RETRACTED ARTICLE: Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-Triazolylpolyaza Heterocyclic Compounds

Article abstract of DOI:10.1002/jhet.3395

In this research article, a highly efficient, cost-effective synthesis of various hybrid molecules possessing 1,2,3-triazolyltetrazoles and evaluation of their biological activity have been addressed. The structure elucidation of these new library hybrid molecules has been carried out by IR, ¹H NMR, ¹³C NMR, and mass spectral analysis. The compounds have been screened for their anticancer activity against human colon cancer cell line Colo-205 and human lung cancer cell line HOP-205, and the results attest that most of the compounds have shown very good therapeutic nature. In particular, compounds 3d, 3j, 6a, and 6e were more cytotoxic than Adriamycin against all tested human cancer cell lines with 68percent, 101.8percent, 94percent, and 104.5percent growth, respectively. In the present investigation, a series of 3a–j and 6a–h were subjected to molecular properties prediction, drug likeness by Molinspiration, and toxicity risks by Molsoft software programs. All the 18 analogues were chosen on the basis of Lipinski “Rule of five” for the synthesis, screening their antibacterial and anticancer as oral bioavailable drugs/leads.

Full text of DOI:10.1002/jhet.3395

Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid
1,2,3-Triazolylpolyaza Heterocyclic Compounds
Srinivasa Rao Dasari,a,b Subbaiah Tondepu,c Lakshmana Rao Vadali,b Mutyala Naidu Ganivada,d and
a
*
Nareshvarma Seelam
aDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh 522502,
India
bMylan Laboratories Ltd, Hyderabad, Telangana 500049, India
cDepartment of Chemical Engineering, Vignan’s Foundation for Science, Technology and Research, Vaddeswaram,
Guntur, Andhra Pradesh 522213, India
dPolymer Research Centre, Department of Chemical Sciences, Indian Institute of Science Education and Research,
Kolkatta, Nadia, West Bengal 741246, India
*E-mail: nareshvarma.klu@gmail.com
Received June 30, 2018
DOI 10.1002/jhet.3395
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
In this research article, a highly efficient, cost-effective synthesis of various hybrid molecules possessing
1,2,3-triazolyltetrazoles and evaluation of their biological activity have been addressed. The structure
elucidation of these new library hybrid molecules has been carried out by IR, 1H NMR, 13C NMR, and mass
spectral analysis. The compounds have been screened for their anticancer activity against human colon
cancer cell line Colo-205 and human lung cancer cell line HOP-205, and the results attest that most of the
compounds have shown very good therapeutic nature. In particular, compounds 3d, 3j, 6a, and 6e were more
cytotoxic than Adriamycin against all tested human cancer cell lines with 68%, 101.8%, 94%, and 104.5%
growth, respectively. In the present investigation, a series of 3a–j and 6a–h were subjected to molecular
properties prediction, drug likeness by Molinspiration, and toxicity risks by Molsoft software programs.
All the 18 analogues were chosen on the basis of Lipinski “Rule of five” for the synthesis, screening their
antibacterial and anticancer as oral bioavailable drugs/leads.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
formation,” “dipole-dipole and π stacking interactions,”
“stable to reduction and oxidation,” and “stable to
hydrolysis under acidic and basic condition” [1]. Some
of the important 1,2,3-triazole compounds have been
showcased as antimicrobial [2], antibacterial [3],
antifungal [4], antimalarial [5], antitubercular [6], anti-
inflammatory [7], antiviral [8], anticancer [9], HIV
protease inhibitors [10], antiobesity [11], antipsychotic
[12], antidiabetes [13], and antiepileptic [14] agents.
Tetrazoles are a class of heterocycles with a wide
range of applications that are receiving considerable
Triazoles are a class of nitrogenous heterocyclic
compounds possessing three nitrogen and two carbon
atoms in a five-membered ring. Although triazoles are
not abundant in nature, they are found to be effective
amide surrogates in bioactive molecules causing for
the exposition of diverse and important biological
properties. 1,2,3-Triazole ring systems have found a
broad spectrum of applications in the field of medicinal
chemistry for their unique features like “hydrogen bond
© 2018 Wiley Periodicals, Inc.

S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
Vol 000
attention [15]. The synthesis of novel tetrazole
derivatives and the investigation of their chemical and
biological behavior have gained more importance in the
recent decades for biological and pharmaceutical
reasons. Recently, several biologically relevant
substances incorporating a tetrazole moiety have been
developed. For example “Losartan” is an angiotensin II
receptor antagonist [16], “Tomelukast” (LY-171883)
mimics the cysteinyl glycine terminus of growth
hormone LTD 4 also functions as a potent anti-
asthmatic drug [17], and “BMS-317180” is a potent
oral agonist of the human growth hormone
secretagogue receptor [18]. Their derivatives were also
reported to possess broad spectrum of biological
activity in both medicinal and pharmaceutical areas
such as antibacterial [19], antinociceptive [20],
immunosuppressive [21], antifungal [22], anticancer,
anti-inflammatory [23], antiulcer [24], antiproliferative
[25], antianalgesic [26], and antiallergic [27] activities.
Hence, the scaffold 1,2,3-triazole, tetrazole seems to be
a potential and privileged pharmacophore that may
attribute important pharmacological properties to the
molecules and have the current focus of the research. We
have designed new hybrid templates A, B, linking two or
three pharmacophoric groups through linkers in search of
promising antibacterial and anticancer agents (Fig. 1).
Novel hybrid molecules containing two or three
biologically active scaffolds were expected to possess
good antibacterial and anticancer activities. Moreover,
these new compounds 3 and 6 and two standard drugs
were subjected to Molsoft/Molinspiration analysis to
obtain insights on the degree of their toxicity, where they
were found to be nontoxic.
RESULTS AND DISCUSSION
Chemistry. In the present work, we hereby report the
synthesis of triazolyl chromenone derivatives as per
Scheme 1. Table 1 represents the list of the product
analogues along with the respective reactants.
The target compound 4-methyl-7-(2-(4-(phenoxymethyl)-
1H-1,2,3-triazol-1-yl)ethoxy)-2H-chromen-2-one (3a) was
synthesized using CuAAC method as shown in Scheme 1.
The required starting compound azide, 7-(2-azidoethoxy)-
4-methyl-2H-chromen-2-one 1a, was prepared according to
the known procedure [28] and reacted with terminal alkyne,
(prop-2-yn-1-yloxy)benzene 2a, in the presence of
CuSO4.5H2O and Na-ascorbate in dry DMF at RT. The
reaction mixture was stirred for 5–10 min, and the progress
Figure 1. Design of new hybrid molecules. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 1. Synthesis of triazole-coumarin library. Reagents and conditions: DMF, CuSO4.5H2O, Na-ascorbate, 5–10 min, RT, 85–90%; R = –H or –CH3,
R1 = alkyl, phenyl, aryl, substituted aryl.
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Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-
Triazolylpolyaza Heterocyclic Compounds
1
of the reaction was monitored by TLC. After completion of
the reaction as indicated by TLC and quenched in crushed
ice, the expected triazole compound was obtained as white
solid in 87% yield, mp 130–132°C; Rf: 0.43 (1:1
dichloromethane : ethyl acetate). The structure of the
synthesized compound 3a was characterized by IR, 1H
NMR, and 13C NMR spectroscopy and mass spectrometry.
The IR spectrum of 3a exhibited a band in the region
3050 cmꢀ1 for aromatic C–H stretching, 1720 cmꢀ1 for
conjugated C¼O stretching of six-membered lactone,
1280 cmꢀ1 for C–O stretching. In the H NMR spectrum,
the compound 3a exhibited a singlet at δ 7.80 ppm due to
CH proton of triazole ring, one olefinic hydrogen on C-3 of
4-methylcoumarin derivatives appeared as singlet at δ
6.15 ppm. Methyl group at C-4 gave signal at δ 2.38 ppm.
Appearance of two triplets at around δ 4.81 and
4.44 ppm confirmed the presence of two methylene groups
in final compounds. And finally, mass spectrum of 3a
showed protonated molecular ion peak at m/z 377.14
(M + 1)+; fragmentation pattern was in accordance with the
Table 1
List of analogues prepared.
Reactants 1 (a–b)
Reactants 2 (a–i)
Products 3 (a–j)
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S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
assigned structure (Please see Experimental section for BIOLOGY
Vol 000
details) (Table 2).
The reaction strategy was extended to synthesize
combination of triazole-tetrazoles 6. We performed
CuAAC reaction between 3 (A), 4, and commercially
available 5 to get the designed 1,2,3-triazole-tetrazoles in
good yields (Scheme 2, Fig. 2).
Antibacterial activity. Table 3 and Figure 3 represent
the antibacterial activity of coumarine hybrids 3.
All the synthesized compounds exhibited mediocre
antibacterial activity against both Gram-positive and
Gram-negative bacteria, and the results are summarized in
Table 2
Physiological properties of the derivatives prepared.
S. No.
Targets (3)
Color
mp
logP/ClogPa
3.64/3.33
3a
White solid
130–132°C
3b
Off white solid
80–82°C
3.21/2.97
3c
3d
3e
White solid
Pale yellow solid
Off white solid
86–88°C
160–162°C
150–152°C
4.12/3.83
4.63/4.50
4.68/4.68
3f
White solid
98–100°C
3.71/3.74
3g
3h
Pale yellow solid
Light yellow solid
148–150°C
140–142°C
4.51/4.18
3.21/2.55
3i
3j
Off white solid
Off white solid
160–162°C
140–142°C
3.53/3.24
4.46/4.01
aThe logP/ClogP is calculated by ChemBioDraw 12.0.
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-
Triazolylpolyaza Heterocyclic Compounds
Scheme 2. Synthesis of designed hybrid triazole-tetrazole molecule. Reagents and conditions: (i) NaBH4, EtOH, RT, 4 h, 85%; (ii) SOCl2, benzene,
80°C, 3 h, 82%; (iii) NaN3/DMF, RT, 2 h, CuSO4.5H2O, Na-ascorbate, RT, 5 min, 92%.
Table 3 and Figure 3. Compounds 3a, 3f, and 3j displayed
best activity against all Gram-positive and Gram-negative
bacterial strains. Compounds 3c, 3d, and 3b exhibited
significant activity against Staphylococcus aureus.
Anticancer activity. Most of the synthesized compounds
were evaluated for in vitro cytotoxic properties. Some of the
compounds 3c, 3d, 3g, 3h, and 3j were tested for their
cytotoxicity against two cancer cell lines, for example,
colon cancer cell line Colo-205 and lung cancer cell line
HOP-62, and the results are summarized in Table 4
and Figure 4. 7-(2-(4-((Naphthalen-2-yloxy)methyl)-1H-
1,2,3-triazol-1-yl)ethoxy)-2H-chromen-2-one (3j) is good
against lung cancer and colon cancer. 4-Methyl-7-(2-(4-
((naphthalen-2-yloxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)
-2H-chromen-2-one 3d is good against colon cancer.
Antibacterial activity. Most of the synthesized hybrid
tetrazolo triazole derivatives were tested in vitro
antibacterial properties against four strains of bacterial
microorganisms (Pseudomonas aeruginosa, S. aureus,
Klebsiella pneumoniae, and Escherichia coli). The results
are summarized in Table 5. Figure 5 represents graphical
representation of antibacterial activity of tested compound.
Most of the compounds showed moderate to reasonable
activities against all the strains. Compounds 6a and 6h
showed superior activity against P. aeruginosa.
Compounds 6e, 6a, and 6g showed better activity against
Figure 2. List of derivatives synthesized with percentage of yield.
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S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
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Table 3
Antibacterial activity of target compounds 3.
Diameter of inhibition zone in mm at 0.5 mg/100 μL
Pseudomonas aeruginosa
Staphylococcus aureus
Klebsiella pneumoniae
Escherichia coli
S. No.
Compound
Gram (ꢀve)
Gram (+ve)
Gram (ꢀve)
Gram (ꢀve)
1
2
4
3
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
18 0.3
12 0.3
11 0.3
11 0.2
13 0.4
13 0.4
11 0.3
12 0.2
12 0.3
16 0.3
28 0.3
15 0.4
14 0.3
15 0.4
15 0.3
13 0.2
14 0.4
13 0.3
11 0.2
12 0.2
15 0.3
36 0.2
16 0.2
14 0.3
12 0.3
13 0.2
15 0.4
13 0.3
12 0.4
12 0.2
13 0.2
14 0.3
35 0.3
16 0.3
12 0.3
13 0.4
14 0.3
12 0.2
17 0.3
11 0.3
13 0.2
12 0.3
15 0.3
31 0.3
9
10
12
3i
3j
Pefloxacin
S. aureus. Compound 6f showed superior activity against
E. coli. Compounds 6g and 6a showed some good
activity against K. pneumoniae. Compound 6a showed
better activity against P. aeruginosa and S. aureus. The
present class of newer hybrids in general appeared to be
more effective against K. pneumoniae and S. aeruginosa.
Anticancer activity. Most of the synthesized compounds
were evaluated for in vitro cytotoxic properties. Results of
some of the tested compounds 6a, 6e, 6g, 6f, and 6h which
were checked for their cytotoxicity against two cancer cell
lines, e.g. colon cancer cell line Colo-205 and lung cancer
cell line HOP-62 were summarized. 2-Chloro-6-methyl-3-
any significant effects, indicating their selectivity towards
the growth inhibition of cancer cells.
Molecular properties.
Molecular property is
a
composite balance of various structural features that
condition whether a particular molecule is similar to the
known drugs. High oral bioavailability is an important
factor for the development of bioactive molecules as
therapeutic agents good intestinal absorption, reduced
molecular flexibility, low polar surface area (PSA), or
total hydrogen bond count (some of donors and some of
accepters) are important predictors of good oral
bioavailability [29]. Computational chemists have
extensive array of tools and approaches available for the
evaluation/analysis of molecular diversity, an important
ingredient in drug design. So computational analysis and
structure analysis have been used to study the drug
likeness of a drug candidate. A good bioavailability can
be achieved with an appropriate balance between
solubility (S) and partitioning properties. Thus, in order
to achieve good oral drugs, we have subjected a series
((4-(((1-phenyl-1H-tetrazol-5-yl)thio)
methyl)-1H-1,2,3-
triazol-1-yl)methyl)quinoline (6a), 5-(((1-(3-Nitrophenyl)-
1H-1,2,3-triazol-4-yl)methyl)thio)-1-phenyl-1H-tetrazole
(6e) are the most active compounds against the Colo-205 and
HOP-62 cell lines. Table 6 and Figure 6 represent the
percentage of growth curve of 6a and 6e. These compounds
were also tested against non-cancerous human embryonic
kidney cells, that is, HEK293, where none of them showed
Figure 3. Graphical representation of antibacterial activity of compound 3. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-
Triazolylpolyaza Heterocyclic Compounds
of title compounds 3 and 6 for the prediction of
lipophilicity, solubility, toxicity, and Lipinski rule of
five [30] by using Molinspiration and Molsoft software
programs [31a, b].
Molinspiration calculations.
MiLogP (octanol/water
partition coefficient) is calculated by the methodology
developed by Molinspiration as a sum of fragment-based
contributions and correction factors. Molecular PSA is
calculated as a sum of fragment contributions. (Oxygen
and nitrogen centered polar fragments are considered
[32]). PSA has been shown to be a very good describer
characterizing drug absorption, including intestinal
absorption, bioavailability, CaCO2 permeability, and
blood–brain barrier crossing. A computational study of
compounds 3a–j and 6a–h for prediction of absorption,
distribution, metabolism, and exertion properties is shown
in Table 7. Lipophilicity (logP) and PSA are considered
to be important properties for the prediction of oral
bioavailability of drug molecules [33]. PSA was used to
calculate the percentage of absorption (%ABS) according
to the equation: %ABS = 109 0.345 × PSA. From all
the parameters, it can be observed that all the compounds
3 and 6 showed %ABS ranging from 64.36% to 84.71%
and compared with standard drugs pefloxacin and ADR,
86.30% and 37.90%, respectively. From the results, the
final compounds 3b, 3f, and 3i exhibit the highest
percentage of absorption 84.71 value, respectively.
The number of rotatable bonds (nrotb) and Lipinski’s
rule of five were also calculated. This rule is widely used
as a filter for drug-like properties. The rules state that
most molecules with good membrane permeability have
MiLogP ≤5, molecular weight ≤500, number of hydrogen
bond acceptors (nON) ≤10, and number of hydrogen
bond donors (nOHNH) ≤5. For all the compounds, the
calculated MiLogP values vary between ꢀ0.10 and 5.04
(≤5), the compounds 3d, 3e, 3j, and 6b that are able to
penetrate through bio-membranes according to Lipinski’s
rule. Molecular PSA is a very useful parameter for the
prediction of drug transport properties, and PSA is a sum
of surfaces of polar atoms (usually oxygen, nitrogen, and
attached hydrogen) in a molecule. PSA was determined
by the fragment-based method of Ertl and coworkers
[30]. Thus, molecules with PSA values around of 160 Å2
or more are expected to exhibit poor intestinal absorption.
Table 7 shows that all the compounds vary from 86.68 to
137.12, indicating their good oral bioavailability. All the
compounds did not violate any of the Lipinski’s rule of
five; however, zero violation was observed for 3, good
permeability was observed for 6, and one violation was
observed for 3d, 6f, and ADR, suggesting poor
permeability across cell membrane for these compounds.
Drug likeness/bioactivity scores of compounds 3 and 6
were also predicted by Molinspiration and are presented in
Table 6. Bioactivity scores of all compounds and standard
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S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
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Figure 4. Percentage of control growth curve of 3d and 3j. [Color figure can be viewed at wileyonlinelibrary.com]
drugs were rigorously analyzed under four criteria of
known successful drug activity in the areas of GPCR
ligand activity, ion channel modulation, kinase inhibition
activity, and nuclear receptor ligand activity. A molecule
having bioactivity score more than 0.00 (3e and 3g)
(Fig. 7) is most likely to exhibit considerable biological
activities, while values ꢀ0.50 to 0.00 are expected to be
moderately active 3a, 3c, 3d, 6a, 6b, 6c, and 6f, and if
score is less than ꢀ0.50, it is presumed to be inactive 6d,
6e, 6f, 6g, and 6h. All the compounds are expected to
have close similar activity to standard drugs based upon
these six rigorous criteria (GPCRL, ICM, KI, NRL, PI,
and EI).
EXPERIMENTAL
Chemistry.
All chemicals were purchased from
commercial suppliers and were used without further
purification. All reactions were performed under inert
Table 5
Antibacterial activity of target compounds.
Diameter of inhibition zone in mm at 0.5 mg/100 μL
Compound
Pseudomonas aeruginosa
Staphylococcus aureus
Klebsiella pneumoniae
Escherichia coli
Gram (ꢀve)
Gram (+ve)
Gram (ꢀve)
Gram (ꢀve)
6a
6b
6c
6d
6e
6f
6g
6h
16 0.4
12 0.3
13 0.3
12 0.2
14 0.2
13 0.3
13 0.4
15 0.4
28 0.3
16 0.4
14 0.2
11 0.3
12 0.4
16 0.4
14 0.3
15 0.3
12 0.3
36 0.2
13 0.3
11 0.2
12 0.2
11 0.2
12 0.3
12 0.3
13 0.4
11 0.2
35 0.3
11 0.2
13 0.2
13 0.3
12 0.3
14 0.2
15 0.4
14 0.2
12 0.3
31 0.3
Pefloxacin
Figure 5. Graphical representation of antibacterial activity of target compounds. [Color figure can be viewed at wileyonlinelibrary.com]
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Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-
Triazolylpolyaza Heterocyclic Compounds
nitrogen atmosphere employing dry solvents. Precoated
TLC silica gel plates (Kieselgel 60 F254, Merck) were
used for monitoring reactions, and the spots are
visualized under UV lamp (254 nm). Purification was
performed by column chromatography using silica gel
(particle size 60–120 mesh, Merck). Melting points were
determined in open capillary tubes on cintex melting
point apparatus and are uncorrected. IR (KBr) spectra
were recorded on a Perkin–Elmer 400 FTIR spectrometer
(υmax in cmꢀ1) or a Varian 670-IR FT-IR spectrometer
(ATR) in the frequency range of 600–4000 cmꢀ1, and we
observed vibrational frequencies for strong (s) and weak
1
(w) peaks. H NMR and 13C NMR spectra were recorded
in CDCl3/DMSO-d6 on
a Bruker DRX-300 (300,
400 MHz FT NMR) or Varian Mercury 500 MHz
spectrometer. Proton chemical shifts are presented in δ
ppm with reference to TMS. J values are presented in Hz.
Mass spectra were recorded using Jeol SX-102
spectrometer. Determinations were carried out using an
equipment VARIO EI III version H of Elementar
Analysensysteme.
Preparation of 1,2,3-triazole derivatives 3a–j. A mixture
of azide 1 (2 mmol), an appropriate terminal alkyne 2
(2 mmol), copper sulphate (62.5 mg, 0.5 mmol), and
sodium ascorbate (49.5 mg, 0.5 mmol) in dry DMF (5 mL)
was stirred vigorously for 5–10 min. The progress of the
reaction was monitored by checking TLC at a regular
interval. After completion of the reaction, the mixture was
poured into crushed ice (30 g). The solid separated was
filtered, dried, and purified by column chromatography on
silica gel (100–200 mesh) using dichloromethane and
ethyl acetate to isolate pure desired products.
Synthesis of target compounds 6a–h.
In order to
perform copper (I) catalyzed 1,3 dipolar cycloaddition
(CuAAC) reaction, a mixture of terminal alkyne 5
(2 mmol), an appropriate azide from chloro compounds 3
(A) or 4 (2 mmol), copper sulphate (125 mg, 0.5 mmol),
and Na-ascorbate (99 mg, 0.5 mmol) was added in dry
DMF (5 mL) and stirred vigorously for 5–10 min. The
progress of the reaction was monitored by checking TLC
at a regular interval. After completion of the reaction, the
mixture was poured into crushed ice (30 g). The solid
separated was filtered; dried and crude product was
purified by column chromatography on silica gel (100–
200 mesh) using chloroform and ethyl acetate (3:1)
mixture as eluent to isolate pure desired products.
4-Methyl-7-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)
ethoxy)-2H-chromen-2-one (3a).
IR (KBr) νmax/cmꢀ1
:
3076, 2955, 2931, 2322, 1786, 1601, 1499, 1449, 1378,
1
1257, 1162, 965, 822. H NMR (400 MHz, CDCl3): δ
7.80 (s, 1H), 7.48 (d, 1H, J = 8.3 Hz), 7.30–7.28 (m,
2H), 6.98 (m, 3H), 6.80–6.78 (m, 2H), 6.15 (s, 1H), 5.22
(s, 2H), 4.81 (t, 2H, J = 4.8 Hz), 4.44 (t, 2H, J = 4.8 Hz),
2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.9,
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S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
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Figure 6. Percentage of growth curve of compounds 6e and 6a. [Color figure can be viewed at wileyonlinelibrary.com]
160.5, 158.1, 155.0, 152.2, 129.5, 125.8, 123.7, 121.2,
(KBr) νmax/cmꢀ1: 3052, 2923, 2430, 1717, 1623, 1580,
114.7, 114.4, 112.5, 112.0, 101.8, 66.6, 61.8, 45.5, 18.6.
Mass (m/z): 377.14 (M + 1, 100%).
1436, 1314, 1245, 920, 737. 1H NMR (400 MHz,
CDCl3): δ 7.49 (s, 1H), 7.25 (s, 1H), 6.86–6.7 (m, 5H),
6.16 (s, 1H), 5.29 (s, 2H), 5.23 (t, 2H, J = 4.8 Hz), 4.51
(t, 2H, J = 4.8 Hz), 2.39 (s, 3H), 2.16 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 160.5, 160.2, 158.3, 154.2, 152.6,
141.8, 133.7, 130.5, 129.3, 128.4, 124.9, 113.8, 113.6,
4-Methyl-7-(2-(4-propyl-1H-1,2,3-triazol-1-yl)ethoxy)-2H-
chromen-2-one (3b).
IR (KBr) νmax/cmꢀ1: 3054, 2932,
1
2431, 1713, 1624, 1584, 1433, 1313, 1242, 929, 736. H
NMR (400 MHz, CDCl3): δ 7.51 (d, 1H, J = 8.5 Hz),
7.46 (s, 1H), 6.82–6.79 (m, 2H), 6.17 (s, 1H), 4.77 (t,
2H, J = 4.8 Hz), 4.43 (t, 2H, J = 5.0 Hz), 2.70 (t, 2H,
J = 7.3 Hz), 2.40 (s, 3H), 1.67–1.64 (m, 2H), 0.97–0.95
(m, 3H). 13C NMR (100 MHz, CDCl3): δ 160.5, 160.2,
155.5, 153.5, 130.3, 126.5, 121.0, 113.1, 111.4, 103.5,
68.3, 46.2, 36.1, 23.4, 17.3, 14.6. Mass (m/z): 313.1
112.3, 111.6, 111.4, 104.7, 72.5, 68.6, 46.3, 19.4, 18.6.
Mass (m/z): 425.11 (M + 1, 100%).
4-Methyl-7-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethoxy)-2H-
chromen-2-one (3f).
IR (KBr) νmax/cmꢀ1: 3053, 2928,
1
2425, 1715, 1626, 1587, 1435, 1314, 1246, 924, 735. H
NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 7.74 (d, 2H,
J = 8.5 Hz), 7.64 (d, 1H, J = 9.6 Hz), 7.40 (d, 1H,
J = 9.3 Hz), 7.29 (s, 1H), 6.84–6.81 (m, 2H), 6.29 (d,
1H, J = 9.8 Hz), 6.17 (s, 1H), 4.87 (t, 2H, J = 5.3 Hz),
4.49 (t, 2H, J = 5.5 Hz), 2.40 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 160.8, 155.7, 143.1, 138.1, 129.5,
129.0, 127.5, 125.6, 113.8, 113.3, 112.3, 101.8, 66.8,
(M + 1, 100%).
4-Methyl-7-(2-(4-((o-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)
ethoxy)-2H-chromen-2-one (3c).
IR (KBr) νmax/cmꢀ1
:
3052, 2924, 2428, 1714, 1625, 1584, 1432, 1312, 1244,
1
925, 736. H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H),
7.52 (d, 1H, J = 8.0 Hz), 7.29 (d, 2H, J = 5.3 Hz), 7.18–
7.1 (m, 2H), 6.97–6.95 (m, 1H), 6.91 (m, 1H), 6.19 (s,
1H), 5.26 (s, 2H), 4.84 (t, 2H, J = 4.8 Hz), 4.47 (t, 2H,
J = 5.0 Hz), 2.42 (s, 3H), 2.26 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 160.8, 156.5, 155.6, 153.4, 143.3,
130.7, 129.3, 126.8, 121.2, 113.5, 113.2, 112.8, 111.6,
101.9, 66.5, 62.4, 49.4, 18.3, 16.2. Mass (m/z): 391.1
49.5, 21.3. Mass (m/z): 347.1 (M + 1, 100%).
7-(2-(4-((4-Chloro-3-methylphenoxy)methyl)-1H-1,2,3-
triazol-1-yl)ethoxy)-2H-chromen-2-one (3g). IR (KBr) νmax
/
cmꢀ1: 3054, 2927, 2435, 1715, 1626, 1597, 1442, 1321,
1
1236, 935, 740. H NMR (400 MHz, CDCl3): δ 7.64 (d,
1H, J = 9.3 Hz), 7.50 (s, 1H), 7.23 (s, 1H), 6.76–6.73
(m, 5H), 6.14 (d, 1H, J = 9.3 Hz), 5.32 (s, 2H), 5.21(t,
2H, J = 4.8 Hz), 4.65 (t, 2H, J = 4.8 Hz), 2.61 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 160.8, 160.4, 158.7,
153.9, 151.9, 142.0, 133.9, 131.5, 130.3, 128.4, 125.9,
113.8, 113.7, 112.4, 111.4, 111.2, 104.3, 72.2, 68.4,
(M + 1, 100%).
4-Methyl-7-(2-(4-((naphthalen-2-yloxy)methyl)-1H-1,2,3-
triazol-1-yl)ethoxy)-2H-chromen-2-one (3d). IR (KBr) νmax
/
cmꢀ1: 3051, 2926, 1715, 1621, 1510, 1460, 1391, 1274,
1207, 11465, 1105, 840, 766. 1H NMR (400 MHz,
CDCl3): δ 7.84 (s, 1H), 7.71 (m, 3H), 7.42–7.30 (m, 4H),
7.16 (d, 1H, J = 11.4 Hz), 6.73–6.69 (m, 2H), 6.10 (s,
1H), 5.32 (s, 2H), 4.78 (t, 2H, J = 4.8 Hz), 4.39 (t, 2H,
J = 4.8 Hz), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 160.9, 160.5, 156.0, 154.9, 152.3, 144.2, 134.3, 129.5,
127.5, 126.8, 126.4, 125.7, 124.0, 123.8, 118.7, 114.2,
112.4, 112.0, 107.2, 101.6, 66.6, 61.8, 49.5, 18.6. Mass
46.8, 19.8. Mass (m/z): 411.1 (M + 1, 100%).
4-((1-(2-((2-Oxo-2H-chromen-7-yl)oxy)ethyl)-1H-1,2,3-
triazol-4-yl)methoxy)benzaldehyde (3h).
IR (KBr) νmax/
cmꢀ1: 3054, 2925, 2424, 1718, 1627, 1594, 1429, 1314,
1
1253, 929, 736. H NMR (400 MHz, CDCl3): δ 9.89 (s,
1H), 7.86 (d, 3H, J = 5.3 Hz), 7.83 (s, 1H), 7.65 (d, 1H,
J = 9.3 Hz), 7.38 (d, 1H, J = 9.0 Hz), 7.29 (s, 1H), 7.10
(d, 1H, J = 7.3 Hz), 6.79 (s, 1H), 6.29 (d, 1H,
J = 9.3 Hz), 5.33 (s, 2H), 4.85 (t, 2H, J = 4.5 Hz), 4.47
(t, 2H, J = 4.5 Hz). 13C NMR (100 MHz, CDCl3): δ
(m/z): 427.1 (M + 1, 100%).
7-(2-(4-((4-Chloro-3-methylphenoxy)methyl)-1H-1,2,3-
triazol-1-yl)ethoxy)-4-methyl-2H-chromen-2-one (3e).
IR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-
Triazolylpolyaza Heterocyclic Compounds
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
Vol 000
Figure 7. Height drug likeness score of final compound 3g with ADR. [Color figure can be viewed at wileyonlinelibrary.com]
192.1, 190.7, 163.0, 160.6, 155.6, 143.1, 131.9, 130.3,
129.0, 124.1, 115.1, 113.8, 113.3, 112.3, 101.8, 66.7,
2-Chloro-7-methyl-3-((4-(((1-phenyl-1H-tetrazol-5-yl)thio)
methyl)-1H-1,2,3-triazol-1-yl) methyl)quinoline (6b).
Off
white solid, mp: 140–142°C. IR (KBr) νmax/cmꢀ1: 3136,
62.0, 49.6. Mass (m/z): 391.1 (M + 1, 100%).
7-(2-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethoxy)-2H-chromen-2-
2946, 2881, 1613, 1596, 1498, 1262, 1249, 1101, 891,
one (3i). IR (KBr) νmax/cmꢀ1: 3051, 2929, 2426, 1715,
1
769. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.12
1626, 1587, 1436, 1316, 1245, 927, 739. 1H NMR
(400 MHz, CDCl3): δ 7.95 (s, 1H), 7.83 (d, 2H,
J = 7.0 Hz), 7.61 (d, 1H, J = 9.6 Hz), 7.42 (t, 2H,
J = 7.4 Hz), 7.35 (t, 2H, J = 8.6 Hz), 6.82–6.80 (m, 2H),
6.26 (d, 1H, J = 7.2 Hz), 4.85 (t, 2H, J = 5.2 Hz), 4.47
(t, 2H, J = 4.8 Hz). 13C NMR (100 MHz, CDCl3): δ
160.8, 155.6, 148.0, 143.1, 130.3, 129.0, 128.8, 128.2,
125.7, 120.6, 113.8, 113.3, 112.9, 112.3, 101.8, 66.8,
(s, 1H), 7.76 (d, 1H, J = 8.5 Hz), 7.7 (s, 1H), 7.47–7.40
(m, 5H), 7.19 (s, 1H), 5.93 (s, 2H), 4.62 (s, 2H), 2.59 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 154.1, 148.1,
146.4, 138.2, 133.1, 131.2, 130.8, 128.6, 127.1, 126.8,
126.4, 122.1, 52.6, 28.3, 21.2. Mass (m/z): 448.10
(M + H, 100%).
2-Chloro-3-((4-(((1-phenyl-1H-tetrazol-5-yl)thio)methyl)-1H-
1,2,3-triazol-1-yl)methyl)quinoline (6c). Yellow solid, mp:
115–117°C. IR (KBr) νmax/cmꢀ1: 3014, 2982, 1627,
1489, 1341, 1263, 1244, 1217, 1051, 887. 1H NMR
(400 MHz, CDCl3): δ 7.96 (d, 1H, J = 8.2 Hz), 7.90 (s,
1H), 7.83 (s, 1H), 7.72–7.68 (m, 2H), 7.52–7.50 (m, 1H),
7.47–7.41 (m, 5H), 7.19 (s, 2H), 5.71 (s, 2H), 4.64 (s,
2H). 13C NMR (100 MHz, CDCl3): δ 148.8, 147.5,
138.6, 133.4, 131.3, 130.2, 129.8, 128.3, 127.7, 126.9,
126.6, 123.6, 51.3, 27.6. Mass (m/z): 434.08 (M + H,
49.5. Mass (m/z): 333.1 (M + 1, 100%).
7-(2-(4-((Naphthalen-2-yloxy)methyl)-1H-1,2,3-triazol-1-yl)
ethoxy)-2H-chromen-2-one (3j).
IR (KBr) νmax/cmꢀ1
:
3055, 2926, 1716, 1616, 1511, 1459, 1396, 1280, 1214,
1
1135, 1115, 834, 765. H NMR (400 MHz, CDCl3): δ
7.82 (s, 1H), 7.76–7.72 (m, 3H), 7.59 (d, 1H,
J = 9.3 Hz), 7.43 (t, 1H, J = 7.0 Hz), 7.34 (t, 1H,
J = 7.8 Hz), 7.29 (d, 1H, J = 8.5 Hz), 7.25–7.23 (m, 1H),
7.18 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H), 6.71 (d, 1H,
J = 8.5 Hz), 6.26 (d, 1H, J = 9.3 Hz), 5.35 (s, 2H), 4.80
(t, 2H, J = 5.0 Hz), 4.42 (t, 2H, J = 5.3 Hz). 13C NMR
(100 MHz, CDCl3): δ 160.7, 156.0, 155.6, 144.4, 143.1,
134.3, 129.5, 129.0, 127.6, 126.9, 126.5, 123.9, 118.7,
113.8, 113.2, 112.3, 107.2, 101.7, 66.7, 61.9, 49.5. Mass
100%).
5-(((1-(2-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1-
phenyl-1H-tetrazole (6d).
Pale yellow solid, mp: 120–
122°C. IR (KBr) νmax/cmꢀ1: 3061, 2971, 1631, 1600,
1450, 1349, 1257, 1219, 1043, 843, 786. 1H NMR
(400 MHz, CDCl3): δ 8.16 (s, 1H), 8.10 (dd, 1H,
J = 6.5 Hz, 1.7 Hz), 7.80 (td, 1H, J = 7.7 Hz, 1.7 Hz),
7.71 (td, 1H, J = 8.0 Hz, 2.0 Hz), 7.59 (dd, 1H,
J = 6.0 Hz, 1.7 Hz), 7.56–7.51 (m, 5H), 4.77 (s, 2H). 13C
NMR (100 MHz, CDCl3): δ 153.4, 144.3, 143.0, 133.5,
134.0, 133.6 130.0, 129.5, 127.6, 125.3, 125.0, 123.4,
(m/z): 413.1 (M + 1, 100%).
2-Chloro-6-methyl-3-((4-(((1-phenyl-1H-tetrazol-5-yl)thio)
methyl)-1H-1,2,3-triazol-1-yl) methyl)quinoline (6a). White
solid, mp: 140–142°C. IR (KBr) νmax/cmꢀ1: 3136,
3085, 2956, 2846, 1599, 1566, 1515, 1456, 1381,
1306, 1226, 1145, 1062, 834. 1H NMR (400 MHz,
CDCl3): δ 7.88 (s, 1H), 7.84 (d, 1H, J = 8.7 Hz), 7.72
(s, 1H), 7.52 (d, 1H, J = 8.7 Hz), 7.48–7.42 (m, 5H),
7.19 (s, 1H), 5.68 (s, 2H), 4.63 (s, 2H), 2.45 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 153.6, 147.9, 146.1,
138.0, 133.6, 130.2, 129.8, 128.0, 127.0, 126.1, 126.4,
123.7, 51.4, 27.6, 21.5. Mass (m/z): 448.10 (M + H,
100%).
27.0. Mass (m/z): 380.08 (M + H, 100%).
5-(((1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1-
phenyl-1H-tetrazole (6e).
Pale yellow solid, mp: 120–
122°C. IR (KBr) νmax/cmꢀ1: 3062, 2975, 1631, 1601,
1451, 1356, 1252, 1221, 1043, 846, 776. 1H NMR
(400 MHz, CDCl3): δ 8.64 (t, 1H, J = 2.2 Hz), 8.44 (s,
1H), 8.32–8.30 (m, 1H), 8.14–8.11 (m, 1H), 7.75 (t, 1H,
J = 8.2 Hz), 7.58–7.51 (m, 5H), 4.78 (s, 2H). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis, Molecular Properties, and Biological Evaluation of Hybrid 1,2,3-
Triazolylpolyaza Heterocyclic Compounds
(100 MHz, CDCl3): δ 153.7, 144.4, 141.1, 136.2, 133.0,
132.1, 130.9, 129.1, 127.1, 126.1, 125.2, 123.4, 27.4.
diameter of inhibition zone around each well was
measured in mm. Experiments were performed in
Mass (m/z): 380.08 (M + H, 100%).
triplicates. Antibiotic such as pefloxacin at
a
5-(((1-(4-Methoxy-2-nitrophenyl)-1H-1,2,3-triazol-4-yl)
concentration of 0.04 mg/50 μL were used as positive
reference to determine sensitivity of microorganisms
tested. DMSO was used as a negative control.
methyl)thio)-1-phenyl-1H-tetrazole (6f).
Off white solid,
mp: 112–114°C. IR (KBr) νmax/cmꢀ1: 3121, 2982, 1634,
1
1612, 1459, 1341, 1258, 1224, 1052, 863, 781. H NMR
In vitro cytotoxicity. The yellow tetrazolium MTT (3-
(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide)
[37] is reduced by metabolically active cells, in part by the
action of dehydrogenase enzymes, to generate reducing
equivalents such as NADH and NADPH. The human tumor
cell lines are grown in RPMI 1640 medium containing 5%
fetal bovine serum and 2 mM L-glutamine. Cells are
inoculated into 96-well microtiter plates in 100 μL at
plating densities ranging from 5000 to 40,000 cells per well
depending on the doubling time of individual cell lines.
After cell inoculation, the microtiter plates are incubated at
37°C, 5% CO2, 95% air, and 100% relative humidity for
24 h prior to addition of test compounds. After 24 h, two
plates of each cell line are fixed in situ with TCA, to
represent a measurement of the cell population for each cell
line at the time of addition of test compound (Tz). Test
compounds are dissolved in DMSO at 400-fold the desired
final maximum test concentration and 17 stored frozen prior
to use. At the time of compound addition, an aliquot of
frozen concentrate is thawed and diluted to twice the
desired final maximum test concentration with complete
medium containing 50 μg/mL gentamicin. Additional four,
10-fold, or ½log serial dilutions are made to provide a total
of five drug (test compound) concentrations plus control.
Aliquots of 100 μL of these different drug dilutions are
added to the appropriate microtiter wells already containing
100 μL of medium, resulting in the required final drug
concentrations. Following drug addition, the plates are
incubated for an additional 48 h at 37°C, 5% CO2, 95% air,
and 100% relative humidity. For adherent cells, the assay is
terminated by the addition of cold TCA. Cells are fixed in
situ by the gentle addition of 50 μL of cold 50% (w/v) TCA
(final concentration, 10% TCA) and incubated for 60 min at
4°C. The supernatant is discarded, and the plates are
washed five times with tap water and air dried.
Sulforhodamine B solution (100 μL) at 0.4% (w/v) in 1%
acetic acid is added to each well, and plates are incubated
for 10 min at room temperature. After staining, unbound
dye is removed by washing five times with 1% acetic acid,
and the plates are air dried. Bound stain is subsequently
solubilized with 10 mM trizma base, and the absorbance is
read on an automated plate reader at a wavelength of
515 nm. Using the seven absorbance measurements [time
zero, (Tz), control growth, (C), and test growth in the
presence of drug at the five concentration levels (Ti)],
the percentage control growth is calculated at each of the
drug concentration levels. Three dose response parameters
are calculated for each test compound.
(400 MHz, CDCl3): δ 8.10 (s, 1H), 7.59–7.53 (m, 5H),
7.46 (d, 1H, J = 8.7 Hz), 7.25–7.23 (m, 1H), 4.77 (s,
2H), 3.96 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 162.4,
155.2, 146.7, 144.5, 134.9, 131.8, 131.4, 130.8, 127.2,
125.3, 124.3, 120.8, 112.2, 57.9, 28.9. Mass (m/z):
410.09 (M + H, 100%).
5-(((1-(3-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-
1-phenyl-1H-tetrazole (6g).
Off white solid, mp: 140–
142°C. IR (KBr) νmax/cmꢀ1: 3142, 3071, 1632, 1494,
1
1063, 1034, 889, 791. H NMR (400 MHz, CDCl3): δ
8.25 (s, 1H), 7.56–7.49 (m, 5H), 7.40 (t, 1H, J = 8.5 Hz),
7.31 (t, 1H, J = 2.5 Hz), 7.23–7.21 (m, 1H), 6.97–6.96
(m, 1H), 4.77 (s, 2H), 3.88 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 162.1, 155.2, 144.1, 133.4, 131.9, 130.4,
125.1, 124.4, 123.1, 117.1, 57.8, 27.9. Mass (m/z):
365.11 (M + H, 100%).
5-(((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-
1-phenyl-1H-tetrazole (6h). Pale yellow solid, mp: 154–
156°C. IR (KBr) νmax/cmꢀ1: 3135, 3015, 2921, 1661,
1514, 1497, 1231, 1141, 1015, 891, 782. 1H NMR
(400 MHz, CDCl3): δ 8.10 (s, 1H), 7.54–7.52 (m, 2H),
7.49–7.43 (m, 5H), 6.95–6.92 (m, 2H), 4.69 (s, 2H), 3.79
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.1, 155.0,
144.4, 134.6, 131.5, 131.1, 124.9, 123.4, 123.2, 116.0,
56.8, 28.8. Mass (m/z): 365.11 (M + H, 100%).
Antibacterial activity. Test organisms and culture
condition. A collection of four organisms including two
Gram-positive and two Gram-negative were used for this
study. E. coli (MTCC 1563) and P. aeruginosa (MTCC
6642) were obtained from Microbial Type Culture
Collection (MTCC), IMTECH, Chandigarh, India. Clinical
isolates such as S. aureus and K. pneumoniae were ob-
tained from microbiology laboratory of Global Hospital,
Hyderabad. All strains were tested for purity by standard
microbiological methods. The bacterial stock cultures were
maintained on Mueller Hinton Agar (MHA) slants and
stored at 4°C.
Determination of antibacterial activity.
An agar-well
diffusion method was employed for evaluation of
antibacterial activity [34–36]. The bacterial strains were
reactivated from stock cultures by transferring into
Mueller Hinton Broth and incubating at 37°C for 18 h. A
final inoculum containing 106 colony forming units
(1 × 106 CFU/mL) was added aseptically to MHA
medium and poured into sterile Petri dishes. Different test
compounds at a concentration of 0.4 mg/50 μL were
added to wells (8 mm in diameter) punched on agar
surface. Plates were incubated overnight at 37°C and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. R. Dasari, S. Tondepu, L. R. Vadali, M. N. Ganivada, and N. Seelam
Vol 000
[7] Jiang, B.; Huang, X.; Yao, H.; Jiang, J.; Wu, X.; Jiang, S.;
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CONCLUSIONS
In summary, this work reveals the hidden potentials in
new framework design. All the synthesized triazole and
tetrazole was evaluated for antibacterial and anticancer
activities. The compounds 3 and 6 were screened for their
in vitro anticancer activity against human colon cancer cell
line Colo-205, human lung cancer cell line HOP-205 by
MTT-micro cultured tetrazolium assay along with the
standard drug Adriamycin. The targets 3j, 3d, 6a, and 6e
were exhibited excellent inhibition in both the cell lines.
These compounds have been further evaluated in
antibacterial studies, and the results revealed that the
compounds 3a, 3f, 3j, 6a, and 6h were found to inhibit the
most antibacterial growth of all the three enzymes. The
designed analogues first report to study the molecular
properties prediction, reveal suitable drug-like properties,
and presume most of the compounds behave as a good
bioavailability profile. From compounds 3e and 3g having
bioactivity score more than 0.00 and the final compounds
3b, 3f, and 3i exhibit highest 84.71% absorption,
respectively. Also, studies to acquire more information
about structure–activity relationships of triazole-tetrazole
derivatives offer promising, friendly substitute and should
be considered as future goal for medicinal chemists
working in the area of anticancer and antibacterial agents.
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Acknowledgments. The authors are thankful to our research
supervisors for providing us the required facilities and
motivation to complete the research work. We also extend our
gratitude towards the Department of Chemistry, KL Education
Foundation, and Mylan Laboratories Ltd. for encouraging us to
root towards the synthesis of novel hybrid compounds and
confirming them by various spectral analyses.
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet