (Figure 5). Further,
14a established carbon hydrogen bond and -donor hydrogen bonds with GLY286 and THR333,
SER332 active site amino acid residues respectively and 14b has formed -cation & -anion
(GLU289, ARG338), alkyl & -alkyl (LYS404), carbon hydrogen bond (THR333, GLY286)
interactions along with its –CONH– group hydrogen bond with THR333 (Figure 5). At the
binding site of α-glucosidase enzyme 14c (Figure 6) −CONH– group hydrogen atom formed H-
bond with GLU289 and other interactions are alky & -alkyl with TRP403, LYS404 and -
cation with ARG338 and carbon hydrogen bond with ILE401, THR333 and van der Walls with
ARG373, ASN371 and THR405. In 15a (Figure 6), one oxygen and two hydrogen atoms of –
C=ONH-N=CH- have connected with LEU287 by two Hydrogen and one carbon hydrogen
bonds. In addition to van der Walls interactions of 15a with ARG338 and ARG373 its three rings
(quinoxaline ring, bridged phenyl ring and p-methyl substituted benzene ring) were displayed -
alkyl, -anion and - stacked interactions with LYS404, GLU289 and TRP403 respectively. At
the active site of the enzyme, acarbose was stabilized by forming conventional H-bonds
(ARG338, SER295, THR333), van der Walls (TRP403, ASN371, LYS404, SER332, TRP288,
ALA292, ARG291, ASN336, ARG290, GLU289), carbon hydrogen bond interactions (ASP504)
and two unfavorable donor-donor interactions with ARG338, ARG373 (Figure 7).

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Figure 5. Binding interactions of 14a, and 14b [here A is 3D image and B is 2D image] in the
active site of α-glucosidase.

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Figure 6. Binding interactions of 14c, and 15a [here A is 3D image and B is 2D image] in the
active site of α-glucosidase.

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Figure 7. Binding interactions of acarbose [here A is 3D image and B is 2D image] in the active
site of α-glucosidase.
Conclusion
Having inspired by the bioactive molecules with quinoxaline, hydrazidehydrazone and
1,2,3-triazole pharmacophoric units, we have designed a novel series of quinoxaline-hydrazide
hydrazone-1,2,3-triazole hybrid derivatives 14a-j, 15a-j and 16a-e via molecular hybridization
approach. The condensation reaction between N/O-alkyl quinoxalinehydrazides (3, 3a) and
triazole linked benzaldehydes (8a-j and 13a-j) in ethanol in the presence of catalytic amount of
AcOH has generated final target compounds. Compounds 8a-j and 13a-j had synthesized from
simple aldehydes by using Cu(I) catalyzed [3+2] azide-alkyne cycloaddition reaction. 3-
Methylquinoxalin-2(1H)-one (1) was formed by cyclization reaction of o-phenylenediamine and
pyruvic acid in presence of water has been used to generate compounds 3 and 3a via a two-step
reaction involving alkylation and hydrazidation. Twenty compounds were synthesized and also
tested for their α-glucosidase inhibitory and antioxidant activities. It has been observed that,
compounds 14a-c and 15a showed significant activities when compare with standards. Further,
molecular docking studies of GH13 α-glucosidase (PDB ID: 2ZE0) revealed that compounds
14a-c and 15a had good binding energies and involved in prominent interactions with active site

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compare to acarbose. This study suggested that, high yields and easy reaction workups in
synthesis, ease in structure modifications, cost-effectiveness and the results obtained from in
vitro α-glucosidase inhibitory and antioxidant activities were favourable to carry out further high
level chemical and biological/computational experiments to develop potent α-glucosidase
inhibitors and antioxidants based on these molecules.
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Experimental section
Chemistry and Chemical Methods
Melting points were performed with Me1 temp apparatus and were uncorrected. IR spectra was
recorded with Brucker FT-IR spectrometer and the values were given as wave numbers with unit
1
cm-1. H-NMR and 13C-NMR spectra were recorded at 400 and 100 MHz frequencies
respectively using ECS-400 JEOL spectrometer by dissolving the samples in DMSO-d6 or
CDCl3. Chemical shift and coupling constant values were expressed in ppm and Hz respectively.
Multiplicities were specified as singlet (s), doublet (d), multiplet (m) double doublet (dd) etc. All
reagents and solvents were purchased from commercial suppliers (Sigma Aldrich, Avra
synthesis, SD Fine, Molychem etc) and used without further purification. Reaction progress was
checked with Merck 60 F254 TLC aluminium plates and the spots were visualized by passage of
UV light or iodine vapors. Column chromatography was performed on silica gel 60-120 mesh
using a mixture of hexane/ethyl acetate or chloroform/methanol as eluents. LC-MS spectra were
recorded on LCMS2010A SHIMADZU spectrometer and the values were expressed in units of
m/z.
General procedure for synthesis of compound (1)
To the stirred solution of o-phenylenediamine (8 g, 74.07 mmol) in water, pyruvic acid (6.51 g,
74.07 mmol) in water was added and the whole reaction mixture was stirred at rt for 1 h. After
the product was confirmed by TLC, the formed off white solid was collected by vacuum
filtration and washed several times with water, finally recrystallized with ethanol. Yield: 78%;
1
(Light green color solid); m.p. = 215-217 ºC; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.40 (s,
3H, quinoxaline −CH3), 7.24-7.29 (m, 2H, Ar-H), 7.46 (t, J = 7.6 Hz, 1H, Ar-H), 7.69 (d, J = 7.6
Hz, 1H, Ar-H), 12.28 (s, 1H, -NH); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 20.42, 115.18,
122.95, 127.82, 129.22, 131.65, 131.91, 154.88, 159.15; LC-MS (ESI) : m/z = 161 (M+H)+ for
C9H8N2O.

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General procedure for synthesis of compounds (2, 2a).
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5
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7
8
At first 3-methylquinoxalin-2(1H)-one (1, 6 g, 37.5 mmol) was dissolved in acetone 60 mL. To
this solution K2CO3 (7.76 g, 56.25 mmol) was added and stirred for 10 min, then ethyl bromo
acetate (7.47 g, 45 mmol) was added drop by drop. Total reaction mixture was kept under reflux
for 6 h at 90 ºC. Then filtered the reaction mixture using vacuum and the filtrate was
concentrated under the reduced pressure. The obtained residue was washed several times with
cold water and dried. The obtained crude light brown color solid was isolated and purified (See
SI Pg. No 1,2 & 22,23 for spectra) by column chromatography using petroleum ether/ethyl
acetate (9:1, 8:2 ratios) as eluents on silica gel 60-120 mesh.
9
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Ethyl 2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetate (2): Yield: 65%; (Off-white solid); m.p.
= 124-126 ºC; 1H NMR (CDCl3, 400 MHz, δ ppm): 1.26 (t, J = 7.2 Hz, 3H, -OCH2CH3), 2.59 (s,
3H, quinoxaline −CH3), 4.23 (q, J = 7.2 Hz, 2H, -OCH2CH3), 5.01 (s, 2H, -NCH2CO-), 7.04 (d, J
= 8.4 Hz, 1H, Ar-H), 7.32 (t, J = 7.2 Hz, 1H, Ar-H), 7.47 (t, J = 8.0 Hz, 1H, Ar-H), 7.81 (d, J =
13
8.0 Hz, 1H, Ar-H); C NMR (CDCl3, 100 MHz, δ ppm): 14.18, 21.57, 43.60, 62.16, 113.12,
123.99, 129.83, 129.88, 132.47, 132.81, 154.85, 158.28, 167.20; LC-MS (ESI) : m/z = 247
(M+H)+ for C13H14N2O3.
Ethyl 2-((3-methylquinoxalin-2-yl)oxy)acetate (2a): Yield: 28%; (Off-white solid); m.p. = 83-
1
85 ºC; H NMR (CDCl3, 400 MHz, δ ppm): 1.25 (t, J = 6.8 Hz, 3H, -OCH2CH3), 2.69 (s, 3H,
quinoxaline −CH3), 4.23 (q, J = 6.8 Hz, 2H, -OCH2CH3), 5.02 (s, 2H, -OCH2CO-), 7.51 (t, J =
6.8 Hz, 1H, Ar-H), 7.56 (t, J = 6.8 Hz, 1H, Ar-H), 7.72 (d, J = 7.6 Hz, 1H, Ar-H), 7.91 (d, J =
13
8.0 Hz, 1H, Ar-H); C NMR (CDCl3, 100 MHz, δ ppm): 14.23, 20.38, 61.29, 62.86, 126.90,
126.93, 128.13, 129.03, 139.12, 139.36, 147.81, 155.06, 168.56; LC-MS (ESI) : m/z = 247
(M+H)+ for C13H14N2O3.
General procedure for synthesis of compound (3)
A mixture of compound (3 g, 12.19 mmol) and hydrazine hydrate (2.43 g, 48.76 mmol) in 30 mL
of ethanol was refluxed for 5 h at 90 ºC. After that the reaction mixture was cooled at -5 ºC for
overnight. The solid separated was filtered, washed several times with pet. ether and
recrystallized from ethanol. 3a was prepared from 2a as per the above procedure.
2-(3-Methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (3): Yield: 68%; (Off-white solid);
1
m.p. = 204-206 ºC; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.45 (s, 3H, quinoxaline −CH3),

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4.29 (s, 2H, −NH2), 4.86 (s, 2H, -NCH2CO-), 7.30 (d, J = 8.4 Hz, 1H, Ar-H), 7.35 (t, J = 7.2 Hz,
1H, Ar-H), 7.54 (t, J = 8.0 Hz, 1H, Ar-H), 7.76 (d, J = 8.0 Hz, 1H, Ar-H), 9.37 (s, 1H, -CONH);
13C NMR (DMSO-d6, 100 MHz, δ ppm): 21.08, 43.41, 114.39, 123.28, 128.69, 129.45, 132.07,
132.84, 154.36, 157.65, 165.49; LC-MS (ESI) : m/z = 231 (M−H)− for C11H12N4O2.
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2-((3-Methylquinoxalin-2-yl)oxy)acetohydrazide (3a): Yield: 62%; (Light orange color solid);
1
m.p. = 196-198 ºC; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.63 (s, 3H, quinoxaline −CH3),
4.32 (s, 2H, −NH2), 4.96 (s, 2H, -OCH2CO-), 7.60 (t, J = 7.2 Hz, 1H, Ar-H), 7.67 (t, J = 7.2 Hz,
1H, Ar-H), 7.75 (d, J = 7.6 Hz, 1H, Ar-H), 7.93 (d, J = 7.6 Hz, 1H, Ar-H), 9.34 (s, 1H, -CONH);
13C NMR (DMSO-d6, 100 MHz, δ ppm): 20.17, 63.76, 126.47, 126.77, 127.72, 129.07, 138.29,
138.69, 148.21, 155.06, 166.34; LC-MS (ESI) : m/z = 233 (M+H)+ for C11H12N4O2.
General procedure for synthesis of compounds (6)
Compound 4 (3 g, 24.59 mmol) was dissolved in 25 mL dry DMF, to this solution K2CO3 (10.18
g, 73.77 mmol) was added and stirred for 20 min. To the above reaction mixture, 3-bromoprop-
1-yne (3.48 g, 29.50 mmol) was added drop by drop up to half an hour using 2 mL glass syringe
needle and the whole reaction mixture was stirred at rt for 10 h. Then, filtrate acquired after
filtration was poured into the crushed ice. Finally resultant solid was collected by vacuum
filtration and dried to obtain the compound 6 in good yields.
Based on the above procedure 7 was obtained from 5.
1
4-(Prop-2-yn-1-yloxy)benzaldehyde (6): Yield: 78%; (Off-white solid); m.p. = 74-76 ºC; H
NMR (CDCl3, 400 MHz, δ ppm): 2.54 (t, J = 2 Hz, 1H, -C≡CH) 4.86 (d, J = 2.4 Hz, 2H, ˗OCH2-
), 7.16 (d, J = 8.0 Hz, 2H, Ar-H), 7.86 (d, J = 8.0 Hz, 2H, Ar-H), 9.86 (s, 1H, -CHO).
3-Methoxy-4-(prop-2-yn-1-yloxy)benzaldehyde (7): Yield: 72%; (Light yellow color solid);
m.p. = 82-84 ºC; 1H NMR (CDCl3, 400 MHz, δ ppm): 2.55 (t, J = 2 Hz, 1H, -C≡CH) 4.84 (d, J =
2.4 Hz, 2H, ˗OCH2-), 7.12 (d, J = 8.0 Hz, 1H, Ar-H), 7.41 (d, J = 1.6 Hz, 1H, Ar-H), 7.44 (dd, J
= 8.0, 2.0 Hz, 1H, Ar-H), 9.85 (s, 1H, -CHO).
General procedure for synthesis of substituted aromatic azides (A1-A10)
600 mg of 4-methyl aniline (5.60 mmol) dissolved in 6 mL dichloromethane was taken in 50 mL
RB and kept at < 0 oC. Then, HCl (2.01 g, 56 mmol) was added drop by drop to the solution and
also aq. NaNO2 (1.93 g, 28.03 mmol) solution for 15 min and aq. NaN3 (1.09 g, 16.82 mmol) for

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30 min under constant stirring. After that, stirring was continued for 30 min and the reaction
mixture was allowed to attain the room temperature. Finally the reaction mixture was extracted
with DCM (3 × 15 mL) and resultant combined organic layers were washed with NaHCO3 (2 ×
10 mL) and dried to obtain the various substituted azides in good yields.
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General procedure for synthesis of compound (8a) and related compounds (8b-e)
4-(Prop-2-yn-1-yloxy)benzaldehyde (6, 350 mg, 2.18 mmol) and 1-azido-4-methylbenzene (579
mg, 4.36 mmol) were suspended in 5 mL THF:Water (1:1) mixture. After that, sodium ascorbate
(863 mg, 4.36 mmol) was added followed by CuSO4.5H2O (545 mg, 2.18 mmol). The resulting
mixture was stirred vigorously at rt for 2 h and then diluted with ice water. The product was
extracted with ethyl acetate (3 × 10 mL) and resultant organic layer was dried over sodium
sulfate and concentrated under reduced pressure to attain crude residue, which was then purified
by column chromatography 60-120 mesh silica gel with n-Hexane/EtOAc (10-20 %) to furnish
8a in good yield. Compounds 8f-j have obtained from 7 according to the above mentioned
procedure.
4-((1-(p-Tolyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (8a): Yield: 68%; (Light yellow
color solid); m.p. = 114-116 ºC; LC-MS (ESI): m/z = 294 (M+H)+ for C17H15N3O2.
4-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (8b): Yield: 66%;
(Dark yellow color solid); m.p. = 120-122 ºC; LC-MS (ESI): m/z = 310 (M+H)+ for C17H15N3O3.
4-((1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (8c): Yield: 60%;
1
(Colorless crystals); m.p. = 104-106 ºC; H NMR (CDCl3, 400 MHz, δ ppm): 5.38 (s, 2H,
˗OCH2-), 7.13-7.18 (m, 3H, Ar-H), 7.48-7.54 (m, 3H, Ar-H), 7.85 (d, J = 7.2 Hz, 2H, Ar-H),
8.08 (s, 1H, triazole-H), 9.89 (s, 1H, -CHO).
4-((1-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (8d): Yield:
72%; (Dark yellow color solid); m.p. = 106-108 ºC; 1H NMR (CDCl3, 400 MHz, δ ppm): 5.39 (s,
2H, ˗OCH2-), 7.14 (d, J = 8.8 Hz, 2H, Ar-H), 7.67-7.73 (m, 2H, Ar-H), 7.86 (d, J = 8.8 Hz, 2H,
Ar-H), 7.97 (d, J = 7.6 Hz, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 8.16 (s, 1H, triazole-H), 9.89 (s, 1H, -
CHO).
4-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (8e): Yield: 72%; (Light
yellow color solid); m.p. = 136-138 ºC; LC-MS (ESI): m/z = 314 (M+H)+ for C16H12ClN3O2.

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3-Methoxy-4-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (8f): Yield: 68%;
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1
(Off-white solid); m.p. = 124-126 ºC; H-NMR (CDCl3, 400 MHz, δ ppm): 2.42 (s, 3H, ˗CH3),
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3.94 (s, 3H, ˗OCH3), 5.46 (s, 2H, ˗OCH2-), 7.27 (d, J = 6.8 Hz, 1H, Ar-H), 7.31 (d, J = 6.8 Hz,
2H, Ar-H), 7.43 (d, J = 1.6 Hz, 1H, Ar-H), 7.45 (dd, J = 6.4, 1.6 Hz, 1H, Ar-H), 7.59 (d, J = 6.8
Hz, 2H, Ar-H) 8.06 (s, 1H, triazole-H), 9.86 (s, 1H, -CHO).
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3-Methoxy-4-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde
(8g):
Yield: 72%; (Yellow color solid); m.p. = 111-113 ºC; 1H NMR (CDCl3, 400 MHz, δ ppm): 3.86
(s, 3H, ˗OCH3), 3.93 (s, 3H, ˗OCH3), 5.45 (s, 2H, ˗OCH2-), 7.01 (d, J = 7.2 Hz, 2H, Ar-H), 7.27
(d, J = 6.0 Hz, 1H, Ar-H), 7.43 (d, J = 1.6 Hz, 1H, Ar-H), 7.45 (dd, J = 6.4, 1.6 Hz, 1H, Ar-H),
7.61 (d, J = 7.2 Hz, 2H, Ar-H) 8.02 (s, 1H, triazole-H), 9.86 (s, 1H, -CHO).
4-((1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzaldehyde (8h): Yield:
1
62%; (Yellow color solid); m.p. = 97-99 ºC; H NMR (CDCl3, 400 MHz, δ ppm): 3.94 (s, 3H,
˗OCH3), 5.46 (s, 2H, ˗OCH2-), 7.16-7.19 (m, 1H, Ar-H), 7.24 (d, J = 8.0 Hz, 1H, Ar-H), 7.44-
7.45 (m, 1H, Ar-H), 7.47 (d, J = 2.0 Hz, 1H, Ar-H), 7.49-7.55 (m, 3H, Ar-H) 8.11 (s, 1H,
triazole-H), 9.86 (s, 1H, -CHO).
3-Methoxy-4-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde
(8i): Yield: 78%; (Off-white solid); m.p. = 142-144 ºC; LC-MS (ESI): m/z = 378 (M+H)+ for
C18H14F3N3O3.
4-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzaldehyde (8j): Yield:
1
76%; (Light orange color solid); m.p. = 112-114 ºC; H NMR (CDCl3, 400 MHz, δ ppm): 3.94
(s, 3H, ˗OCH3), 5.46 (s, 2H, ˗OCH2-), 7.25 (d, J = 6.4 Hz, 1H, Ar-H), 7.44 (d, J = 1.6 Hz, 1H,
Ar-H), 7.45 (dd, J = 6.4, 1.6 Hz, 1H, Ar-H), 7.50 (d, J = 7.2 Hz, 2H, Ar-H), 7.68 (d, J = 7.2 Hz,
2H, Ar-H), 8.09 (s, 1H, triazole-H), 9.86 (s, 1H, -CHO).
General procedure for synthesis of compound (9, 9a)
At first, p-hydroxybenzaldehyde (4, 4 g, 32.78 mmol) was dissolved in 40 mL dry DMF, along
with 13.57 g of K2CO3 (98.34 mmol) and 18.29 g of 1,2-dibromoethane (98.34 mmol) were
added. The entire reaction mixture was stirred at rt for 12 h and the product was added 10 mL
cold water and partitioned with chloroform (3 × 5 mL). The organic layer was dried over sodium
sulfate and concentrated under the reduced pressure which gave 9 and 9a as two products. They
were isolated and purified (See SI Pg. No 7 & 8 for spectra) by column chromatography on

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silica gel (60-120 mesh) using n-Hexane/Ethyl acetate (9:1, 8:2) to obtain good yields. In the
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5
same way 10 was prepared from 5.
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4-(2-Bromoethoxy)benzaldehyde (9): Yield: 56%; (White crystals); m.p. = 48-50 ºC; 1H NMR
(CDCl3, 400 MHz, δ ppm): 3.65 (t, J = 6.4 Hz, 2H, −OCH2CH2Br ), 4.35 (t, J = 6.4 Hz, 2H,
−OCH2CH2Br), 7.00 (d, J = 8.4 Hz, 2H, Ar-H), 7.82 (d, J = 8.8 Hz, 2H, Ar-H), 9.87 (s, 1H,
−CHO).
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4,4'-(Ethane-1,2-diylbis(oxy))dibenzaldehyde (9a): Yield: 42%; (Light yellow color solid);
m.p. = 106-108 ºC; 1H NMR (CDCl3, 400 MHz, δ ppm): 4.43 (s, 2H, −OCH2CH2O-), 7.04 (d, J
= 8.0 Hz, 2H, Ar-H), 7.83 (d, J = 8.4 Hz, 2H, Ar-H), 9.87 (s, 1H, −CHO).
4-(2-Bromoethoxy)-3-methoxybenzaldehyde (10): Yield: 79%; (White crystals); m.p. = 62-64
1
ºC; H NMR (CDCl3, 400 MHz, δ ppm): 3.67 (t, J = 6.8 Hz, 2H, −OCH2CH2Br ), 3.90 (s, 3H,
Ar-H), 4.38 (t, J = 6.8 Hz, 2H, −OCH2CH2Br), 6.95 (d, J = 8.4 Hz, 2H, Ar-H), 7.40-7.42 (m, 2H,
Ar-H), 9.83 (s, 1H, −CHO).
General procedure for synthesis of compound (11)
A mixture of compound 9 (2 g, 8.81 mmol), NaN3 (1.71 g, 26.43 mmol) and K2CO3 (3.64 g,
26.43 mmol) in 40 mL dry DMF was stirred at 50-60 ºC for 4h. After that, reaction mixture was
poured into the 100 mL ice cold water after reaching the room temperature. Extracted the
solution with CHCl3 (3 × 10mL). The resultant organic layer was dried over Na2SO4 and the
excess solvent was removed under the reduced pressure. The crude compound was purified by
column chromatography using Hexane/Ethyl acetate as eluent to obtain compound 11. 12 was
prepared from the 10 as per the above discussed method.
1
4-(2-Azidoethoxy)benzaldehyde (11): Yield: 76%; (Color less oil); H NMR (CDCl3, 400
MHz, δ ppm): 3.61 (t, J = 5.2 Hz, 2H, −OCH2CH2N3), 4.19 (t, J = 5.2 Hz, 2H, −OCH2CH2N3),
13
6.99 (d, J = 8.4 Hz, 2H, Ar-H), 7.82 (d, J = 8.8 Hz, 2H, Ar-H), 9.85 (s, 1H, −CHO); C NMR
(CDCl3, 100 MHz, δ ppm): 50.04, 67.29, 114.91, 130.50, 132.09, 163.22, 190.87.
1
4-(2-Azidoethoxy)-3-methoxybenzaldehyde (12): Yield: 79%; (Pale yellow oil); H NMR
(CDCl3, 400 MHz, δ ppm): 3.39 (t, J = 5.2 Hz, 2H, −OCH2CH2N3 ), 3.59 (s, 3H, Ar-H), 3.96 (t, J
= 5.2 Hz, 2H, −OCH2CH2N3), 6.72 (d, J = 7.6 Hz, 1H, Ar-H), 7.09 (d, J = 1.2 Hz, 1H, Ar-H),

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7.14 (dd, J = 8 Hz, 2 Hz, 1H, Ar-H), 9.52 (s, 1H, −CHO); C NMR (DMSO-d6, 100 MHz, δ
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ppm): 49.84, 55.78, 67.77, 109.65, 112.18, 126.11, 130.48, 149.83, 153.14, 190.76.
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General procedure for synthesis of compound (13a) and related compound (13b-e).
9
At first morpholine (1092 mg, 12.56 mmol) was added to 5 mL of CH3CN followed by NaHCO3
(1055 mg, 12.56 mmol) and stirred for 10 min. Then 3-bromoprop-1-yne (0.37 g, 3.14 mmol)
was added drop by drop up to 30 min and continued stirring at rt for overnight. To the same
reaction mixture, 4-(2-azidoethoxy)benzaldehyde (9, 300 mg, 1.57 mmol) dissolved in sufficient
CH2Cl2 was added followed by 2 mL aq. solution of sodium ascorbate (117 mg, 0.47 mmol)
and CuSO4.5H2O (93 mg, 0.47 mmol) and stirred at rt for 2 h, then 100 mL of chilled water was
added. The solution was extracted with ethyl acetate (3 × 5 mL), the combined organic layer was
dried over Na2SO4 and evaporated to dryness. Finally, the residue was purified by column
chromatography to obtain the 13a in good yield.
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Compounds 13f-j synthesized from 12 as per the above demonstrated method.
4-(2-(4-(Morpholinomethyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (13a): Yield: 58%;
(Dark red color gummy solid); LC-MS (ESI): m/z = 317 (M+H)+ for C16H20N4O3.
4-(2-(4-(Piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (13b): Yield: 66%;
(Dark red color gummy solid); LC-MS (ESI): m/z = 315 (M+H)+ for C17H22N4O2.
4-(2-(4-(Pyrrolidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (13c): Yield:
1
62%; (Wine red color gummy solid); H NMR (DMSO-d6, 400 MHz, δ ppm): 1.88 (s, 4H,
[˗N(CH2CH2)2]), 2.82 (s, 4H, [˗N(CH2CH2)2]), 3.99 (s, 2H, ˗CH2N-), 4.44 (t, J = 5.2 Hz, 2H,
˗OCH2CH2N-), 4.78 (t, J = 5.2 Hz, 2H, ˗OCH2CH2N-), 6.96 (d, J = 8.4 Hz, 2H, Ar-H), 7.80 (d, J
= 8.8 Hz, 2H, Ar-H), 7.96 (s, 1H, triazole-H), 9.86 (s, 1H, -CHO); LC-MS (ESI) : m/z = 301
(M+H)+ for C16H20N4O2.
4-(2-(4-((Dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (13d): Yield:
1
58%; (Wine red color gummy solid); H NMR (DMSO-d6, 400 MHz, δ ppm): 2.13 (s, 6H,
˗N(CH3)2), 3.52 (s, 2H, ˗CH2N-), 4.52 (t, 2H, ˗OCH2CH2N-), 4.78 (t, 2H, ˗OCH2CH2N-), 7.09 (d,
J = 6.0 Hz, 2H, Ar-H), 7.83 (d, J = 6.0 Hz, 2H, Ar-H), 8.06 (s, 1H, triazole-H), 9.85 (s, 1H, -
CHO); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 44.76, 49.24, 53.78, 67.04, 115.44, 124.86,
130.43, 132.28, 143.88, 163.22, 191.85; LC-MS (ESI) : m/z = 275 (M+H)+ for C14H18N4O2.

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4-(2-(4-((Diethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (13e): Yield:
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64%; (Dark red color gummy solid); LC-MS (ESI): m/z = 303 (M+H)+ for C16H22N4O2.
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9
3-Methoxy-4-(2-(4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde
(13f):
Yield: 61%; (Wine red color gummy solid); LC-MS (ESI): m/z = 347 (M+H)+ for C17H22N4O4.
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3-Methoxy-4-(2-(4-(piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde (13g):
1
Yield: 58%; (Wine red color gummy solid); H NMR (CDCl3, 400 MHz, δ ppm): 1.44-1.45 (m,
2H, [-N(CH2CH2)2CH2]), 1.63-1.65 (m, 4H, [-N(CH2CH2)2CH2]), 2.57 (s, 4H, [-
N(CH2CH2)2CH2]), 3.78 (s, 2H, ˗CH2N-), 3.91 (s, 3H, −OCH3), 4.46 (t, J = 5.2 Hz, 2H,
−OCH2CH2N-), 4.81 (t, J = 5.2 Hz, 2H, −OCH2CH2N-), 6.89 (d, J = 8.4 Hz, 1H, Ar-H), 7.38-
7.40 (m, 2H, Ar-H), 7.95 (s, 1H, triazole-H), 9.83 (s, 1H, -CHO); LC-MS (ESI): m/z = 345
(M+H)+ for C18H24N4O3.
3-Methoxy-4-(2-(4-(pyrrolidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzaldehyde
(13h): Yield: 57%; (Wine red color gummy solid); LC-MS (ESI): m/z = 331 (M+H)+ for
C17H22N4O3.
4-(2-(4-((Dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-3-methoxybenzaldehyde
(13i): Yield: 59%; (Wine red color gummy solid); 1H NMR (CDCl3, 400 MHz, δ ppm): 2.34 (s,
6H, [-N(CH3)2]), 3.74 (s, 2H, ˗CH2N-), 3.87 (s, 3H, −OCH3), 4.43 (t, J = 4.8 Hz, 2H,
−OCH2CH2N-), 4.80 (t, J = 4.4 Hz, 2H, −OCH2CH2N-), 6.87 (d, J = 8.4 Hz, 1H, Ar-H), 7.36-
7.37 (m, 2H, Ar-H), 7.93 (s, 1H, triazole-H), 9.80 (s, 1H, -CHO); 13C NMR (CDCl3, 100 MHz, δ
ppm): 44.36, 49.63, 53.71, 56.03, 67.50, 109.71, 112.48, 125.11, 126.44, 131.10, 143.26, 150.08,
152.74, 190.90; LC-MS (ESI): m/z = 305 (M+H)+ for C15H20N4O3.
4-(2-(4-((Diethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-3-methoxybenzaldehyde (13j):
Yield: 63%; (Wine red color gummy solid); 1H NMR (CDCl3, 400 MHz, δ ppm): 1.06 (t, J = 7.2
Hz, 6H, [-N(CH2CH3)2]), 2.53 (q, J = 7.2 Hz, 4H, [-N(CH2CH3)2]), 3.80 (s, 2H, ˗CH2N-), 3.88 (s,
3H, −OCH3), 4.43 (t, J = 4.8 Hz, 2H, −OCH2CH2N-), 4.79 (t, J = 4.8 Hz, 2H, −OCH2CH2N-),
6.87 (d, J = 8.8 Hz, 1H, Ar-H), 7.36-7.38 (m, 2H, Ar-H), 7.83 (s, 1H, triazole-H), 9.80 (s, 1H, -
CHO); LC-MS (ESI) : m/z = 333 (M+H)+ for C17H24N4O3.
General procedure for synthesis of compound (14a) and related compound (14b-e).

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The equimolar mixture of compounds 3 (100 mg, 0.43 mmol) and 13a (135 mg, 0.43 mmol) in
10 mL of dry ethanol with catalytic amount of AcOH was refluxed for 12h at 90 ºC. The
precipitated solid was collected by vacuum filtration and washed several times with ethanol and
dried. The obtained product was purified by column chromatography using Chloroform/MeOH
(2-6 %) as eluents to obtain 16a in good yields.
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Compounds of 14f-j, 15a-e and 16a-e also obtained with the corresponding acid hydrazides (3,
3a) and 1,2,3 triazoles (13f-j, 8a-j) by following the above procedure.
(E)-2-(3-Methyl-2-oxoquinoxalin-1(2H)-yl)-N'-(4-(2-(4-(morpholinomethyl)-1H-1,2,3-
triazol-1-yl)ethoxy)benzylidene)acetohydrazide (14a): Yield: 76%; (Off-white solid); m.p. =
184-186 ºC; IR (KBr) ν (cm−1): 3080, 2925, 2844, 1658, 1599, 1416, 1238, 1110, 834, 737, 561;
1H NMR (DMSO-d6, 400 MHz, δ ppm): 2.39 (s, 4H, [-N(CH2CH2)2O], 2.47 (s, 3H, quinoxaline
−CH3), 3.54 (s, 6H, [-N(CH2CH2)2O] + ˗CH2-), 4.46 (t, J = 5.2 Hz, 2H, -OCH2-CH2N-), 4.76 (t,
J = 4.8Hz, 2H, -OCH2-CH2N-), 5.42 (s, 2H, -NCH2CO-), 6.98 (d, J = 8.8 Hz, 2H, Ar-H), 7.33-
7.45 (m, 2H, Ar-H), 7.50-7.54 (m, 1H, Ar-H), 7.67 (d, J = 8.8Hz, 2H, Ar-H), 7.78 (d, J = 8.0
Hz, 1H, Ar-H), 8.01 (s, 1H, triazole-H), 8.06 (s, 1H, -N=CH), 11.74 (s, 1H, -CONH); 13C NMR
(DMSO-d6, 100 MHz, δ ppm): 21.00, 43.39, 48.86, 52.61, 65.90, 66.28, 114.69, 114.85, 123.24,
124.42, 127.01, 128.52, 128.66, 129.58, 131.89, 132.89, 143.93, 147.02, 154.29, 157.28, 159.33,
167.13; LC-MS (ESI) : m/z = 531 (M+H)+ for C27H30N8O4.
(E)-2-(3-Methyl-2-oxoquinoxalin-1(2H)-yl)-N'-(4-(2-(4-(piperidin-1-ylmethyl)-1H-1,2,3-
triazol-1-yl)ethoxy)benzylidene)acetohydrazide (14b): Yield: 69%; (Light yellow color
solid); m.p. = 175-177 ºC; IR (KBr) ν (cm−1): 3085, 2969, 1654, 1555, 1417, 1238, 1117, 987,
840, 737; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.33 (s, 2H, [-N(CH2CH2)2CH2]), 1.46 (s,
4H, [-N(CH2CH2)2CH2]), 2.43 (s, 7H, quinoxaline -CH3 + [-N(CH2CH2)2CH2]), 3.60 (s, 2H,
˗CH2- ), 4.34 (s, 2H, -OCH2-CH2N-), 4.73 (s, 2H, -OCH2-CH2N-), 5.38 (s, 2H, -NCH2CO-), 6.95
(d, J = 8.4 Hz, 2H, Ar-H), 7.29-7.42 (m, 2H, Ar-H), 7.47-7.51 (m, 1H, Ar-H), 7.64 (d, J = 8.4
Hz, 2H, Ar-H), 7.74 (d, J = 8.0 Hz, 1H, Ar-H), 7.97 (s, 1H, triazole-H), 8.04 (s, 1H, -N=CH),
11.66 (s, 1H, -CONH); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 21.62, 23.20, 24.61, 43.99,
49.61, 53.15, 53.22, 66.84, 115.30, 115.44, 123.89, 123.98, 127.61, 129.13, 129.27, 130.21,
132.47, 133.47, 144.52, 147.51, 154.90, 157.89, 159.90, 167.75; LC-MS (ESI) : m/z = 529
(M+H)+ for C28H32N8O3.

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(E)-2-(3-Methyl-2-oxoquinoxalin-1(2H)-yl)-N'-(4-(2-(4-(pyrrolidin-1-ylmethyl)-1H-1,2,3-
triazol-1-yl)ethoxy)benzylidene)acetohydrazide (14c): Yield: 80%; (Light yellow color solid);
m.p. = 179-181 ºC; IR (KBr) ν (cm−1): 3462, 3163, 2923, 1658, 1595, 1353, 1235, 1034, 840,
737, 560; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.82 (s, 4H, [-N(CH2CH2)2], 2.46 (s, 3H,
quinoxaline -CH3), 3.00 (s, 4H, [-N(CH2CH2)2], 4.22 (s, 2H, -CH2-) 4.46 (s, 2H, -OCH2-CH2N-),
4.81 (s, 2H, -OCH2-CH2N-), 5.41 (s, 2H, -NCH2CO-), 7.00 (d, J = 7.2 Hz, 2H, Ar-H), 7.33-7.44
(m, 2H, Ar-H), 7.53 (t, J = 7.6 Hz, 1H, Ar-H), 7.67 (d, J = 7.6 Hz, 2H, Ar-H), 7.77 (d, J= 7.6
Hz, 1H, Ar-H), 8.02 (s, 1H, triazole-H), 8.29 (s, 1H, -N=CH), 11.72 (s, 1H, -CONH); 13C NMR
(DMSO-d6, 100 MHz, δ ppm): 21.60, 23.30, 44.00, 48.72, 49.69, 53.35, 66.81, 115.26, 115.45,
123.92, 126.43, 127.61, 129.13, 129.30, 130.23, 132.45, 133.43, 144.59, 147.56, 154.91, 157.89,
159.85, 167.76; LC-MS (ESI): m/z = 515 (M+H)+ for C27H30N8O3.
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(E)-N'-(4-(2-(4-((Dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzylidene)-2-(3-
methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14d): Yield: 74%; (Reddish brown color
solid); m.p. = 195-197 ºC; IR (KBr) ν (cm−1): 3469, 2925, 2850, 1660, 1597, 1421, 1235, 1023,
1
832, 735, 557; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.10 (s, 6H, [-N(CH3)2]), 2.42 (s, 3H,
quinoxaline -CH3), 3.47 (s, 2H, -CH2-) 4.40 (t, J = 5.2 Hz, 2H, -OCH2-CH2N-), 4.72 (s, J = 4.8
Hz, 2H, -OCH2-CH2N-), 5.37 (s, 2H, -NCH2CO-), 6.94 (d, J = 8.4 Hz, 2H, Ar-H), 7.28-7.38 (m,
2H, Ar-H), 7.48 (t, J = 8.0 Hz, 1H, Ar-H), 7.63 (d, J = 8.8 Hz, 2H, Ar-H), 7.73 (d, J= 8.0 Hz,
1H, Ar-H), 7.96 (s, 1H, triazole-H), 8.01 (s, 1H, -N=CH), 11.66 (s, 1H, -CONH); 13C NMR
(DMSO-d6, 100 MHz, δ ppm): 21.61, 44.00, 44.91, 49.41, 53.93, 66.86, 115.28, 115.42, 123.89,
124.87, 127.56, 129.14, 129.30, 130.22, 132.45, 133.45, 144.58, 147.56, 154.91, 157.90, 159.91,
167.77; LC-MS (ESI): m/z = 487 (M−H)− for C25H28N8O3.
(E)-N'-(4-(2-(4-((Diethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzylidene)-2-(3-
methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14e): Yield: 78%; (Light yellowish green
color solid); m.p. = 185-187 ºC; IR (KBr) ν (cm−1): 3388, 3039, 2927, 1659, 1590, 1402, 1236,
1030, 819, 735, 556; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.08 (m, 6H, [-N(CH2CH3)2]),
2.43 (s, 3H, quinoxaline -CH3), 2.54 (m, 4H, [-N(CH2CH3)2]), 3.82 (s, 2H, -CH2-) 4.43 (t, J =
4.8 Hz, 2H, -OCH2-CH2N-), 4.78 (t, J = 4.8 Hz, 2H, -OCH2-CH2N-), 5.41 (s, 2H, -NCH2CO-),
6.98 (d, J = 8.2 Hz, 2H, Ar-H), 7.34-7.43 (m, 2H, Ar-H), 7.52 (t, J = 8.0 Hz, 1H, Ar-H), 7.69 (d,
J = 8.4 Hz, 2H, Ar-H), 7.78 (d, J= 7.8 Hz, 1H, Ar-H), 8.02 (s, 1H, triazole-H), 8.13 (s, 1H, -
13
N=CH), 11.72 (s, 1H, -CONH); C NMR (DMSO-d6, 100 MHz, δ ppm): 11.23, 21.01, 43.40,
46.09, 46.27, 48.87, 66.29, 114.69, 114.85, 123.26, 124.71, 127.03, 128.53, 128.67, 129.59,

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131.90, 132.89, 143.94, 146.97, 154.31, 157.29, 159.33, 167.15; LC-MS (ESI): m/z = 517
(M+H)+ for C27H32N8O3.
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(E)-N'-(3-Methoxy-4-(2-(4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)ethoxy) benzylidene)-
2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14f): Yield: 82%; (Light yellow color
solid); m.p. = 212-214 ºC; IR (KBr) ν (cm−1): 3390, 3097, 2921, 1652, 1585, 1420, 1233, 1116,
1014, 848, 737, 561; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 2.37 (s, 4H, [-N(CH2CH2)2O], 2.46
(s, 3H, quinoxaline -CH3), 3.54 (s, 4H, [-N(CH2CH2)2O]), 3.55 (s, 2H, -CH2-), 3.78 (s, 3H, -
OCH3), 4.44 (t, J = 4.0 Hz, 2H, -OCH2-CH2N-), 4.76 (t, J = 3.6 Hz, 2H, -OCH2-CH2N-), 5.44
(s, 2H, -NCH2CO-), 7.00 (d, J = 8.0 Hz, 1H, Ar-H), 7.21 (d, J = 8.0 Hz, 1H, Ar-H), 7.30-7.45
(m, 3H, Ar-H), 7.55 (t, J = 8.0 Hz, 1H, Ar-H), 7.78 (d, J = 8.0 Hz, 1H, Ar-H), 7.98 (s, 1H,
triazole-H), 8.04 (s, 1H, -N=CH), 11.75 (s, 1H, -CONH); 13C NMR (DMSO-d6, 100 MHz, δ
ppm): 21.61, 44.08, 49.49, 53.22, 53.34, 56.23, 66.59, 67.64, 109.94, 114.00, 115.28, 121.71,
123.89, 124.98, 128.08, 129.26, 130.20, 132.46, 133.44, 143.41, 144.68, 149.69, 149.82, 154.91,
157.89, 167.81; LC-MS (ESI) : m/z = 561 (M+H)+ for C28H32N8O5.
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(E)-N'-(3-Methoxy-4-(2-(4-(piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)ethoxy) benzylidene
)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14g): Yield: 76%; (Light yellow
color solid); m.p. = 195-197 ºC; IR (KBr) ν (cm−1): 3387, 3087, 2920, 1656, 1593, 1413, 1237,
1
1122, 1021, 738, 662, 561; H NMR (DMSO-d6, 400 MHz, δ ppm): 1.34 (s, 2H, [-
N(CH2CH2)2CH2]), 1.45 (s, 4H, [-N(CH2CH2)2CH2]), 2.34 (s, 4H, [-N(CH2CH2)2CH2]), 2.46 (s,
3H, quinoxaline -CH3), 3.52 (s, 2H, ˗CH2-), 3.77 (s, 3H, -OCH3), 4.43 (t, J = 4.8 Hz, 2H, -OCH2-
CH2N-), 4.75 (s, J = 4.4 Hz, 2H, -OCH2-CH2N-), 5.43 (s, 2H, -NCH2CO-), 7.00 (d, J = 8.0 Hz,
1H, Ar-H), 7.20 (d, J = 8.8 Hz, 1H, Ar-H), 7.34-7.41 (m, 3H, Ar-H), 7.54 (t, J = 6.8 Hz, 1H, Ar-
H), 7.79 (d, J = 7.6 Hz, 1H, Ar-H), 7.98 (s, 1H, triazole-H), 8.01 (s, 1H, -N=CH), 11.74 (s, 1H, -
CONH); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 21.61, 24.25, 25.85, 44.08, 49.47, 53.73,
53.93, 56.24, 67.68, 109.95, 114.03, 115.30, 121.72, 123.91, 124.87, 128.09, 129.27, 130.21,
132.46, 133.44, 143.87, 144.68, 149.70, 149.83, 154.91, 157.90, 167.81; LC-MS (ESI) : m/z =
559 (M+H)+ for C29H34N8O4.
(E)-N'-(3-Methoxy-4-(2-(4-(pyrrolidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)ethoxy)
benzylidene)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14h):
Yield: 78%;
(Dark yellow color solid); m.p. = 199-201 ºC; IR (KBr) ν (cm−1): 3398, 3094, 2918, 2853, 1651,
1415, 1256, 1127, 1021, 731; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.68 (s, 4H, [-

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N(CH2CH2)2]), 2.45 (s, 3H, quinoxaline -CH3), 3.26 (s, 4H, [-N(CH2CH2)2]), 3.76 (s, 2H, ˗CH2-),
3.79 (s, 3H, -OCH3), 4.42 (t, J = 5.2 Hz, 2H, -OCH2-CH2N-), 4.78 (t, J = 4.8 Hz, 2H, -OCH2-
CH2N-), 5.43 (s, 2H, -NCH2CO-), 7.02 (d, J = 8.0 Hz, 1H, Ar-H), 7.22 (d, J = 8.4 Hz, 1H, Ar-H),
7.33-7.44 (m, 3H, Ar-H), 7.53 (t, J = 7.6 Hz, 1H, Ar-H), 7.78 (d, J = 8.0 Hz, 1H, Ar-H), 7.99 (s,
1H, triazole-H), 8.02 (s, 1H, -N=CH), 11.74 (s, 1H, -CONH); 13C NMR (DMSO-d6, 100 MHz, δ
ppm): 21.00, 23.04, 43.49, 48.85, 49.71, 53.06, 55.64, 67.10, 109.42, 113.50, 114.72, 121.10,
123.26, 123.93, 127.54, 128.67, 129.58, 131.88, 132.89, 144.04, 149.11, 149.27, 154.31, 157.29,
167.19; LC-MS (ESI) : m/z = 545 (M+H)+ for C28H32N8O4.
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(E)-N'-(4-(2-(4-((Dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-3-methoxy
benzylidene)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14i): Yield: 70%;
(Reddish brown color solid); m.p. = 179-181 ºC; IR (KBr) ν (cm−1): 3462, 3180, 2925, 2826,
1
1650, 1411, 1227, 1016, 851, 732, 651, 565; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.18 (s,
6H, [-N(CH3)2]), 2.47 (s, 3H, quinoxaline -CH3), 3.56 (s, 2H, ˗CH2-), 3.78 (s, 3H, -OCH3), 4.44
(t, J = 5.2 Hz, 2H, -OCH2-CH2N-), 4.77 (t, J = 4.8 Hz, 2H, -OCH2-CH2N-), 5.45 (s, 2H, -
NCH2CO-), 7.03 (d, J = 8.4 Hz, 1H, Ar-H), 7.23 (d, J = 8.4 Hz, 1H, Ar-H), 7.34-7.43 (m, 3H,
Ar-H), 7.54 (t, J = 8.0 Hz, 1H, Ar-H), 7.79 (d, J = 8.4 Hz, 1H, Ar-H), 7.99 (s, 1H, triazole-H),
13
8.05 (s, 1H, -N=CH), 11.76 (s, 1H, -CONH); C NMR (DMSO-d6, 100 MHz, δ ppm): 21.62,
44.09, 44.83, 49.45, 53.91, 56.19, 67.66, 109.91, 114.05, 115.34, 121.72, 123.89, 125.01, 128.11,
129.26, 130.21, 132.47, 133.46, 143.73, 144.66, 149.68, 149.84, 154.91, 157.89, 167.81; LC-MS
(ESI) : m/z = 519 (M+H)+ for C26H30N8O4.
(E)-N'-(4-(2-(4-((Diethylamino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-3-methoxy
benzylidene)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide (14j): Yield: 79%;
(Light yellow color solid); m.p. = 208-210 ºC; IR (KBr) ν (cm−1): 3379, 3096, 2966, 2838, 1658,
1
1593, 1414, 1222, 1126, 1026, 857, 740, 580; H NMR (DMSO-d6, 400 MHz, δ ppm): 0.99 (s,
6H, [-N(CH2CH3)2]), 2.42 (m, 4H, [-N(CH2CH3)2]), 2.47 (s, 3H, quinoxaline -CH3), 3.70 (s, 2H,
˗CH2-), 3.78 (s, 3H, -OCH3), 4.44 (s, 2H, -OCH2-CH2N-), 4.76 (s, 2H, -OCH2-CH2N-), 5.45 (s,
2H, -NCH2CO-), 7.02 (d, J = 6.8 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 7.31-7.42 (m,
3H, Ar-H), 7.54 (t, J = 7.2 Hz, 1H, Ar-H), 7.78 (d, J = 6.8 Hz, 1H, Ar-H), 7.99 (s, 1H, triazole-
H), 8.02 (s, 1H, -N=CH), 11.76 (s, 1H, -CONH); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 12.32,
21.61, 44.08, 46.57, 47.06, 49.44, 56.21, 67.64, 109.88, 113.95, 115.30, 121.72, 123.90, 124.79,
128.07, 129.27, 130.20, 132.46, 133.44, 143.82, 144.68, 149.68, 149.82, 154.91, 157.89, 167.81;
LC-MS (ESI) : m/z = 547 (M+H)+ for C28H34N8O4.

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(E)-2-(3-Methyl-2-oxoquinoxalin-1(2H)-yl)-N'-(4-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)
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5
6
7
methoxy) benzylidene)acetohydrazide (15a): Yield: 75%; (White solid); m.p. = 180-182 ºC;
1
IR (KBr) ν (cm−1): 3396, 3176, 2925, 1656, 1595, 1426, 1227, 1033, 834, 731, 563; H NMR
(DMSO-d6, 400 MHz, δ ppm): 2.29 (s, 3H, ˗CH3), 2.44 (s, 3H, quinoxaline ˗CH3), 5.26 (s, 2H,
˗OCH2- ), 5.40 (s, 2H, ˗NCH2CO-), 7.13 (d, J = 8.4 Hz, 2H, Ar-H), 7.32 (t, J = 7.6 Hz, 1H, Ar-
H), 7.36-7.43 (m, 3H, Ar-H), 7.50 (t, J = 8.0 Hz, 1H, Ar-H), 7.63 (d, J = 8.8 Hz, 1H, Ar-H), 7.69
(d, J = 8.4 Hz, 2H, Ar-H), 7.75 (d, J = 8.4 Hz, 2H, Ar-H), 8.00 (s, 1H, triazole-H), 8.87 (s, 1H, -
N=CH), 11.66 (s, 1H, -CONH); LC-MS (ESI) : m/z = 508 (M+H)+ for C28H25N7O3.
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(E)-N'-(4-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-2-(3-methyl-
2-oxoquinoxalin-1(2H)-yl)acetohydrazide (15b): Yield: 82%; (White solid); m.p. = 232-234
ºC; IR (KBr) ν (cm−1): 3394, 3040, 2970, 1664, 1601, 1419, 1240, 1117, 1038, 833, 750, 671,
554; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 2.46 (s, 3H, quinoxaline ˗CH3), 3.82 (s, 3H,
˗OCH3), 5.26 (s, 2H, ˗OCH2- ), 5.42 (s, 2H, ˗NCH2CO-), 7.12-7.13 (m, 4H, Ar-H), 7.34-7.44 (m,
2H, Ar-H), 7.52 (t, J = 8.4 Hz, 1H, Ar-H), 7.64-7.79 (m, 5H, Ar-H), 8.02 (s, 1H, triazole-H),
13
8.82 (s, 1H, -N=CH), 11.70 (s, 1H, -CONH); C NMR (DMSO-d6, 100 MHz, δ ppm): 21.60,
44.00, 56.10, 61.70, 115.27, 115.43, 115.65, 122.38, 123.46, 123.88, 127.48, 129.16, 129.31,
130.21, 130.48, 132.16, 133.47, 143.88, 144.64, 154.91, 157.90, 159.88, 160.04, 167.76; LC-MS
(ESI) : m/z = 522 (M−H)− for C28H25N7O4.
(E)-N'-(4-((1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-2-(3-methyl-2-
oxoquinoxalin-1(2H)-yl)acetohydrazide (15c): Yield: 78%; (White solid); m.p. = 259-262 ºC;
1
IR (KBr) ν (cm−1): 3463, 3087, 2921, 1672, 1601, 1430, 1238, 1024, 855, 750, 671, 552; H
NMR (DMSO-d6, 400 MHz, δ ppm): 2.48 (s, 3H, quinoxaline ˗CH3), 5.32 (s, 2H, ˗OCH2- ), 5.44
(s, 2H, ˗NCH2CO-), 7.17 (d, J = 8.8 Hz, 2H, Ar-H), 7.34-7.47 (m, 3H, Ar-H), 7.54 (t, J = 7.2 Hz,
1H, Ar-H), 7.64-7.69 (m, 1H, Ar-H), 7.74 (d, J = 8.8 Hz, 2H, Ar-H), 7.78-7.84 (m, 2H, Ar-H),
7.87 (d, J = 8.4Hz, 1H, Ar-H), 8.04 (s, 1H, triazole-H), 9.04 (s, 1H, -N=CH), 11.74 (s, 1H, -
13
CONH); C NMR (DMSO-d6, 100 MHz, δ ppm): 21.63, 44.00, 61.67, 108.07, 108.34, 115.31,
115.66, 115.95, 116.16, 116.60, 123.68, 123.86, 127.56, 129.17, 129.27, 130.20, 132.37, 132.48,
133.49, 144.33, 144.55, 154.90, 157.89, 159.98, 164.16, 167.78; LC-MS (ESI) : m/z = 510
(M−H)− for C27H22FN7O3.
(E)-2-(3-Methyl-2-oxoquinoxalin-1(2H)-yl)-N'-(4-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-
triazol-4-yl)methoxy)benzylidene)acetohydrazide (15d): Yield: 68%; (White solid); m.p. =

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264-267 ºC; IR (KBr) ν (cm−1): 3330, 3092, 2974, 1668, 1603, 1420, 1248, 1118, 1034, 814,
4
5
1
748, 697, 550; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.47 (s, 3H, quinoxaline ˗CH3), 5.33 (s,
6
7
8
9
2H, ˗OCH2- ), 5.44 (s, 2H, ˗NCH2CO-), 7.17 (d, J = 7.2 Hz, 2H, Ar-H), 7.34-7.47 (m, 2H, Ar-H),
7.54 (t, J = 7.6 Hz, 1H, Ar-H), 7.67 (d, J = 8.4 Hz, 1H, Ar-H), 7.74 (d, J = 8.4 Hz, 1H, Ar-H),
7.78 (d, J = 8.0 Hz, 1H, Ar-H), 7.86-7.88 (m, 2H, Ar-H), 8.04 (s, 1H, triazole-H), 8.27-8.31 (m,
2H, Ar-H), 9.16 (s, 1H, -N=CH), 11.74 (s, 1H, -CONH); 13C NMR (DMSO-d6, 100 MHz, δ
ppm): 21.62, 43.99, 61.69, 115.31, 115.65, 117.36, 122.75, 123.84, 124.62, 125.83, 127.57,
129.17, 129.27, 130.20, 130.94, 131.26, 131.88, 132.48, 133.49, 137.53, 144.48, 144.54, 154.90,
157.89, 159.99, 167.78; LC-MS (ESI) : m/z = 562 (M+H)+ for C28H22F3N7O3.
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(E)-N'-(4-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-2-(3-methyl-2-
oxoquinoxalin-1(2H)-yl)acetohydrazide (15e): Yield: 76%; (White color solid); m.p. = 238-
240 ºC; IR (KBr) ν (cm−1): 3387, 3176, 2926, 2848, 1663, 1599, 1418, 1232, 1021, 824, 738,
568; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 2.44 (s, 3H, quinoxaline ˗CH3), 5.26 (s, 2H,
˗OCH2- ), 5.39 (s, 2H, ˗NCH2CO-), 7.11 (m, 2H, Ar-H), 7.31-7.64 (m, 8H, Ar-H), 7.91 (m, 2H,
Ar-H), 7.98 (s, 1H, triazole-H), 8.96 (s, 1H, -N=CH), 11.69 (s, 1H, -CONH); 13C NMR (DMSO-
d6, 100 MHz, δ ppm): 21.63, 44.00, 61.65, 115.30, 115.64, 122.38, 123.59, 123.86, 127.53,
129.16, 129.27, 130.20, 130.41, 132.48, 133.48, 133.60, 135.86, 144.30, 144.55, 154.90, 157.89,
159.99, 167.76; LC-MS (ESI) : m/z = 526 (M−H)− for C27H22ClN7O3.
(E)-N'-(3-Methoxy-4-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)-2-((3-
methylquinoxalin-2-yl)oxy)acetohydrazide (16a): Yield: 70%; (White solid); m.p. = 228-230
ºC; IR (KBr) ν (cm−1): 3454, 3037, 2917, 1683, 1588, 1509, 1429, 1268, 1182, 1043, 865, 769,
1
607, 551; H NMR (DMSO-d6, 400 MHz, δ ppm): 2.39 (s, 3H, -CH3), 2.66 (s, 3H, quinoxaline
˗CH3), 3.81 (s, 3H, ˗OCH3), 5.27 (s, 2H, ˗OCH2-), 5.59 (s, 2H, ˗OCH2CO-), 7.20-7.28 (m, 2H,
Ar-H), 7.38 (s, 1H, Ar-H), 7.41 (d, J = 8.0 Hz, 2H, Ar-H), 7.58-7.69 (m, 2H, Ar-H), 7.73 (d, J =
8.8 Hz, 1H, Ar-H), 7.80 (d, J = 8.4 Hz, 2H, Ar-H), 7.94 (d, J = 8.0 Hz, 1H, Ar-H), 7.98 (s, 1H,
triazole-H), 8.91 (s, 1H, -N=CH), 11.56 (s, 1H, -CONH); 13C NMR (DMSO-d6, 100 MHz, δ
ppm): 20.06, 20.53, 55.50, 61.68, 63.24, 109.17, 113.57, 120.07, 120.98, 122.96, 126.46, 126.68,
126.87, 127.42, 127.78, 129.15, 130.21, 134.33, 138.41, 138.82, 143.44, 143.86, 147.71, 149.22,
149.41, 155.32, 168.05; LC-MS (ESI) : m/z = 538 (M+H)+ for C29H27N7O4.
(E)-N'-(3-Methoxy-4-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy) benzylidene)-
2-((3-methylquinoxalin-2-yl)oxy)acetohydrazide (16b): Yield: 66%; (White solid); m.p. =