Synthesis, characterization, and antiplasmodial efficacy of sulfonamide-appended [1,2,3]-triazoles

Article abstract of DOI:10.1002/jhet.3888

A series of benzenesulfonamide-appended [1,2,3]-triazole hybrids was synthesized by using [3 + 2] cycloaddition of primary, secondary, and tertiary sulfonamide azides with various phenoxymethylacetylenes under click reaction conditions. After structural c

Full text of DOI:10.1002/jhet.3888

Received: 4 June 2019
DOI: 10.1002/jhet.3888
Revised: 14 December 2019
Accepted: 19 December 2019
A R T I C L E
Synthesis, characterization, and antiplasmodial efficacy
of sulfonamide-appended [1,2,3]-triazoles
Neha Batra1 | Vinoth Rajendran2 | Ishan Wadi1 | Ankit Lathwal1
|
Roshan Kumar Dutta3 | Prahlad C. Ghosh2 | Rinkoo D. Gupta3
Mahendra Nath1
|
1Department of Chemistry, University of
Abstract
Delhi, Delhi 110 007, India
2Department of Biochemistry, University
of Delhi South Campus, New Delhi, India
3Faculty of Life Sciences and
Biotechnology, South Asian University,
New Delhi, India
A series of benzenesulfonamide-appended [1,2,3]-triazole hybrids was synthe-
sized by using [3 + 2] cycloaddition of primary, secondary, and tertiary sulfon-
amide azides with various phenoxymethylacetylenes under click reaction
conditions. After structural characterization, the compounds were subjected to
in-silico absorption, distribution, metabolism, excretion and toxicity (ADMET)
screening to evaluate their drug-likeness and other pharmacokinetic parame-
ters. Furthermore, their in vitro antiplasmodial potential was assessed against
Plasmodium falciparum (3D7) strain, and some of the synthesized compounds
displayed promising antimalarial potency. On cytotoxicity evaluation using
MTT cell viability assay, the most active candidate N-(4,6-dimethylpyridin-2-yl)-
4-(4-(4-nitrophenoxy)methyl)-1H-[1,2,3]-triazol-1-yl)benzenesulfonamide
(14; IC50 6.2 μg/mL) demonstrated CC50 7.5 μg/mL against human
hepatocarcinoma (HUH-7) cells.
Correspondence
Mahendra Nath, Department of
Chemistry, University of Delhi, Delhi
110 007, India.
Email: mnath@chemistry.du.ac.in
Funding information
University of Delhi, Delhi, India, Grant/
Award Number: R&D Grant
1 | INTRODUCTION
antimalarial drug for which the resistance in P. falciparum
emerged in the Southeast Asia and later spread to South
Malaria is one of the leading causes of mortality and mor-
bidity worldwide, especially in countries of sub-Saharan
Africa and Southeast Asia. This disease is caused by the
parasite of genus Plasmodium and is transmitted by the
bites of infected female Anopheles mosquitoes. A total of
five species of Plasmodium, namely, Plasmodium
falciparum, Plasmodium vivax, Plasmodium ovale, Plas-
modium malariae, and Plasmodium knowlesi, are known
to infect humans out of which P. falciparum is responsi-
ble for the majority of severe malaria cases and deaths
worldwide. The World Malaria Report 2018 accounted for
approximately 219 million malaria cases and an esti-
mated 435 000 deaths worldwide in the year 2017.[1] One
of the primary reasons of not being able to completely
abrogate the disease is the rapid emergence and dissemi-
nation of drug resistance, especially in P. falciparum. His-
torically, chloroquine was the first major primary
America and Africa.[2,3] Later, P. falciparum became
resistant to other commonly used antimalarials. To over-
come the problem of drug resistance, combination ther-
apy, particularly artemisinin combination therapy (ACT)
was introduced by the World Health Organization
(WHO), as the first line treatment for uncomplicated
P. falciparum malaria,[4] which combines a fast-acting
artemisinin derivative such as artesunate or artemether
and slow-acting partner drug(s) such as lumefantrine or
sulfadoxine-pyrimethamine.[5] However, artemisinin
resistance has been knocking our doors since past few
years, and reduced efficacy to artemisinin has already
been witnessed from various parts of Southeast Asia[6]
and India.[7] In case, artemisinin-resistant parasites
spread to other parts of the world, such as sub-Saharan
Africa, it can have disastrous consequences as
an effective and safe transmission-blocking drug is
J Heterocyclic Chem. 2020;1–12.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

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BATRA ET AL.
currently unavailable for the entire malaria-susceptible
population.[8,9]
pharmacophores, namely, sulfonamides and [1,2,3]-
triazoles, are expected to possess multiple mechanisms of
action and minimum risk of development of drug resis-
tance. In the backdrop of drug resistance, our aim was to
synthesize novel hybrid compounds with two “biologi-
cally active” moieties that can act at multiple target sites
and to evaluate these hybrids for their absorption, distri-
Meanwhile, continued and focused efforts should be
directed
towards
the
development
of
novel
antiplasmodial drugs in order to overcome drug resis-
tance and also to be one step ahead of malaria parasite.
To this end, the sulfonamide scaffold, a constituent of
several types of drugs collectively termed as sulfonamides
or sulfa drugs, is a suitable base for the development of
novel antimalarial drugs. One such sulfonamide-based
antimalarial drug, sulfadoxine, is used as a part of first
line ACT for malaria treatment along with artesunate
and pyrimethamine.[10] Moreover, sulfadoxine, along
with pyrimethamine, is also used as a first line antimalar-
ial drug therapy in intermittent preventive treatment in
pregnancy.[10] Apart from sulfadoxine, sulfadiazine and
sulfalene are also available in the market as antimalarial
drugs in which sulfonamide group is directly linked to a
six-membered nitrogen heterocycle (Figure 1).[11]
Besides, the sulfonamide moiety is found to be a constitu-
ent of many other pharmacologically active molecules
having antimicrobial,[12] antiepileptic,[13] carbonic
bution,
metabolism,
excretion
and
toxicity
(ADMET) profile and antiplasmodial activity. We herein
report synthesis, structural characterization, and in vitro
antiplasmodial activity of
a
panel of new
benzenesulfonamide-appended [1,2,3]-triazoles.
2 | RESULTS AND DISCUSSION
2.1 | Synthesis and structural
characterization
To synthesize a new series of benzenesulfonamide-
appended [1,2,3]-triazoles (5-34) as antimalarials, a com-
mon approach of click chemistry has been adapted, by
reacting various 4-azidobenzenesulfonamides with phe-
noxymethylacetylenes as depicted in Scheme 1. The sul-
fonamide (1a) and sulfamethazine (1b) were
procured from Aldrich, and tertiary sulfonamide-based
anhydrase
inhibitory,[13,14]
antiprotozoal,[15]
hypoglycemic,[16] diuretic,[17] anticancer,[18,19] anti-
inflammatory,[19] and antiviral[19,20] properties.
However, it is hypothesized that the prospective anti-
malarial compounds would show similar cross-resistance
patterns to other established sulfonamides such as
sulfadoxine, in areas with reported sulfadoxine resistance
due to the presence of the same sulfonamide moiety. So,
in order to diversify the chemical structure, another mol-
ecule of significant pharmacological importance, [1,2,3]-
triazole, was introduced into the structure to create a
sulfonamide-triazole hybrid. [1,2,3]-Triazoles, possess
multitude of medicinal properties, which includes, but
not limited to, antifungal,[21] antibacterial,[22] and
antitubercular properties.[23] Studies suggest that [1,2,3]-
triazole group cannot only play a role of being a passive
linker between two scaffolds, but [1,2,3]-triazoles can
themselves act as critical constituents of antimalar-
ials.[24,25] Therefore, hybrids based on these two distinct
amines (1c-e) were synthesized
by reacting
4-acetamidobenzenesulfonyl chloride with cyclic second-
ary amines such as piperidine, morpholine, and
1-pyridin-2-yl-piperazine in water at ambient tempera-
ture followed by the hydrolysis using concentrated
hydrochloric acid at 100ꢀC.[26,27] Further, these
4-aminobenzenesulfonamides (1a-e) were diazotized on
treatment with NaNO2 in the presence of conc. HCl at
0ꢀC followed by the reaction with NaN3 in water to afford
the corresponding azide precursors (2a-e) in good
yields.[28,29] In addition, phenoxymethylacetylenes (4a-i)
have been prepared in good to excellent yields from
substituted phenols after the reaction with propargyl bro-
mide in dry acetone-containing anhydrous K2CO3.[30,31]
Lastly, the construction of desired benzenesulfonamide-
appended [1,2,3]-triazoles (5-34) was accomplished via
Cu(I)-catalyzed Huisgen [3 + 2] cycloaddition reaction of
4-azidobenzenesulfonamides (2a-e) with substituted phe-
noxymethylacetylenes (4a-i) in the presence of CuS-
O4ꢁ5H2O and sodium ascorbate in 50% t-butanol in water
at 40ꢀC for 5 hours.[32] All the prepared products were
obtained in good to excellent yields, and their structural
characterization was done on the basis of spectral data
analysis. The infrared (IR) spectrum of a representative
compound,
1-((4-(4-(phenoxymethyl)-1H-1,2,3-triazol-
1-yl)phenyl)sulfonyl)-piperidine (18) showed a character-
FIGURE 1 Representative examples of sulfonamide-based
antimalarial drugs
istic absorption peak at 1242 cm−1 corresponding to the

BATRA ET AL.
3
SCHEME 1 Synthesis of
benzenesulfonamide-appended [1,2,3]-
triazoles
1
SO2 group. In the H NMR of compound 18, a peak at δ
2.2 | ADMET prediction
9.11 ppm was observed as a singlet due to the presence of
triazole proton, whereas a singlet at δ 5.25 ppm corre-
sponds to CH2O protons. Also, a characteristic triplet for
4 protons at δ 2.93 ppm and two sets of multiplets in the
range of δ 1.33 to 1.57 ppm for 4 and 2 protons, respec-
tively, were assigned for the piperidine ring. The protons
of aromatic ring were appeared either as doublet or trip-
let in the down field region between δ 8.20 and 6.96 ppm.
Similarly, the characteristic peaks at δ 158.06 and
60.92 ppm in 13C NMR of molecule 18 correspond to the
carbons of 1,2,3-triazole and OCH2, respectively. Addi-
tionally, the peaks at δ 46.81, 24.85, and 22.97 ppm were
assigned to the carbons of the piperidine moiety. Further,
the formation of the product 18 was confirmed on the
basis of mass spectral analysis, which displayed [M
+ H]+ peak at m/z 399.1485 for molecular formula
C20H23N4O3S.
Various physically significant descriptors and pharma-
ceutically relevant properties such as molecular weight,
lipophilicity, donor/acceptor hydrogen bonds, volume,
solvent accessible surface area (SASA), percentage of
human gastrointestinal (GI) absorption, Caco-2 (human
epithelial colorectal adenocarcinoma), and madin-darby
canine kidney (MDCK) cell permeability, aqueous solu-
bility, human serum albumin (HSA) binding, and drug-
likeness parameters of synthesized benzenesulfonamide-
appended 1,2,3-triazoles were predicted by using Qikprop
3.5 module offered by Schrodinger.[33] In the context of
pharmacokinetics and pharmacodynamics, lipophilicity
of drug candidates is a major driving force for determin-
ing the ease of their passage through intestinal lipid bila-
yers and binding to the receptor targets.[34] This is
determined from octanol/water partition coefficient (log

4
BATRA ET AL.
TABLE 1 Isolated yields and in vitro antiplasmodial potency of benzenesulfonamide-appended [1,2,3]-triazoles (5-34)
Antiplasmodial activity (after 42 h)
Compounds
R0
R
Yield (%)
IC50 (μg/mL)
IC50 (μM)
5
-NH2
-NH2
-NH2
-NH2
-NH2
-NH2
-NH2
-NH2
-NH2
4-NO2
70
99
94
92
83
65
93
88
93
65
>50
15
>133.31
45.44
6
4-H
4-F
7
15.4
44
44.24
8
4-Cl
120.86
>122.55
>109.65
>125.62
>145.31
76.91
9
4-Br
>50
>50
>50
>50
28
10
11
12
13
14
4-I
2,4-Cl2
4-CH3
3-Cl
4-NO2
6.2
12.88
15
16
4-H
63
>50
>114.64
2,4-Cl2
56
16.7
33.13
17
18
19
20
21
22
23
4-NO2
4-H
90
82
73
88
80
83
69
>50
>50
>50
>50
>50
>50
>50
>112.83
>125.58
>120.15
>115.71
>105.03
>95.23
4-F
4-Cl
4-Br
4-I
4-NO2
>112.33
24
4-H
91
>50
>124.96
25
26
4-F
88
48
114.80
4-Cl
92
>50
>115.18
27
28
29
4-Br
4-I
70
77
65
48
>50
>50
100.41
>95.05
>95.94
4-NO2
(Continues)

BATRA ET AL.
5
TABLE 1 (Continued)
Antiplasmodial activity (after 42 h)
Compounds
30
R0
R
Yield (%)
72
IC50 (μg/mL)
IC50 (μM)
4-H
4-F
4-Cl
4-Br
4-I
48.5
101.85
>101.18
>98.01
83.02
31
32
33
34
75
89
79
81
-
>50
>50
46
12
19.93
CQ
-
-
0.034
0.066
Abbreviation: CQ, chloroquine.
Po/w), which is predicted to be positive and on the
higher side for all the synthesized compounds. This is
also evident from oral absorption profile of the com-
pounds as all compounds demonstrated >50% human
oral absorption with 4 compounds showing >90% absorp-
tion and 5 compounds showing 100% absorption through
oral route. Majority of compounds were predicted to have
good cell permeability profile (MDCK values and/or
Caco-2 values greater than 500). Out of 30 compounds,
21 compounds were found to have no Lipinski rule[35]
violation, 8 compounds showed one violation while one
compound showed 2 violations (Table S1 in supporting
information). All other properties such as volume, SASA,
and human serum albumin binding were in the range of
recommended values for the majority of compounds.
Compounds were also scored according to their overall
drug-likeness by ADMET compliance score (indicated by
#stars), which indicates the number of properties or
descriptor values which are on the outside of the 95%
range of similar values for known drugs. In short, all of
these compounds showed promising ADMET profile and
were subsequently used for in vitro experiments.
used as a positive control for our experiments. IC50 values
(half maximal inhibitory concentration) of the tested
compounds are summarized in Table 1.
Among
the
screened
compounds,
N-(4,-
6-dimethylpyridin-2-yl)-4-(4-(4-nitrophenoxy)methyl)-
1H-[1,2,3]-triazol-1-yl)benzene-sulfonamide (14) was
found to be the most effective candidate against
P. falciparum (3D7) strain with IC50 6.2 μg/mL, followed
by
1-yl)-phenyl)sulfonyl)-4-(pyridine-2-yl)-piperazine
IC50 12 μg/mL), 4-(4-(phenoxymethyl)-1H-[1,2,3]-triazol-
1-yl)benzene-sulfonamide (6; IC50 15 μg/mL),
4-(4-((4-fluorophenoxy)methyl)-1H-[1,2,3]-triazol-1-yl)-
benzenesulfonamide (7; IC50 15.4 μg/mL) and
4-(4-(2,4-dichlorophenoxy)methyl)-1H-[1,2,3]-triazol-
1-((4-(4-((4-iodophenoxy)methyl)-1H-[1,2,3]-triazol-
(34;
1-yl)-N-(4,6-dimethyl-pyrimidin-2-yl)benzenesulfonamide
(16; IC50 16.7 μg/mL). The structure-activity relationship
revealed that in case of triazoles of primary ben-
zenesulfonamides, the presence of p-fluoro substituent
on the phenoxymethyl moiety such as compound (7)
increases the antimalarial potency as compared with
other halogen containing molecules (8-10). The triazole-
benzenesulfonamide conjugate (6), having no substitu-
tion on the phenoxymethyl group enhances the antima-
larial potency as compared to the compound (12)
containing an electron donating p-methylphenoxymethyl
substituent on the [1,2,3]-triazole scaffold. On the con-
trary, secondary benzenesulfonamide based [1,2,3]-
triazole (15) having no substitution on phenoxymethyl
group was found to be inactive. However, the secondary
2.3 | Biological evaluation
The antiplasmodial potential of benzenesulfonamide-
appended 1,2,3-triazoles (5-34) was evaluated against
P. falciparum (3D7) strain by using radioactive [3H]
hypoxanthine incorporation method.[36] Chloroquine was

6
BATRA ET AL.
benzenesulfonamide-[1,2,3]-triazole hybrids (14 and 16)
containing electron withdrawing 4-nitrophenoxymethyl-
and 2,4-dichlorophenoxymethyl substituents displayed
significant potency with IC50 6.2 and 16.7 μg/mL, respec-
tively. In contrast, a series of tertiary sulfonamide-[1,2,3]-
triazoles (17-22) having a piperidine ring attached to the
SO2 group demonstrated no positive effect on the potency
as all the compounds exhibited IC50 values >50 μg/mL.
Further by replacing the piperidine with morpholine, a
significant antiplasmodial activity (IC50 48 μg/mL) was
observed in the case of compounds (25 and 27) decorated
with p-fluoro- and p-bromophenoxymethyl groups,
respectively. In addition, the presence of 1-pyridin-2-yl-
piperazine moiety along with either unsubstituted pheno-
xymethyl group or 4-bromo- or 4-iodophenoxymethyl
groups such as in benzenesulfonamide-1,2,3-triazole
hybrids (30, 33, and 34) demonstrated antiplasmodial
potency in the range of IC50 12 to 48.5 μg/mL. Further-
potential to be further investigated as the prototype for
the antimalarials of the future.
4 | EXPERIMENTAL SECTION
4.1 | Chemistry
The reagents and solvents used in the synthesis of target
compounds were procured from Sigma-Aldrich and
Merck and utilized as received without further purifica-
tion. The progress of the reactions was monitored by thin
layer chromatography using silica gel 60 F254 (pre-coated
aluminum sheets) from Merck, and the spots were visual-
ized under ultraviolet (UV) light. The synthesized com-
pounds were purified by column chromatography on
1
silica gel (60-120 mesh). H and 13C NMR spectra were
recorded in dimethyl sulfoxide (DMSO-d6) using tetra-
methylsilane (TMS) as an internal standard on Jeol ECX
400 MHz nuclear magnetic resonance (NMR) spectrome-
ter. The chemical shifts are reported in parts per million
(ppm) and coupling constants (J) are expressed in Hertz
(Hz). Infrared spectra were recorded on Perkin-Elmer IR
spectrometer, and absorption maxima (νmax) are given in
cm−1. High-resolution mass spectra were recorded on
Agilent G6530 AA LC-HRMS Q-TOF system. The melting
points were determined in open-capillary tubes on Buchi
M-560 melting point apparatus and are uncorrected. The
more,
the
most
potent
compound,
N-(4,-
6-dimethylpyridin-2-yl)-4-(4-(4-nitrophenoxy)methyl)-
1H-[1,2,3]-triazol-1-yl)benzenesulfonamide (14) has dem-
onstrated
hepatocarcinoma
CC50
7.5 μg/mL
(HUH7)
against
cells in
human
MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide) cell viability assay.[37,38]
3 | CONCLUSIONS
4-azidobenzenesulfonamides
(2a-e)
and
phe-
In conclusion, a series of benzenesulfonamide-appended
[1,2,3]-triazoles was synthesized in good to excellent
yields via [3 + 2] cycloaddition reaction between primary,
secondary, and tertiary sulfonamide-based azides and
various phenoxymethyl-acetylenes. After spectroscopic
characterization, their ADMET properties were predicted
by in silico tools, and compounds were evaluated for their
in vitro antiplasmodial activity against P. falciparum
(3D7) strain. Majority of the compounds showed promis-
ing pharmacokinetic profiles and displayed variable
antiplasmodial potency. The most active candidate (14)
demonstrated IC50 and CC50 (human HUH7 cells) values
6.2 and 7.5 μg/mL, respectively. Although sulfonamide
moiety is known to be part of some major antimalarial
drugs of today (eg, sulfadoxine), P. falciparum has already
become resistant to such drugs. Appending the sulfon-
amide moiety with other pharmacologically active func-
tional groups (eg, [1,2,3]-triazoles) will result in hybrids
that might surpass the drug resistance markers and might
give rise to the second generation of sulfonamide-based
antimalarials. Futuristic studies would definitely be
aimed towards evaluating the potency of these sulfon-
amide based [1,2,3]-triazoles against sulfadoxine-resistant
malaria parasites. The lead molecule of this study has the
noxymethylacetylenes (4a-i) were synthesized according
to the literature methods.[28–31]
4.2 | General synthetic protocol for
benzenesulfonamide-appended [1,2,3]-
triazoles (5-34)
To a suspension of 4-azidobenzenesulfonamides (2a-e;
0.51 mmol)
and
phenoxymethylacetylenes
(4a-i;
0.56 mmol) in t-BuOH (8 mL) was added a solution of
sodium ascorbate (0.30 mmol) in water (4 mL) followed
by the addition of a solution of CuSO4ꢁ5H2O (0.20 mmol)
in water (4 mL). The reaction mixture was stirred at 40ꢀC
under inert atmosphere for 5 hours. The completion of
the reaction was monitored by TLC. After completion of
the reaction, the desired products were extracted from
ethyl acetate (5 × 20 mL). The organic layers were com-
bined, washed with water (5 × 20 mL) followed by brine
solution (5 × 20 mL), and dried over anhydrous Na2SO4.
Finally, the organic solvent was evaporated to dryness
under reduced pressure to afford the crude solid, which
after purification on silica-gel column using ethyl acetate:
hexane (7:3) as eluent, afforded the pure products in good

BATRA ET AL.
7
to excellent yields. The compounds (5-14) are known,
and their spectral data were found to be in agreement
with the reported data.[32] The characterization data of
unknown sulfonamide-appended [1,2,3]-triazoles (15-34)
are given below.
J = 5.13 Hz, piperidine H), 1.57-1.52 (m, 4H, piperidine
H), 1.39-1.34 (m, 2H, piperidine H) ppm; HRMS (ESI):
Calcd for C20H22N5O5S: m/z 444.1336 [M + H]+. Found:
444.1336.
4.2.4 | 1-((4-(4-(Phenoxymethyl)-1H-
[1,2,3]-triazol-1-yl)phenyl)sulfonyl)-
piperidine (18)
4.2.1 | N-(4,6-Dimethylpyrimidin-2-yl)-
4-(4-(4-phenoxymethyl)-1H-[1,2,3]-triazol-
1-yl)benzene-sulfonamide (15)
Crimson solid; yield 82%; mp 155-157ꢀC; IR (KBr) νmax
2939, 2855, 1598, 1339, 1242, 1163, 1044, 927, 834,
746, 607, 583 cm−1 1H NMR (400 MHz, DMSO-d6): δ
:
Dark brown solid; yield 65%; mp 198-200ꢀC; IR (Nujol)
ν
max: 3151, 1728, 1589, 1548, 1496, 1425, 1377, 1282,
;
1242, 1139, 1111, 1080, 981, 869, 835, 790, 754, 692,
9.11 (s, 1H, triazole H), 8.20 (d, 2H, J = 8.79 Hz, ArH),
7.94 (d, 2H, J = 8.79 Hz, ArH), 7.32 (t, 2H, J = 8.05 Hz,
ArH), 7.07 (d, 1H, J = 8.05 Hz, ArH), 6.96 (t, 2H,
J = 8.05 Hz, ArH), 5.25 (s, 2H, CH2O), 2.93 (t, 4H,
J = 5.13 Hz, piperidine H), 1.57-1.52 (m, 4H, piperidine
H), 1.39-1.33 (m, 2H, piperidine H) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 158.06, 144.63, 139.59, 135.53,
129.82, 129.60, 123.30, 121.28, 120.83, 114.91, 60.92,
46.81, 24.85, 22.97 ppm; HRMS (ESI): Calcd for
C20H23N4O3S: m/z 399.1485 [M + H]+. Found: 399.1484.
1
638, 607, 569, 507 cm−1; H NMR (400 MHz, DMSO-d6):
δ 9.03 (s, 1H, triazole H), 8.16 (d, 2H, J = 8.79 Hz, ArH),
8.10 (d, 2H, J = 8.79 Hz, ArH), 7.58 (d, 1H, J = 1.46 Hz,
ArH), 7.41 (d, 4H, J = 2.93 Hz, ArH), 6.74 (s, 1H, ArH),
5.35 (s, 2H, CH2O), 2.26 (s, 6H, 2CH3) ppm; HRMS (ESI):
Calcd for C21H21N6O3S: m/z 437.1390 [M + H]+. Found:
437.1396.
4.2.2 | 4-(4-(2,4-Dichlorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)-N-
(4,6-dimethylpyrimidin-2-yl)
benzenesulfonamide (16)
4.2.5 | 1-((4-(4-((4-Fluorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)piperidine (19)
Brown solid; yield 56%; mp 189-192ꢀC; IR (Nujol) νmax
:
3105, 1593, 1550, 1500, 1431, 1386, 1336, 1298, 1255,
1147, 1097, 1018, 850, 758, 700 cm−1; 1H NMR (400 MHz,
DMSO-d6): δ 9.03 (s, 1H, triazole H), 8.16 (d, 2H,
J = 8.05 Hz, ArH), 8.09 (d, 2H, J = 8.05 Hz, ArH), 7.58
(d, 1H, J = 1.40 Hz, ArH), 7.41 (d, 2H, J = 2.93 Hz, ArH),
6.74 (s, 1H, ArH), 5.36 (s, 2H, CH2O), 2.26 (s, 6H, 2CH3)
ppm; 13C NMR (100 MHz, DMSO-d6): δ 152.42, 143.45,
138.90, 138.67, 129.84, 129.41, 128.11, 125.03, 123.44,
122.60, 119.82, 118.93, 115.69, 79.15, 62.15, 28.99 ppm;
HRMS (ESI): Calcd for C21H19N6O3SCl2: m/z 505.0611
[M + H]+. Found: 505.0598.
Light yellow solid; yield 73%; mp 178-180ꢀC; IR (KBr)
ν
max: 2924, 2857, 1600, 1508, 1339, 1208, 1162, 1096,
1044, 926, 823, 735, 605, 581, 507 cm−1 1H NMR
;
(400 MHz, DMSO-d6): δ 9.09 (s, 1H, triazole H), 8.20 (d,
2H, J = 8.05 Hz, ArH), 7.94 (d, 2H, J = 8.05 Hz, ArH),
7.17-7.07 (m, 4H, ArH), 5.23 (s, 2H, CH2O), 2.93 (t, 4H,
J = 5.13 Hz, piperidine H), 1.57-1.51 (m, 4H, piperidine
H), 1.39-1.33 (m, 2H, piperidine H) ppm; HRMS (ESI):
Calcd for C20H22FN4O3S: m/z 417.1397 [M + H]+.
Found: 417.1385.
4.2.6 | 1-((4-(4-((4-Chlorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)piperidine (20)
4.2.3 | 1-((4-(4-((4-Nitrophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)piperidine (17)
Light brown solid; yield 88%; mp 191-193ꢀC; IR (KBr)
Off white solid; yield 90%; mp 200-202ꢀC; IR (Film) νmax
:
νmax: 2926, 2857, 1598, 1492, 1338, 1247, 1162, 1044,
3081, 2923, 2854, 1917, 1712, 1609, 1594, 1513, 1497,
927, 822, 755, 605, 582 cm−1; 1H NMR (400 MHz, DMSO-
d6): δ 9.09 (s, 1H, triazole H), 8.19 (d, 2H, J = 8.79 Hz,
ArH), 7.94 (d, 2H, J = 8.79 Hz, ArH), 7.35 (d, 2H,
J = 8.79 Hz, ArH), 7.10 (d, 2H, J = 8.79 Hz, ArH), 5.26 (s,
2H, CH2O), 2.93 (t, 4H, J = 5.13 Hz, piperidine H),
1.57-1.51 (m, 4H, piperidine H), 1.39-1.33 (m, 2H,
1463, 1338, 1263, 1160, 1044, 923, 824, 750, 689 cm−1; H
1
NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H, triazole H),
8.24 (d, 2H, J = 8.79 Hz, ArH), 8.19 (d, 2H, J = 9.52 Hz,
ArH), 7.95 (d, 2H, J = 8.79 Hz, ArH), 7.30 (d, 2H,
J = 9.52 Hz, ArH), 5.45 (s, 2H, CH2O), 2.93 (t, 4H,

8
BATRA ET AL.
piperidine H) ppm; HRMS (ESI): Calcd for
C20H22ClN4O3S: m/z 433.1096 [M + H]+. Found:
433.1093.
123.74, 122.34, 120.94, 115.55, 65.39, 61.82, 46.03 ppm;
HRMS (ESI): Calcd for C19H20N5O6S: m/z 446.1129 [M
+ H]+. Found: 446.1110.
4.2.7 | 1-((4-(4-((4-Bromophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)piperidine (21)
4.2.10 | 4-((4-(4-Phenoxymethyl)-1H-
[1,2,3]-triazol-1-yl)phenyl)sulfonyl)-
morpholine (24)
Light yellow solid; yield 80%; mp 163-165ꢀC; IR (KBr)
Crimson solid; yield 91%; mp 163-165ꢀC; IR (KBr) νmax
:
ν
max: 2941, 2856, 1598, 1490, 1338, 1248, 1163, 1044,
2976, 2864, 1596, 1492, 1350, 1251, 1165, 1110, 1043,
927, 774, 603, 582 cm−1; H NMR (400 MHz, DMSO-d6):
δ 9.07 (s, 1H, triazole H), 8.19 (d, 2H, J = 8.79 Hz, ArH),
7.94 (d, 2H, J = 8.79 Hz, ArH), 7.47 (d, 2H, J = 8.79 Hz,
ArH), 7.05 (d, 2H, J = 8.79 Hz, ArH), 5.26 (s, 2H, CH2O),
2.93 (t, 4H, J = 5.13 Hz, piperidine H), 1.57-1.51 (m, 4H,
piperidine H), 1.39-1.32 (m, 2H, piperidine H) ppm;
HRMS (ESI): Calcd for C20H22BrN4O3S: m/z 477.0591
[M + H]+. Found: 477.0582 and 479.0566 [(M + H) + 2].
946, 750, 600, 543 cm−1; H NMR (400 MHz, DMSO-d6):
1
1
δ 9.11 (s, 1H, triazole H), 8.22 (brs, 2H, ArH), 7.95 (brs,
2H, ArH), 7.30 (brs, 2H, ArH), 7.06 (brs, 2H, ArH), 6.95
(brs, 1H, ArH), 5.26 (s, 2H, CH2O), 3.61 (brs, 4H, mor-
pholine H), 2.89 (brs, 4H, morpholine H) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 157.97, 144.53, 139.78, 134.21,
129.73, 129.67, 123.23, 121.13, 120.76, 114.78, 65.35,
60.86, 45.96 ppm; HRMS (ESI): Calcd for C19H21N4O4S:
m/z 401.1278 [M + H]+. Found: 401.1274.
4.2.8 | 1-((4-(4-((4-Iodophenoxy)methyl)-
1H-[1,2,3]-triazol-1-yl)phenyl)-sulfonyl)
piperidine (22)
4.2.11 | 4-((4-(4-((4-Fluorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)morpholine (25)
Yellow solid; yield 83%; mp 195-197ꢀC; IR (KBr) νmax
:
2936, 2853, 1598, 1487, 1338, 1248, 1162, 1097, 1043,
928, 839, 811, 773, 582 cm−1; 1H NMR (400 MHz, DMSO-
d6): δ 9.09 (s, 1H, triazole H), 8.19 (d, 2H, J = 8.79 Hz,
ArH), 7.94 (d, 2H, J = 8.79 Hz, ArH), 7.61 (d, 2H,
J = 8.79 Hz, ArH), 6.93 (d, 2H, J = 8.79 Hz, ArH), 5.25 (s,
2H, CH2O), 2.93 (t, 4H, J = 5.13 Hz, piperidine H),
1.57-1.51 (m, 4H, piperidine H), 1.38-1.32 (m, 2H, piperi-
dine H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 158.03,
144.33, 139.63, 138.57, 135.64, 129.68, 123.50, 120.96,
117.91, 84.04, 61.16, 46.90, 24.93, 23.06 ppm; HRMS
(ESI): Calcd for C20H22IN4O3S: m/z 525.0452 [M + H]+.
Found: 525.0446.
Light yellow solid; yield 88%; mp 172-174ꢀC; IR (KBr)
ν
max: 2976, 2858, 1595, 1506, 1347, 1257, 1178, 1095,
1045, 939, 831, 761, 733, 598, 538 cm−1 1H NMR
;
(400 MHz, DMSO-d6): δ 9.12 (s, 1H, triazole H), 8.23 (d,
2H, J = 8.70 Hz, ArH), 7.96 (d, 2H, J = 8.70 Hz, ArH),
7.17-7.07 (m, 4H, ArH), 5.24 (s, 2H, CH2O), 3.64 (t, 4H,
J = 4.58 Hz, morpholine H), 2.92 (t, 4H, J = 4.58 Hz,
morpholine H) ppm; 13C NMR (100 MHz, DMSO-d6): δ
1
156.81 (d, JC-F = 235.78 Hz), 154.27, 144.3, 139.74,
134.21, 129.70, 123.24, 120.73, 116.17 (d, 3JC-F = 8.63 Hz),
2
115.98 (d, JC-F = 23.00 Hz), 65.32, 61.53, 45.93 ppm;
HRMS (ESI): Calcd for C19H20FN4O4S: m/z 419.1184 [M
+ H]+. Found: 419.1178.
4.2.9 | 4-((4-(4-((4-Nitrophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)morpholine (23)
4.2.12 | 4-((4-(4-((4-Chlorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)morpholine (26)
Light brown solid; yield 69%; mp 227-229ꢀC; IR (KBr)
ν
max: 2918, 2867, 1595, 1507, 1341, 1267, 1161, 1108,
Light brown solid; yield 92%; mp 180-182ꢀC; IR (KBr)
1044, 949, 832, 747, 595, 538 cm−1; H NMR (400 MHz,
DMSO-d6): δ 9.13 (s, 1H, triazole H), 8.22 (brs, 4H, ArH),
7.95 (d, 2H, J = 8.79 Hz, ArH), 7.30 (d, 2H, J = 8.79 Hz,
ArH), 5.44 (s, 2H, CH2O), 3.63 (brs, 4H, morpholine H),
2.92 (brs, 4H, morpholine H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 163.24, 143.56, 134.39, 129.82, 126.08,
ν
max: 2849, 1490, 1351, 1245, 1169, 1113, 1003, 950, 826,
1
757, 598, 540 cm−1 1H NMR (400 MHz, DMSO-d6): δ
;
9.09 (s, 1H, triazole H), 8.21 (d, 2H, J = 8.79 Hz, ArH),
7.95 (d, 2H, J = 8.79 Hz, ArH), 7.34 (d, 2H, J = 8.79 Hz,
ArH), 7.09 (d, 2H, J = 8.79 Hz, ArH), 5.26 (s, 2H, CH2O),
3.63 (m, 4H, morpholine H), 2.91 (m, 4H, morpholine H)

BATRA ET AL.
9
ppm; 13C NMR (100 MHz, DMSO-d6): δ 156.99, 144.43,
139.94, 134.52, 130.02, 129.68, 125.13, 123.58, 121.11,
116.92, 65.60, 61.41, 46.20 ppm; HRMS (ESI): Calcd for
C19H20ClN4O4S: m/z 435.0888 [M + H]+. Found:
435.0884.
6.62 (d, 1H, J = 6.87 Hz, pyridyl H), 5.43 (s, 2H, CH2O),
3.60 (t, 4H, J = 4.58 Hz, piperazine H), 3.03 (t, 4H,
J = 4.58 Hz, piperazine H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 163.14, 158.27, 147.55, 143.43, 141.20,
139.62, 137.78, 134.61, 129.63, 125.96, 123.62, 120.81,
115.43, 113.65, 107.52, 61.75, 45.60, 44.02 ppm; HRMS
(ESI): Calcd for C24H24N7O5S: m/z 522.1533 [M + H]+.
Found: 522.1550.
4.2.13 | 4-((4-(4-((4-Bromophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)morpholine (27)
4.2.16 | 1-((4-(4-(Phenoxymethyl)-1H-
[1,2,3]-triazol-1-yl)phenyl)sulfonyl)-
4-(pyridine-2-yl)piperazine (30)
Light brown solid; yield 70%; mp 190-191ꢀC; IR (KBr)
ν
max: 2927, 2852, 1591, 1483, 1350, 1245, 1168, 1112,
949, 824, 757, 597, 539 cm−1; 1H NMR (400 MHz, DMSO-
d6): δ 9.09 (s, 1H, triazole H), 8.21 (d, 2H, J = 8.79 Hz,
ArH), 7.95 (d, 2H, J = 8.79 Hz, ArH), 7.47 (d, 2H,
J = 8.79 Hz, ArH), 7.05 (d, 2H, J = 8.79 Hz, ArH), 5.26 (s,
2H, CH2O), 3.63 (m, 4H, morpholine H), 2.92 (m, 4H,
morpholine H) ppm; HRMS (ESI): Calcd for
C19H20BrN4O4S: m/z 479.0383 [M + H]+. Found:
479.0372 and 481.0360 [(M + H) + 2].
Off white solid; yield 72%; mp 184-186ꢀC; IR (Film) νmax
:
2916, 2852, 1594, 1491, 1349, 1314, 1246, 1161, 1043,
1
948, 853, 775, 749 cm−1; H NMR (400 MHz, DMSO-d6):
δ 9.09 (s, 1H, triazole H), 8.21 (d, 2H, J = 8.70 Hz, ArH),
8.06 (d, 1H, J = 5.50 Hz, pyridyl H), 7.97 (d, 2H,
J = 8.70 Hz, ArH), 7.50 (t, 1H, J = 7.79 Hz, ArH), 7.31 (t,
2H, J = 7.79 Hz, ArH), 7.06 (d, 2H, J = 7.79 Hz, ArH),
6.96 (t, 1H, J = 7.79 Hz, pyridyl H), 6.80 (d, 1H,
J = 8.70 Hz, pyridyl H), 6.63 (t, 1H, J = 5.50 Hz, pyridyl
H), 5.24 (s, 2H, CH2O), 3.59 (t, 4H, J = 4.58 Hz, pipera-
zine H), 3.03 (t, 4H, J = 4.58 Hz, piperazine H) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 158.50, 158.11, 147.77,
144.69, 139.88, 138.10, 134.72, 129.90, 123.39, 121.37,
121.01, 114.97, 113.99, 107.80, 60.95, 45.82, 44.28 ppm;
HRMS (ESI): Calcd for C24H25N6O3S: m/z 477.1703 [M
+ H]+. Found: 477.1696.
4.2.14 | 4-((4-(4-((4-Iodophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)morpholine (28)
Light brown solid; yield 77%; mp 201-203ꢀC; IR (KBr)
ν
max: 2924, 1476, 1349, 1244, 1166, 1111, 948, 824,
775, 615, 596 cm−1 1H NMR (400 MHz, DMSO-d6): δ
;
9.09 (s, 1H, triazole H), 8.21 (d, 2H, J = 8.79 Hz, ArH),
7.95 (d, 2H, J = 8.79 Hz, ArH), 7.61 (d, 2H, J = 8.79 Hz,
ArH), 6.93 (d, 2H, J = 8.79 Hz, ArH), 5.25 (s, 2H, CH2O),
3.63 (brs, 4H, morpholine H), 2.91 (brs, 4H, morpholine
H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 158.03,
144.38, 138.39, 134.50, 130.00, 123.57, 121.09, 117.93,
65.58, 61.15, 46.18 ppm; HRMS (ESI): Calcd for
C19H20IN4O4S:m/z 527.0244 [M + H]+. Found: 527.0236.
4.2.17 | 1-((4-(4-((4-Fluorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)-4-(pyridine-2-yl)piperazine (31)
White solid; yield 75%; mp 194-196ꢀC; IR (Film) νmax
:
2854, 2636, 1506, 1349, 1203, 1161, 1041, 950, 828,
1
737 cm−1; H NMR (400 MHz, DMSO-d6): δ 9.07 (s, 1H,
triazole H), 8.20 (d, 2H, J = 7.33 Hz, ArH), 8.06 (d, 1H,
J = 5.50 Hz, pyridyl H), 7.97 (d, 2H, J = 7.33 Hz, ArH),
7.50 (t, 1H, J = 7.79 Hz, pyridyl H), 7.15-7.05 (m, 4H,
ArH), 6.79 (d, 1H, J = 7.79 Hz, pyridyl H), 6.62 (t, 1H,
J = 5.50 Hz, pyridyl H), 5.22 (s, 2H, CH2O), 3.59 (brs, 4H,
piperazine H), 3.02 (brs, 4H, piperazine H) ppm; 13C
4.2.15 | 1-((4-(4-((4-Nitrophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)-4-(pyridine-2-yl)piperazine (29)
White solid; yield 65%; mp 244-246ꢀC; IR (Film) νmax
:
2922, 2853, 1722, 1592, 1463, 1341, 1260, 1164, 1097,
NMR (100 MHz, DMSO-d6):
δ
157.24 (d, 1JC-
1
799, 774 cm−1; H NMR (400 MHz, DMSO-d6): δ 9.13 (s,
= 246.33 Hz), 154.40, 147.74, 144.51, 139.85, 138.06,
F
1H, triazole H), 8.22 (t, 4H, J = 9.16 Hz, ArH), 8.06 (d,
1H, J = 6.87 Hz, pyridyl H), 7.98 (d, 2H, J = 8.70 Hz,
ArH), 7.50 (t, 1H, J = 6.87 Hz, pyridyl H), 7.29 (d, 2H,
J = 9.16 Hz, ArH), 6.80 (d, 1H, J = 8.82 Hz, pyridyl H),
134.70, 129.85, 123.39, 120.97, 116.37 (d, 3JC-F = 8.63 Hz),
2
116.17 (d, JC-F = 23.00 Hz), 113.93, 107.76, 61.62, 45.80,
44.24 ppm; HRMS (ESI): Calcd for C24H24FN6O3S: m/z
495.1609 [M + H]+. Found: 495.1599.

10
BATRA ET AL.
4.2.18 | 1-((4-(4-((4-Chlorophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)-4-(pyridine-2-yl)piperazine (32)
1H, J = 4.58 Hz, pyridyl H), 7.97 (d, 2H, J = 7.79 Hz,
ArH), 7.61 (d, 2H, J = 8.24 Hz, ArH), 7.50 (t, 1H,
J = 7.79 Hz, pyridyl H), 6.92 (d, 2H, J = 8.24 Hz, ArH),
6.82 (d, 1H, J = 8.70 Hz, pyridyl H), 6.62 (t, 1H,
J = 5.95 Hz, pyridyl H), 5.23 (s, 2H,CH2O), 3.59 (brs, 4H,
piperazine H), 3.03 (brs, 4H, piperazine H) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 158.23, 157.77, 147.49,
144.02, 138.02, 137.95, 137.73, 134.51, 129.58, 123.25,
120.68, 117.62, 117.57, 113.61, 107.49, 60.99, 45.57,
44.00 ppm; HRMS (ESI): Calcd for C24H24IN6O3S: m/z
603.0700 [M + H]+. Found: 603.0656.
Pale white solid; yield 89%; mp 206-208ꢀC; IR (Film)
ν
max: 2919, 2855, 1595, 1490, 1438, 1349, 1240, 1163,
1042, 950, 822, 772, 750 cm−1 1H NMR (400 MHz,
;
DMSO-d6): δ 9.09 (s, 1H, triazole H), 8.20 (d, 2H,
J = 8.24 Hz, ArH), 8.06 (d, 1H, J = 5.95 Hz, pyridyl H),
7.97 (d, 2H, J = 8.24 Hz, ArH), 7.52 (t, 1H, J = 7.79 Hz,
pyridyl H), 7.34 (d, 2H, J = 8.70 Hz, ArH), 7.09 (d, 2H,
J = 8.70 Hz, ArH), 6.83 (d, 1H, J = 7.79 Hz, pyridyl H),
6.64 (t, 1H, J = 5.95 Hz, pyridyl H), 5.25 (s, 2H, CH2O),
3.61 (brs, 4H, piperazine H), 3.03 (brs, 4H, piperazine H)
ppm; 13C NMR (100 MHz, DMSO-d6): δ 157.63, 156.93,
144.33, 139.87, 138.94, 134.76, 129.89, 129.61, 125.03,
123.49, 121.03, 120.60, 116.84, 113.91, 108.53, 61.35,
45.72, 44.42 ppm; HRMS (ESI): Calcd for C24H24ClN6O3S:
m/z 511.1314 [M + H]+. Found: 511.1303.
4.3 | ADMET prediction
ADMET prediction of targeted benzenesulfonamide-
appended [1,2,3]-triazoles was carried out using Qikprop
3.5 module offered by Schrödinger.[33] Qikprop predicts
physically significant descriptors and pharmaceutically
relevant properties either individually or in batches. The
procedure used for Qikprop is described below.
4.2.19 | 1-((4-(4-((4-Bromophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)-4-(pyridine-2-yl)piperazine (33)
1. Structures of the compounds were sketched by
Chemdraw 8.0/builder module of Schrödinger and
saved using .mol file extension.
2. Structures were imported into the Maestro Graphical
User Interface (GUI).
Light brown solid; yield 79%; mp 216-218ꢀC; IR (Film)
ν
max: 1474, 1344, 1245, 1159, 1041, 947, 813, 770 cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H, triazole H),
8.20 (d, 2H, J = 8.24 Hz, ArH), 8.06 (d, 1H, J = 5.50 Hz,
pyridyl H), 7.97 (d, 2H, J = 8.24 Hz, ArH), 7.51 (d, 1H,
J = 8.70 Hz, pyridyl H), 7.46 (d, 2H, J = 9.16 Hz, ArH),
7.04 (d, 2H, J = 9.16 Hz, ArH), 6.88 (d, 1H, J = 8.70 Hz,
pyridyl H), 6.63 (t, 1H, J = 5.50 Hz, pyridyl H), 5.24 (s,
2H,CH2O), 3.60 (brs, 4H, piperazine H), 3.02 (brs, 4H,
piperazine H) ppm; 13C NMR (100 MHz, DMSO-d6): δ
158.47, 157.36, 147.74, 144.27, 139.83, 138.07, 134.73,
132.48, 129.86, 123.49, 120.99, 117.35, 113.96, 112.74,
107.77, 61.26, 45.80, 44.25 ppm; HRMS (ESI): Calcd for
C24H24BrN6O3S: m/z 555.0808 [M + H]+. Found:
555.0784 and 557.0781 [M + H) + 2].
3. All the structures were processed using Ligprep tool of
Maestro. “Neutralize” option was selected as Qikprop
is unable to successfully process ligands which con-
tain charged groups or molecules.
4. Structures were eventually processed by Ligprep and
saved using .mae file extension for further use in
Qikprop.
5. Qikprop module was selected in Maestro GUI and
compounds were processed in normal mode.
6. Predicted properties were exported to Microsoft excel
for further analysis.
4.3.1 | In vitro cultivation of
P. falciparum
4.2.20 | 1-((4-(4-((4-Iodophenoxy)
methyl)-1H-[1,2,3]-triazol-1-yl)phenyl)-
sulfonyl)-4-(pyridine-2-yl)piperazine (34)
Cryopreserved strain 3D7 of P. falciparum was revived
according to standard protocols and introduced into the
culture. Asexual erythrocytic stages were cultivated by
the procedures of Trager and Jensen with minor modifi-
cations.[39] The parasites were cultivated in RPMI-1640
medium containing 2 g/L sodium bicarbonate, 40 μg/mL
gentamicin sulfate supplemented with 0.5% AlbuMAX-II.
Human erythrocytes at 10% hematocrit were used to
Light brown solid; yield 82%; mp 226-228ꢀC; IR (Film)
ν
max: 2856, 1593, 1481, 1436, 1352, 1315, 1278, 1244,
1163, 1120, 1093, 1041, 954, 815, 777, 748, 615, 596,
1
569, 441 cm−1; H NMR (400 MHz, DMSO-d6): δ 9.09 (s,
1H, triazole H), 8.20 (d, 2H, J = 7.79 Hz, ArH), 8.06 (d,

BATRA ET AL.
11
culture the parasites, and the cultures were maintained
at 37ꢀC in the presence of mixture of gasses, 5% CO2, 5%
O2, and 90% N2.
in phosphate-buffered saline [PBS]) was added to each
well and the plates were incubated in the dark for
4 hours. The by-product (dark blue formazan) formed by
viable cells was dissolved in DMSO, and absorbance was
recorded at 570 nm by using a Biotek Synergy HT micro-
plate reader. A 50% cytotoxic concentration (CC50) was
determined using nonlinear regression analysis. The
CC50 obtained in μM was converted to μg/mL for further
analysis.
4.4 | Evaluation of antimalarial
activity of sulfonamide-appended [1,2,3]-
triazoles (5-34) against P. falciparum 3D7
strain
For the evaluation of antimalarial activity, [3H]-
hypoxanthine incorporation inhibition assay was per-
formed as reported earlier.[36] Chloroquine was used as a
positive control. The test compounds and chloroquine
were solublized in DMSO and double distilled water,
respectively, and the working solutions were prepared in
RPMI-1640 medium at two-fold dilutions and plated in
96 well plates (final solvent concentration <0.5%). Sepa-
rate wells were prepared without the test compounds/
chloroquine and used as negative control for our experi-
ments. Asynchronous P. falciparum cultures suspended
in 2% parasitemia and 4% final hematocrit were added to
each well. After 24 hours of incubation, 20 μL of 0.2 μCi
per well [3H] hypoxanthine was added to each well for
an additional 18 hours. At the end of incubation, the con-
tents in each well were harvested on a glass-fiber filter
mat (Whatman GF/C) using a 96-well Skatron semi-
automated cell harvester. The radioactive associated
nucleic acids on the filters were transferred to 5 mL of
toluene-based scintillation cocktail, and radioactive
counts were determined using Perkin Elmer liquid scin-
tillation beta-counter. The IC50 values were determined
by plotting the drug concentration against the percentage
of viability of the parasites after 42 hours of growth assay
period.
ACKNOWLEDGMENTS
We would like to thank the University of Delhi for pro-
viding the financial and infrastructural support to carry
out the present work and also extend our gratitude to
USIC, University of Delhi for providing NMR and high-
resolution mass data. N.B., A.L., and I.W. are thankful to
UGC, India, for providing Senior Research Fellowships.
ORCID
Mahendra Nath https://orcid.org/0000-0002-3088-1422
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Batra N, Rajendran V,
Wadi I, et al. Synthesis, characterization, and
antiplasmodial efficacy of sulfonamide-appended
[1,2,3]-triazoles. J Heterocyclic Chem. 2020;1–12.
https://doi.org/10.1002/jhet.3888
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