Cite this paper: Vietnam J. Chem.

, 2022, 60(1), 92-100 Research article

DOI: 10.1002/vjch.202100090

A facile synthesis, characterization and docking studies of 2-methyl-3-

(5-phenyl-4H-(1,2,4)triazol-3-yl)-quinoxaline and its derivatives
S. Ramakrishna Reddy1, G. Ganga Reddy1, Ch. Venkata Ramana Reddy1*, B. Srinivasa Reddy2,
E. Laxminarayana3
1
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad
-500 085, India
2
Mahatma Gandhi Institute of Technology, Kokapet, Gandipet, Hyderabad - 500075 India
3
Sreenidhi Institute of Science and Technology (Autonomous) Yamnampet, Ghatkesar, Hyderabad-501301
India
Submitted July 21, 2021; Revised September 13, 2021; Accepted September 21, 2021

Abstract
A new series of 2-Methyl-3-(5-phenyl-4H-(1,2,4)triazol-3-yl)-quinoxaline derivatives have been synthesized by
simple and efficient method by using 3-methyl-quinoxaline-2-carboxylic acid, 3-methyl-quinoxaline-2-
carboxylicacidethylester and 3-methyl-quinoxaline-2-carboxylichydrazide as reaction intermediates in good yields. All
the synthesized compounds were characterized by spectral and elemental analysis. The molecular docking studies of 2-
Methyl-3-(5-phenyl-4H-(1,2,4)triazol-3-yl)-quinoxalinecarried to predict the anti bacterial potential.
Keywords. Triazoles, quinoxalines, esterification, condensation, docking studies.

INTRODUCTION 3-yl)-quinoxalines (4a-f). The compounds

synthesized were characterized by analyzing their
1,2,4-triazoles have attracted the attention of many IR, 1H NMR, 13C NMR, Mass spectral and elemental
researchers due to their wide range of biological,[1,2] data.
pharmacological[3,4] and applications as anti-
inflammatory,[5] anti-cancer,[6] anti-bacterial,[7] 2. MATERIALS AND METHODS
tuberculosis, and anti-hypertensive.[9] Moreover,
[8]

synthesis of triazoles fused to Quinoxaline found to
possess numerous applications as antibacterial,[10]
antidepressant,[11] antiviral,[12] anti-cancer,[13] and
anti-inflammatory agents.[14]
Many drugs containing triazole fused with six-
member ring are also known to possess various
applications in the field of medicinal chemistry.[15]
The commonly known triazole systems are triazolo-
pyridines,[16] triazolo-pyridazines,[17] triazolo-
pyrimidines, [18]
triazolo-triazines,[19] triazolo-
pyrazines,[20] and a few monomeric triazolo-
thiadiazine.[21] The literature indicates heterocyclic
pharmaceutical agents containing N-C-S linkage in
their skeleton exhibit a broad spectrum of
pharmacological activities,[22-24] Some drugs
containing triazole moiety are shown in figure 1.
In view of the importance of the triazoles,
Quinoxalines and in continuation of our earlier
work,[25,26] we report herein the new methodology or
synthesis of 2-methyl-3-(5-phenyl-4H-[1,2,4]triazol-
All the reagents and solvents used were purchased
from Sigma-Aldrich and used without further
purification. Melting points were determined on a
Fisher–Johns melting point apparatus and were
uncorrected. Crude products were purified by
column chromatography on silica gel of 60-120
mesh. IR spectra were recorded on a PerkinElmer
BX series FT-IR 5000 spectrometer using KBr
pellet. 1H and 13C-NMR spectra were recorded on a
Varian 300 MHz and 100 MHz spectrometers
respectively. The chemical shifts, δ ppm were
reported down-field using TMS as an internal
standard. Mass spectra were recorded on a VG-
Micromass 7070H spectrometer operating at 70 eV.
Molecular docking studies aid in the discovery
of novel small molecular scaffolds and provide a
clear understanding of properties such as binding
energy, electron distribution, hydrogen bond donor
acceptors, polarizability, hydrophobicity, and protein
ligand interaction with target selectivity/affinity,

92 Wiley Online Library © 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH
Vietnam Journal of Chemistry Ch. Venkata Ramana Reddy et al.

drug likeness, and lead identification. Molecular
docking experiments have also been conducted to
better understand how synthesized quinoxaline
derivatives (4a-f) interact with the DHFR enzyme,
which could be used as a therapeutic target.
Molecular docking study was performed using
FLARE V5 Cresset U.K software to find the mode
of corresponding interactions of test compounds
with the target. The Protein Data Bank was used to
obtain the protein structure of dihydrofolate
reductase from Staphylococcus aureus (PDB ID-
4XE6). Marvin Sketch created energy minimized 3D
structures for the synthesized quinoxaline
derivatives to prepare them for docking. The entire
protein preparation process, including the removal of
crystallized ligand and water molecules, was carried
out within the Flare V5 software and all loops were
filled using the freed loop builder in the extension
window. Discovery studio software was used to
determine the protein-ligand interactions.

I II

III IV
Figure 1: Drugs containing thiozole ring

R: a) = H, b) = 2-CH3, c) = 2-Cl, d) = 4-Cl, e) = 2-NO2, f) = 4-NO2

Scheme 1: Synthesis of 2-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-yl)-quinoxalines
Reagents: (i) EtOH, H2SO4, reflux, 6 h; (ii) NH2–NH2. H2O, EtOH, reflux, 5 h; (iii) Ar-CHO, NH4OAc,
EtOH, reflux, 12-15 h

2.1. Synthesis of 3-methyl-quinoxaline-2- carboxylic acid (1) (0.01 mol) in absolute ethyl
carboxylic acid ethyl ester (2) alcohol (15 ml), conc. H2SO4 (1.5 ml) was added.
The mixture was constantly stirred at reflux
To the solution of 3-methyl-quinoxaline-2- temperature for 6 h. After completion of the reaction

© 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 93
Vietnam Journal of Chemistry
(monitored by TLC), the mixture was poured into
ice-cold water. Crude product was collected by
filtration, washed with 10% NaHCO3 solution, dried
and recrystallized from ethanol to get pure 3-methyl-
quinoxaline-2-carboxylic acid ethyl ester (2).
Yellow solid, yield: 71 %, M.P: 118-120 °C, IR
(KBr): 3040 (C-H, Ar), 2984 (C-H, CH3), 1659
(C=N), 1565, 1545 (C=C, Ar), 1735 (C=O), 1135
(C-O) cm-1. 1H NMR (300 MHz, CDCl3) δ: 7.51-
7.32 (m, 4H, Ar-H), 3.21 (q, 2H, CH2, J = 5.2 Hz),
2.89 (s, 3H, CH3), 1.85 (t, 3H, CH3, J = 5.2 Hz). 13C
NMR (100 MHz, DMSO-d6): δ 165.3, 137.6, 133.4,
129.7, 125.3, 123.7, 121.8, 117.1, 112.0, 44.6, 39.1,
21.8. MS: m/z 216 (M+); Anal. Calcd. For
C12H12N2O2: C-66.65, H-5.59, N-12.69, O-14.80.
Found: C-65.36, H-5.58, N-12.61, O-14.71.
2.2. Synthesis of 3-methyl-quinoxaline-2-
carboxylic acid hydrazide (3)
A mixture of 3-methyl-quinoxaline-2-carboxylic
acid ethyl ester (2) (0.01 mol) and hydrazine hydrate
(0.02 mol) in ethanol (25 ml) was refluxed on water
bath for 5 h. After completion of the reaction
(monitored by TLC), the reaction mixture was
cooled. The solid which was separated was filtered
and recrystallized from ethanol to get 3-methyl-
quinoxaline-2-carboxylic acid hydrazide (3).
White solid, Yield: 68 %, M.P: 105-107 °C, IR
(KBr): 3362 (N-H), 3042 (C-H, Ar), 2978 (C-H,
CH3), 1670 (C=O), 1645 (C=N), 1584, 1565 (C=C,
Ar) cm-1. 1H NMR (300 MHz, CDCl3) δ: 11.11 (s,
1H, NH), 7.52-7.21 (m, 4H, Ar-H), 5.21 (s, 2H,
NH2), 2.86 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ 161.3, 139.7, 134.6, 130.2, 125.4,
122.3, 122.7, 120.3, 115.6, 41.0. MS: m/z 202 (M+);
Anal. Calcd. For C10H10N4O: C-59.40, H-4.98,
N-27.71, O-7.91. Found: C-58.36, H-4.97, N-27.65,
O-7.89.
2.3. Synthesis of 2-methyl-3-(5-phenyl-4H-
[1,2,4]triazol-3-yl)-quinoxalines (4a-f)
To a solution of 3-methyl-quinoxaline-2-carboxylic
acid hydrazide (3) in ethanol (10 ml) was added
equimolar ratio of ammonium acetate (0.01 mol)
followed by the addition of benzaldehyde (0.01
mol) and the mixture was stirred for 12-15 h. After
completion of the reaction (examined by the TLC),
the solution was neutralized with ammonia solution
to get 2-methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-yl)-
quinoxaline (4a) whichwasrecrystalized from
ethanol. All other compounds 4b-f of this series
were synthesized by following the same
methodology.
© 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de
A facile synthesis, characterization and docking…
2.3.1. 2-Methyl-3-(5-phenyl-4H-[1,2,4]triazol-3-yl)-
quinoxaline (4a)
White solid, yield: 70 %, M.P: 131-133 °C, IR
(KBr):3215 (N-H), 3025 (C-H, Ar), 2984 (C-H,
CH3), 1632 (C=N), 1570, 1555 (C=C, Ar) cm-1. 1H
NMR (300 MHz, DMSO-d6) δ: 11.14 (s, 1H, NH),
7.59-7.41 (m, 9H, Ar-H), 2.84 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ 136.4, 131.2, 130.4,
128.5, 126.3, 125.8, 123.0, 121.4, 120.2, 119.8,
118.7, 116.3, 114.8, 110.1, 41.0. MS: m/z 287 (M+);
Anal. Calcd. For C17H13N5: C-71.06, H-4.56, N-
24.37. Found: C-70.12, H-4.55, N-24.21.
2.3.2. 2-Methyl-3-(5-o-tolyl-4H-[1,2,4]triazol-3-yl)-
quinoxaline (4b)
Yellow solid, yield: 66 %, M.P: 130-132 °C, IR
(KBr): 3224 (N-H), 3030 (C-H, Ar), 2977 (C-H,
CH3), 1641 (C=N), 1565, 1574 (C=C, Ar) cm-1. 1H
NMR (300 MHz, CDCl3) δ: 11.10 (s, 1H, NH), 7.51-
7.35 (m, 8H, Ar-H), 2.95 (s, 3H, CH3), 2.68 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): δ 136.2,
134.2, 131.3, 130.8, 129.4, 128.4, 127.5, 126.5,
125.6, 123.2, 121.0, 120.7, 119.2, 117.5, 116.4,
115.3, 114.7, 42.3. MS: m/z 301 (M+); Anal. Calcd.
For C18H15N5: C-71.74, H-5.02, N-23.24. Found:
C-70.67, H-5.01, N-23.12.
2.3.3. 2-[5-(2-Chloro-phenyl-4H-[1,2,4]triazol-3-
yl)-quinoxaline (4c)
Pink solid, Yield: 68 %, M.P: 122-124 °C, IR (KBr):
3231 (N-H), 3028 (C-H, Ar), 2969 (C-H, CH3), 1644
(C=N), 1571, 1562 (C=C, Ar) cm-1. 1H NMR (300
MHz, CDCl3) δ: 11.14 (s, 1H, NH), 7.50-7.42 (m,
8H, Ar-H), 3.00 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ 139.4, 134.2, 130.6, 128.4, 127.6,
125.7, 124.3, 123.0, 122.0, 121.7, 120.5, 119.5,
118.1, 116.2, 115.6, 114.1, 38.9. MS: m/z 321 (M+);
Anal. Calcd. For C17H12ClN5: C-63.46, H-3.76,
Cl-11.02, N-21.77. Found: C-62.84, H-3.75, Cl-
11.00, N-21.56.
2.3.4. 2-[5-(4-Chloro-phenyl-4H-[1,2,4]triazol-3-
yl)-quinoxaline (4d)
Brown solid, yield: 69 %, M.P: 136-138 °C, IR
(KBr): 3236 (N-H), 3040 (C-H, Ar), 2974 (C-H,
CH3), 1636 (C=N), 1584, 1558 (C=C, Ar) cm-1. 1H
NMR (300 MHz, CDCl3) δ: 11.18 (s, 1H, NH), 7.54
(d, 2H, J = 7.4 Hz, Ar-H), 7.48-7.32 (m, 4H, Ar-H),
7.28 (d, 2H, J = 7.4 Hz, Ar-H), 3.04 (s, 3H, CH3).
13
C NMR (100 MHz, DMSO-d6): δ 138.4, 137.2,
94
Vietnam Journal of Chemistry
135.6, 134.7, 128.7, 126.3, 124.3, 122.8, 121.8,
120.7, 119.4, 117.4, 116.3, 115.6, 40.2. MS: m/z 321
(M+); Anal. Calcd. For C17H12ClN5: C-63.46,
H-3.76, Cl-11.02, N-21.77. Found: C-62.84, H-3.75,
Cl-11.00, N-21.56.
2.3.5. 2-[5-(2-Nitro-phenyl-4H-[1,2,4]triazol-3-yl)-
quinoxaline (4e)
Yellow solid, yield: 71 %, M.P: 121-123 °C, IR
(KBr): 3248 (N-H), 3052 (C-H, Ar), 2976 (C-H,
CH3), 1644 (C=N), 1588, 1565 (C=C, Ar), 1545
(N=O)cm-1. 1H NMR (300 MHz, CDCl3) δ: 11.08 (s,
1H, NH), 7.57-7.40 (m, 8H, Ar-H), 2.98 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): δ 139.7,
137.6, 134.8, 133.4, 130.2, 129.7, 127.2, 126.4,
125.3, 123.7, 122.4, 121.8, 117.1, 115.3, 113.6,
112.0, 39.1. MS: m/z 332 (M+); Anal. Calcd. For
C17H12N6O2: C-61.44, H-3.64, N-25.29, O-9.63.
Found: C-60.47, H-3.63, N-25.14, O-9.62.
2.3.6. 2-[5-(4-Nitro-phenyl-4H-[1,2,4]triazol-3-yl)-
quinoxaline (4f)
Pale yellow solid, Yield: 72 %, M.P: 140-142 °C, IR
(KBr): 3260 (N-H), 3046 (C-H, Ar), 2966 (C-H,
CH3), 1648 (C=N), 1571, 1535 (C=C, Ar), 1552
(N=O) cm-1. 1H NMR (300 MHz, CDCl3) δ: 11.12
(s, 1H, NH), 7.56 (d, 2H, J = 7.2 Hz, Ar-H), 7.45-
7.30 (m, 4H, Ar-H), 7.25 (d, 2H, J = 7.2 Hz, Ar-H),
2.96 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6):
δ 138.3, 137.1, 135.2, 134.3, 129.7, 128.6, 127.0,
126.2, 125.0, 123.2, 120.8, 117.8, 115.7, 113.0, 41.2.
MS: m/z 332 (M+); Anal. Calcd. For C17H12N6O2:
C-61.44, H-3.64, N-25.29, O-9.63. Found: C-60.47,
H-3.63, N-25.14, O-9.62.
3. RESULTS AND DISCUSSION
The initial intermediate, 3-methyl-quinoxaline-2-
carboxylic acid ethyl ester (2) was prepared by the
esterification of 3-methyl-quinoxaline-2-carboxylic
acid (1) with ethanol and catalytic amount of
sulfuric acid under reflux with uniform stirring for 6
h. Preparation of the compound 2 was confirmed by
IR, 1H &13C NMR and mass spectra. In the IR
spectrum of compound 2, the absorption bands
appeared at 3040 (C-H, Ar), 2984 (C-H, CH3), 1659
(C=N), 1565, 1545 (C=C, Ar), 1735 (C=O), and
1135 (C-O) cm-1. The proton NMR spectrum of the
compound 2 showed a signal for four protons in the
range of  7.51-7.32 ppm which correspond to
aromatic ring. The signal appeared as quartet for two
protons with coupling constant, 5.2 Hz at 3.21 ppm
corresponds to CH2 group. The signal of three
© 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de
Ch. Venkata Ramana Reddy et al.
protons of CH3 group appeared as singlet at  2.89
ppm. The signal at  1.85 ppm as triplet for three
protons corresponding to the CH3 group with J value
5.2 Hz. The 13C NMR spectrum of this compound
showed the signals at varied chemical shifts 165.3,
137.6, 133.4, 129.7, 125.3, 123.7, 121.8, 117.1,
112.0, 44.6, 39.1, and 21.8 ppm. The mass spectrum
of this compound showed molecular ion peak at
m/z 216.
The final intermediate, 3-methyl-quinoxaline-2-
carboxylic acid hydrazide (3) was obtained when the
compound 2 undergone condensation with hydrazine
hydrate in ethanol. Formation of the compound 3 is
confirmed by the IR, NMR and mass spectral
analysis. The IR spectrum of compound 3 showed
the bands at 3362 (N-H), 3042 (C-H, Ar), 2978
(C-H, CH3), 1670 (C=O), 1645 (C=N), 1584 and
1565 (C=C, Ar) cm-1. The 1H NMR spectrum of the
compound 3 showed a signal as singlet at δ 11.11
ppm for one proton corresponding to the NH group.
The signal appeared from δ 7.52 to 7.21 ppm as
multiplet for four protons indicates the existence of
aromatic ring. The peak at δ 5.21 ppm as singlet for
two protons corresponds to the NH2 group. The
signal as singlet for three protons at δ 2.86 ppm
corresponds to CH3 group. The 13C NMR spectrum
of this compound showed signals at various
chemical shifts such as 161.3, 139.7, 134.6, 130.2,
125.4, 122.3, 122.7, 120.3, 115.6, and 41.0 ppm.
The mass spectrum of the compound 3 showed a
molecular ion peak at m/z 202 (M+).
The title compounds, 2-methyl-3-(5-phenyl-4H-
[1,2,4]triazol-3-yl)-quinoxalines (4a-f) were
obtained in good yields by cyclization of compound
3 on treatment with different aromatic aldehydes in
presence of ammonium acetate in ethanol.
Compound 4a was confirmed by IR, NMR and mass
spectral examination. The IR spectrum of 4a showed
the absorption bands at 3215 (N-H), 3025 (C-H, Ar),
2984 (C-H, CH3), 1632 (C=N) and 1570, 1555
(C=C, Ar) cm-1. The proton NMR spectrum of the
compound 4a showed a signal of the NH group as
singlet for one proton at  11.14 ppm. Nine protons
of the aromatic ring were appeared as multiplet in
the span of  7.59-7.41 ppm. The signal appeared at
 2.84 ppm as singlet for three protons corresponds
to CH3 group. The 13C NMR spectrum of this
compound showed the signals at various 136.4,
131.2, 130.4, 128.5, 126.3, 125.8, 123.0, 121.4,
120.2, 119.8, 118.7, 116.3, 114.8, 110.1, and 41.0
ppm. The mass spectrum of this compound showed
molecular ion peak at m/z 287. The chemical
structure of other derivatives 4b-f were
characterized in similar manner as 4a.
95
Vietnam Journal of Chemistry A facile synthesis, characterization and docking…

Docking studies of the Quinoxaline ring in test compounds were

The docking study gives a notion of how the
quinoxaline derivatives (4a-f) interact with the target
protein. Test compounds were docked over the
dihydrofolate reductase protein from S. aureus in
this work (PBD ID-4XE6).[27] All the compounds
had good LF dG docking scores against the
dihydrofolate reductase protein fragment, ranging
from -8.63 to -6.24. Different forms of interaction
with amino acids situated at the active region of
dihydrofolate reductase were observed in test
compounds are shown in figure 2. The nitrogen atom
of the 1,2,4-triazole ring and the nitrogen heteroatom
shown to be available for hydrogen bond formation
with distinct amino groups of the chosen PBD file
with a certain bond distance in a docking research.
The amino group of Isoleucine (Ile X14, 2.5 Å) and
the nitrogen atom of the 1,3,4-triazole ring and
nitrogen atom of quinoxaline compounds and amino
group of alanine generate hydrogen bond
interactions (Ala X7, 2.6 Å) and pi-pi stacked
interactions with (Phe X92, 4.5 Å). These amino
acids form a cascade that helps the test compounds
bind and stay in the active site of dihydrofolate
reductase protein. All the compounds had good
docking score which is shown in table 1.

Table 1: FLARE V5 GUI for docking parameters

LF
LF
Name Substituent MW SlogP TPSA Rank LF dG LF LE
HBA HBD VSscore
Score

co-
crystallised
ligand 373.5 3.7 99.9 5 1 -5.351 -8.668 -9.858 -0.31
4a R=H 287.3 3.4 67.3 4 1 -5.551 -6.923 -8.173 -0.315
4b R = oCH3 301.4 3.7 67.3 4 1 -6.464 -7.561 -8.899 -0.329
4c R = oCl 321.8 4.1 67.3 4 1 -6.666 -8.036 -9.361 -0.349
4d R = pCl 321.8 4.1 67.3 4 1 -6.322 -7.929 -9.088 -0.345
4e R = pNitro 332.3 3.2 113.2 6 1 -6.527 -7.033 -8.727 -0.281
4f R = oNitro 332.3 3.2 113.2 6 1 -6.308 -6.243 -7.542 -0.25

4a

Figure 2: 2D and 3D Interaction study of Quinoxaline derivatives (4a-f) with

binding domain of 4XE6 target protein

© 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 96
Vietnam Journal of Chemistry Ch. Venkata Ramana Reddy et al.

4b

4c

4d

Figure 2: 2D and 3D Interaction study of Quinoxaline derivatives (4a-f) with

binding domain of 4XE6 target protein

© 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 97
Vietnam Journal of Chemistry A facile synthesis, characterization and docking…

4e

4f
Figure 2: 2D and 3D Interaction study of Quinoxaline derivatives (4a-f) with
binding domain of 4XE6 target protein

4. CONCLUSION Consent for publication. Not applicable.

A library of triazole derivatives containing
quinoxaline have been synthesized and all the
compounds were characterized by 1H-NMR,
13
C NMR and Mass spectral analysis. The yields
obtained for the synthesized compounds were good.
The compounds 4c (-8.036) and 4d (-7.29) with the
chloro group at ortho and para positions had a higher
docking score compared to other derivatives.
Accordingly, these compounds can show anti
bacterial activity.
Acknowledgement. Authors are thankful to
Jawaharlal Nehru Technological University
Hyderabad, India for providing necessary facilities
to carry out this work.
Ethics approval and consent to participate. Not
applicable.
Competing Interests. The authors declare that they
have no competing interests.
Funding. No funding has been received from any
source.
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Corresponding author: Ch. Venkata Ramana Reddy

Department of Chemistry
Jawaharlal Nehru Technological University Hyderabad Kukatpally
Hyderabad, Telangana, India - 500085
E-mail: vrr9@jntuh.ac.in.

© 2022 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 100