Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors

Article abstract of DOI:10.1016/j.ejmech.2018.03.030

The design, synthesis and biological evaluation of a library of 1,2,3-triazole carboxylates incorporating carboxylic acid, hydroxymethyl, carboxylic acid hydrazide, carboxamide and benzenesulfonamide moieties is disclosed. All the novel compounds were inv

Full text of DOI:10.1016/j.ejmech.2018.03.030

Accepted Manuscript
Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing
benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors
Lalit Vats, Vikas Sharma, Andrea Angeli, Rajiv Kumar, Claudiu T. Supuran, Pawan K.
Sharma
PII:
S0223-5234(18)30273-3
10.1016/j.ejmech.2018.03.030
EJMECH 10295
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 17 January 2018
Revised Date: 9 March 2018
Accepted Date: 9 March 2018
Please cite this article as: L. Vats, V. Sharma, A. Angeli, R. Kumar, C.T. Supuran, P.K. Sharma,
Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety
as carbonic anhydrase I, II, IV and IX inhibitors, European Journal of Medicinal Chemistry (2018), doi:
10.1016/j.ejmech.2018.03.030.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing
benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX
inhibitors
Lalit Vats, Vikas Sharma, Andrea Angeli, Rajiv Kumar, Claudiu T. Supuran, Pawan K. Sharma
A
series of thirty novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing
benzenesulfonamide moiety were synthesized and evaluated for their inhibition potential
against human carbonic anhydrase isoforms, hCA I, II, IV and IX.

ACCEPTED MANUSCRIPT
Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles
containing benzenesulfonamide moiety as carbonic anhydrase I, II,
IV and IX inhibitors
Lalit Vatsa, Vikas Sharmaa, Andrea Angelib, Rajiv Kumara, Claudiu T. Supuranb*, Pawan K.
Sharmaa*
aDepartment of Chemistry, Kurukshetra University, Kurukshetra, Haryana-136119
bUniversità degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and
Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto
Fiorentino (Firenze), Italy.
*Corresponding authors: Tel.: +91 9416457355; Fax: +91 1744 238277; e-mail:
pksharma@kuk.ac.in (PKS); Tel/Fax: +39-055-4573005, e-mail: claudiu.supuran@unifi.it
(CTS)
Abstract
The design, synthesis and biological evaluation of a library of 1,2,3-triazole carboxylates
incorporating carboxylic acid, hydroxymethyl, carboxylic acid hydrazide, carboxamide and
benzenesulfonamide moieties is disclosed. All the novel compounds were investigated for
their inhibition potential against carbonic anhydrase (CA, EC 4.2.1.1) human (h) isoforms
hCA I, II, IV and IX, well established drug targets. The cytosolic isoform hCA I was
inhibited with Ki’s ranging between 53.2 nM to 7.616 µM whereas the glaucoma associated
cytosolic isoform hCA II was inhibited with Ki’s in the range 21.8 nM-0.807 µM. The
membrane bound isoform hCA IV, involved in glaucoma and retinitis pigmentosa among
others, was effectively inhibited by some of these compounds with Ki < 60 nM, better than
the reference drug acetazolamide (AAZ). The tumor associated isoform hCA IX, a recently
validated antitumor/antimetastatic drug target, was also effectively inhibited by some of the
new sulfonamides, which possess thus the potential to be used as tools for exploring in more
details the selective inhibition of hCAs involved in various pathologies.
Keywords: Carbonic anhydrase inhibitors; Isoforms I, II, IV, IX; Benzenesulfonamide;
1,2,3-Triazole.
Abbreviations: CA: Carbonic anhydrase; hCA: human carbonic anhydrase; CAIs: Carbonic
anhydrase inhibitors; AAZ: Acetazolamide; Ki: Inhibition constant; nM: nanomolar; µM:
micromolar; py: pyridyl; th: thienyl.
1

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1. Introduction: Carbonic anhydrases (CAs, EC 4.2.1.1), also known as carbonate
dehydratases, are widely distributed zinc containing metalloenzymes present in all life phyla
which maintain pH homeostasis in the body by catalyzing the CO2 hydration reaction to
bicarbonate and proton as well as other hydrolytic reactions [1]. Depending upon their
localisation in various organisms, catalytic activity and susceptibility to different classes of
inhibitors, carbonic anhydrases are divided in seven genetically distinct families, α-, β-, γ-, δ-,
and θ- CAs [2-4]. Out of these, only the α- class is known to be present in humans, in which
16 isoforms were described which differ in their subcellular localisation, distribution in
tissues and molecular and kinetic properties [5-7]. The CA isoforms are involved in
numerous biochemical and physiological processes such as acid base regulation, bone
resorption, calcification, ureagenesis, gluconeogenesis, and tumorigenicity, thus representing
interesting biological targets for the design of CA inhibitors (CAIs) with many biomedical
applications [8-9]. The ubiquitous isoform hCA I is involved in retinal and cerebral edema,
and its inhibition may be a valuable tool for fighting these conditions [10-12]. hCA II is
involved in glaucoma, edema and epilepsy among others [13]. hCA IV is a membrane bound
isoform and its deregulated activity is associated with glaucoma, retinitis pigmentosa and
stroke [10]. hCA IX, a transmembrane isoform, being involved in tumor growth, metastases
formation and cancer stem cell population dynamics, mainly by causing acidification of
extracellular environment and several other process connected to tumorigenesis [14-17]. Thus
selective inhibition of some isoforms over others is a challenging approach for obtaining a
multitude of different drugs, with minimum side effects.
In the last decade, a lot of work has been done on the synthesis of CA inhibitors (CAIs)
belonging to various classes, such as sulfonamides, coumarins, phenols, carboxylic acids,
heterocyclic derivatives, dithiocarbamates, etc [18-30]. Out of these, sulfonamides and their
bioisosteres like the sulfamates and the sulfamides are potent active site coordinating CAIs
which, in deprotonated form, bind to the Zn(II) ion present within the active site of enzyme
[31-32]. Many sulfonamide-based drugs, such as acetazolamide (AAZ), methazolamide
(MZA), ethoxzolamide (EZA), dorzolamide (DZA), brinzolamide (BRZ), celecoxib (CLX)
are known. Some of them are in clinical use as diuretics (targeting hCA II, IV, XII and XIV),
antiepileptics (targeting hCA VII and XIV), antiglaucoma (targeting hCA II, IV and XII), or
in clinical trials as antitumor/antimetastatic agents (targeting hCA IX and XII) [33-34].
Furthermore, compounds containing 1,2,3-triazole ring system has been studied extensively
for the synthesis of novel derivatives, such as 1-3 with pharmacologic applications (Fig. 1)
[35-37].
2

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Recently, our research group has reported the synthesis and biological evaluation of some
benzenesulfonamide bearing 1,2,3-triazoles, as hCA I, II, IV and XI inhibitors, which showed
excellent inhibition profile for several CA isoforms [28]. Motivated by the results of our
previous work and continuing our interest in designing heterocyclic compounds of potential
pharmacologic interest [20-23,27-29,38-39] we report here novel 4-functionalized 1,5-diaryl-
1,2,3-triazoles bearing benzenesulfonamide moieties for evaluation of their CA inhibiton
potential against hCA I, II, IV and IX.
Fig. 1. Clinically used sulfonamide CA inhibitors (AAZ-CLX), and derivatives incorporating the 1,2,3-
triazole ring (1-3), together with the newly designed sulfonamides 4-8.
2. Results and discussion
2.1. Chemistry
Synthesis of the 1,2,3-triazole derivatives 4a-4f, 5a-5f, 6a-6f, 7a-7f and 8a-8f was performed
according to the general synthetic routes as outlined in Schemes 1 and 2. The coveted 1,5-
diaryl-1,2,3-triazole carboxylates 4a-4f were synthesized (Scheme 1) starting from
commercially available sulfanilamide (9) which upon diazotisation and subsequent reaction
with sodium azide at 0o C yielded 4-azidobenzenesulfonamide (10) [40]. Compound 10 was
subsequently treated with differently substituted β-ketoesters 11a-11f, which were in turn
3

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synthesized according to literature procedure [ 41 ] to afford 1,5-diaryl-1,2,3-triazole
carboxylates 4a-4f.
Scheme 1. Synthesis of target compounds 4a-4f. Reaction conditions: (i) HCl, NaNO2, H2O, 0oC; (ii)
NaN3, 0oC; (iii) Piperidine, DMSO, 70oC.
Other derivatives of 1,5-diaryl-1,2,3-triazoles incorporating carboxylic acids 5a-5f, methyl
alcohols 6a-6f, carboxylic acid hydrazides 7a-7f and carboxamides 8a-8f were synthesized
by reacting ethyl carboxylates 4a-4f with aqueous NaOH, LiAlH4, hydrazine hydrate, and
ammonia solution respectively (Scheme 2) [42-43]. The structures of the synthesized 1,2,3-
trizolic benzenesulfonamides were confirmed by rigorous analysis of their spectral data (IR,
13
1H NMR, C NMR and HRMS). In general, ethyl 1,2,3-triazole carboxylates 4a-4f were
characterized by appearance of a strong characteristic band for C=O in the range of 1713-
1736 cm-1 in their FT-IR spectra and appearance of a characteristic quartet of two protons and
a triplet of three protons in the range 4.23-4.26 ppm and 1.14-1.33 ppm respectively for ethyl
1
protons in their H NMR spectra. The 1,2,3-triazole carboxylic acids 5a-5f were
characterized by a sharp absorption band at 1705-1744 cm-1 corresponding to the C=O
stretching vibration along with a broad band at 3209 cm-1 - 3265 cm-1 due to O-H stretching
of COOH in FT-IR spectra and a broad exchangeable singlet in the range 13.15-13.36 ppm
1
due to acidic proton in the H NMR spectra. The methyl alcohols 6a-6f exhibited a broad
band at 3250-3472 cm-1 corresponding to the O-H stretching in the FT-IR spectra, whereas
1
their H NMR spectra exhibited a triplet in the range 5.17-5.64 ppm along with a doublet in
the range 4.50-4.64 ppm corresponding to the OH and CH2 protons respectively. The
corresponding hydrazinocarbonyl derivatives 7a-7f were characterized by a sharp band at
1651-1682 cm-1 for the C=O stretching in the FT-IR spectrum, and two exchangeable singlets
in the range 9.92-10.01 ppm and 4.49-4.55 ppm for the NH and NH2 protons, respectively in
1
the H NMR spectra. The 1,2,3-triazole carboxamides 8a-8f displayed a sharp absorption
4

ACCEPTED MANUSCRIPT
band at 1643-1675 cm-1 corresponding to the C=O stretching in FT-IR spectrum and two
exchangeable singlets in the range 8.00-8.15 ppm and 7.50-7.65 ppm corresponding to the
1
NH/OH protons in the H NMR spectra. Furthermore, all the synthesized compounds
exhibited sharp absorption bands in their FT-IR spectra at ~1342 cm-1 and ~1165 cm-1 for
SO2 stretching, and a sharp singlet at ~7.56 ppm for SO2NH2 protons in the 1H NMR spectra.
Scheme 2. Synthesis of target compounds 5a-5f, 6a-6f, 7a-7f and 8a-8f. Reaction conditions: (i) aq.
NaOH, reflux; (ii) H3O+ (iii) LiAlH4, dry THF; (iv) NH2NH2.H2O, EtOH, Reflux; (v) NH3 solution.
;
2.2. CA inhibition studies
The target compounds 4a-4f, 5a-5f, 6a-6f, 7a-7f and 8a-8f were tested for their efficacy to
inhibit the physiologically relevant hCA isoforms, cytosolic hCA I (associated with edema),
cytosolic hCA II (associated with glaucoma), membrane bound hCA IV (associated with
glaucoma and retinitis pigmentosa) and transmembrane hCA IX (associated with tumors). All
5

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the synthesized compounds were screened for their inhibition potential by means of stopped
flow carbon dioxide hydration assay and compared with the clinically used reference drug
acetazolamide (AAZ).
a) All the synthesized compounds strongly inhibited the cytosolic isoform hCA I with Ki
ranging between 53.2 nM to 7.616 µM. Seventeen compounds 4a-4f, 6e-6f, 7b-7d, 7f,
8a-8c, 8e-8f showed even better inhibiton potential (with Ki < 250 nM) against the
cytosolic isoform hCA I than the standard drug AAZ (Ki = 250 nM). Furthermore,
among the synthesized compounds, ethyl carboxylates 4a-4f were found to be the best
hCA I inhibitors (Ki ranging between 53.2-232.1 nM) while carboxylic acids 5a-5f
were found to be the weakest inhibitors (Ki ranging between 377.9-7616.1 nM). It
was also found that, amongst the haloderivatives, the compounds with 4-
flurorophenyl and 4-chlorophenyl moieties were more effective inhibitors of hCA I as
compared to those with 4-bromophenyl moiety (Table 1).
b) All the synthesized compounds moderately inhibited the cytosolic isoform hCA II
with Ki ranging between 21.8 nM to 0.807 µM as compared to reference drug AAZ
(Ki = 12.1 nM). However, it was found that amongst the synthesized compounds
methyl alcohols 6a-6f, carboxylic acid hydrazides 7a-7f, and carboxamides 8a-8f,
except 8b and 8c, inhibited the cytosolic isoform hCA II with Ki < 100 nM.
Furthermore, carboxylic acid hydrazide 7a was the best inhibitor (Ki = 27.2 nM)
whereas carboxylic acid 5e was the weakest inhibitor (Ki = 807.5 nM) of cytosolic
isoform hCA II. Interestingly, the compounds containing 4-chlorophenyl moiety as Ar
group were found to be more effective inhibitors of hCA II as compared to those
having 4-fluorophenyl moiety (Table 1).
c) The membrane bound isoform hCA IV was strongly inhibited by some of the
synthesized sulfonamides, with Ki ranging between 35.7 nM and 2.50 µM. Eleven
compounds 4a, 4c, 4d, 5c, 5d, 5f, 5e, 7c, 7d, 8a and 8c were found to be the most
potent inhibitors among the synthesized compounds, with Ki ranging from 35.7 nM to
66.2 nM which is even better than the reference drug AAZ (Ki = 74 nM). In a broader
sense, derivatives containing 4-chlorophenyl and 4-bromophenyl moieties were found
to be more effective inhibitors of hCA IV as compared to those having 2-pyridyl
moieties as Ar group (Table 1).
d) The membrane bound tumor associated isoform hCA IX was weakly inhibited by all
the synthesized compounds, with Ki’s in the range 70 nM-2.9 µM, except for
derivative 6e which showed even better inhibitory potency (Ki = 14.3 nM) as
6

ACCEPTED MANUSCRIPT
compared to the reference drug AAZ (Ki = 25.8 nM). Furthermore, the compounds
containing 4-fluorophenyl moiety were found to be less effective inhibitors of tumor
associated isoform hCA IX as compared to those containing 4-methylphenyl moiety
(Table 1).
e) Interestingly, in terms of structure activity relationship (SAR), derivatives containing
carboxylic acid 5a-5f have shown a weaker inhibiton of cytosolic isoform hCA I as
compared to standard drug AAZ. In particular, carboxylic acid derivatives 5a and 5d
were found to be selective inhibitors of glaucoma associated isoforms hCA II and IV,
with efficacies in the low nanomolar range. However, the study of the tumor
associated trans-membrane isoform hCA IX, provided only one compound 6e, as a
better inhibitor compared to standard drug AAZ (Table 1).
f) A comparative study with our previous work [28] in terms of structure activity
relationship (SAR) revealed that, though a regular trend is not discernible, compounds
containing methyl group at C-5 position of the 1,2,3-triazole ring were the most
effective CAIs of cytosolic isoform hCA I in their respective class and as bulk of
moiety at C-5 position of 1,2,3-triazole ring increases, their inhibition potency for
cytosolic isoform hCA I decreases. It is worthy to mention here that 1,2,3-triazole
benzenesulfonamide carboxamide having –CH3 group at C-5 position of triazole ring
was found to be the best inhibitor of hCA I (Ki = 8.3 nM) whereas 1,2,3-triazole
benzenesulfonamide carboxylic acid having 4-methylphenyl moiety at C-5 position of
triazole ring was found to be the weakest inhibitor of cytosolic isoform hCA I (Ki =
7616.6 nM).
g) Changing the methyl group at C-5 position of 1,2,3-triazole ring with a heterocyclic
moiety, as in 4e-8e, 4f-8f, also resulted into an overall decrease of inhibition potency
for all hCA isoforms studied here. At the same time it also led to better selective
inhibition of one isoform over others; e.g. compounds 4f, 5f, 6e and 7e were found to
be selective inhibitors of isoforms hCA I, IV, IX and II respectively. Furthermore, in a
broader sense, compounds containing pyridyl moiety 4e-8e at C-5 position of 1,2,3-
triazole ring were found to be less effective inhibitors for all hCA isoforms studied
here as compared to those having thienyl moiety 4f-8f.
h) Although it is well demonstrated in literature, on the basis of X-ray crystallography
studies, that sulfonamide moiety, in deprotonated form, binds with the Zn (II) ion, the
inhibition of CA isoforms by binding of other functionalities like -COOH can’t be
neglected here. Thus any irregular pattern in the inhibition potential of synthesized
7

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compounds may be due to binding of other functionalities in the molecule via some
different mechanism as reported in literature, like –COOH group anchoring to the Zn
(II) coordinated water molecule rather than directly binding with Zn (II) ion [31] .
Ki (nM)*
Compounds
Ar
R
hCA I
53.2
87.1
68
hCA II
747.6
356.3
91.5
hCA IV
36.2
84
hCA IX
198.3
633
-COOEt
4-CH3 C6H4
4-F C6H4
4-Cl C6H4
4a
4b
4c
-COOEt
-COOEt
-COOEt
44.3
1477
4-Br C6H4
2-Pyridyl
173.8
232.1
79.7
518.2
666.3
376.4
553
53
227.5
1423
237.2
1415
4d
4e
4f
-COOEt
-COOEt
-COOH
836.1
2506.7
152.9
2-Thienyl
4-CH3 C6H4
7616.1
5a
-COOH
-COOH
-COOH
4-F C6H4
613.9
377.9
730.7
459
85.7
44.8
1581
5b
5c
4-Cl C6H4
715.5
4-Br C6H4
2-Pyridyl
4715.1
881.2
479.2
916.1
406.3
807.5
707.8
84.9
66.2
736.1
59.8
1406
2089
1307
2333
5d
5e
5f
-COOH
-COOH
-CH2OH
2-Thienyl
4-CH3 C6H4
648.7
6a
-CH2OH
-CH2OH
-CH2OH
4-F C6H4
322.1
554.3
51.8
29.6
229.5
88.3
2373
1213
6b
6c
4-Cl C6H4
4-Br C6H4
2-Pyridyl
655.7
88.4
71.2
395
41
277.9
1954.2
169.2
295.4
1730
14.3
6d
6e
6f
-CH2OH
-CH2OH
57.1
21.8
27.2
2-Thienyl
4-CH3 C6H4
71.2
-CONHNH2
737.7
7a
-CONHNH2
-CONHNH2
-CONHNH2
4-F C6H4
95.2
79.7
71.3
48.9
272.5
49.5
2451
909
7b
7c
4-Cl C6H4
4-Br C6H4
2-Pyridyl
203.2
477.6
91
66.2
92.6
53.3
83.7
36.6
884.9
628.2
35.7
1353
2905
2833
73
7d
7e
7f
-CONHNH2
-CONHNH2
-CONH2
2-Thienyl
4-CH3 C6H4
194.9
8a
-CONH2
-CONH2
-CONH2
4-F C6H4
72.1
90.5
637.9
559.5
229.4
49.9
107.2
116.7
8b
8c
4-Cl C6H4
4-Br C6H4
2-Pyridyl
2-Thienyl
272.9
76
88.7
38.3
51.6
79.2
478.4
569.7
256.4
730.3
225.4
8d
8e
8f
-CONH2
-CONH2
87.4
8

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-
250
12.1
74
25.8
AAZ
-
*
Mean from 3 different assays, by a stopped flow technique (errors were in the range of ± 5-10 % of the reported values).
Table 1: Inhibitory potency data for compounds 4a-4f, 5a-5f, 6a-6f, 7a-7f and 8a-8f against isozymes
hCA I, hCA II, hCA IV, and hCA IX.
3. Conclusions
In the present work, we report a series of thirty novel 1,2,3-triazole derivatives containing
primary benzenesulfonamide moiety at N-1 position, and different functionalities such as
ethyl carboxylate 4a-4f, carboxylic acid 5a-5f, methyl alcohol 6a-6f, carboxylic acid
hydrazide 7a-7f and carboxamide 8a-8f at C-4 position. Furthermore, different/differently
substituted aromatic scaffolds are present at C-5 position of 1,2,3-triazole ring. All the
synthesized compounds were assayed as inhibitors of CA isoforms of pharmacological
relevance i.e. cytosolic isoforms (hCA I and hCA II), membrane bound isoform (hCA IV)
and transmembrane isoform (hCA IX). These isoforms were inhibited by the synthesized
compounds in the low to medium nanomolar range. Most of the compounds showed rather a
weak inhibitory potency against hCA I, whereas some others (4a, 4c, 4f, 6f, 7c, 8b and 8e)
showed better potency, with Ki in the range 53 to 80 nM. Against hCA II, nearly all the tested
compounds showed moderate inhibition potential, with Ki’s in the range of 21.8 nM to 0.807
µM. For the transmembrane isoform hCA IV, the compounds having 4-chlorophenyl 4c-8c
and 4-bromophenyl 4d-8d at the C-5 position of 1,2,3-triazole ring were found to be the most
potent inhibitors with low Ki values. Compound 6e showed the most effective inhibitory
action for the tumor associated isoform hCA IX (Ki = 14.3 nM) being a better inhibitor
compared to the reference drug AAZ (Ki = 25.8 nM). It may be thus concluded that 1,2,3-
triazole benzenesulfonamide scaffold is associated with hCAs inhibitory properties and on
further study might be proved to be an important pharmacophore for the synthesis of isoform
selective CAIs.
4. Experimental protocols
4.1. Chemistry
4.1.1. General
All the commercially available chemicals were used without further purification. All the
solvents were dried and/or purified according to standard procedures prior to use. All the air-
or moisture-sensitive reactions were performed under a nitrogen atmosphere using dried
glassware and syringes techniques to transfer solutions. All the reactions were monitored by
9

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thin layer chromatography (TLC) on TLC silica gel on F254 aluminium plates using a mixture
of chloroform and methanol as eluent while UV lamp was used to visualize the spots. Melting
points were determined in open capillaries in an electrical melting point apparatus and are
uncorrected. IR spectra were recorded on ABB MB 3000 DTGS IR instrument using the KBr
pellet technique. 1H NMR spectra were recorded on 400 MHz, while 13C NMR spectra were
registered at 100 MHz, using deuterated dimethyl sulfoxide (DMSO-d6) as solvent, and
tetramethylsilane (TMS) as internal standard at room temperature. Chemical shifts are
reported as δ values in parts per million (ppm) downfield from TMS. High resolution mass
spectra were obtained from a MicroMass ESI-TOF MS spectrometer. Multiplicities are
described as singlet (s), doublet (d), doublet of doublet (dd), doublet of triplet (dt), triplet (t),
quartet (q), multiplet (m), exchangeable proton (ex) for NMR assignments and strong (s),
medium (m), broad (br) for IR assignments. The coupling constants are expressed in hertz
(Hz).
4.1.2. Synthesis of ethyl 1-[4-(aminosulfonyl)phenyl]-5-aryl-1H-1,2,3-triazole-4-carboxylates
(4a-4f)
General procedure: To a solution of appropriate β-diketoester 11a-11f (16.00 mmol) in
DMSO (5 mL) was added piperidine (5 mol%). After 5 min. of stirring at 70o C in silicon oil
bath, 4-azidobenzenesulfonamide (15.01 mmol) was added and the mixture was stirred at 70o
C for an additional 4-6 hrs and the progress of reaction was monitored by TLC. After the
reaction was completed, the reaction mixture was poured into the ice water and the
precipitates formed were filtered, washed with water and recrystallized from ethanol.
4.1.2.1. Ethyl 1-[4-(aminosulfonyl)phenyl]-5-(p-tolyl)-1H-1,2,3-triazole-4-carboxylate (4a)
Yield 80%; mp: 209oC; IR(KBr) (ν, cm-1): 3317, 3225 (m, N-H stretch), 1713 (s, C=O
1
stretch), 1335, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.94-7.93 (m,
2H, Ar), 7.62-7.57 (m, 4H, Ar, SO2NH2), 7.30-7.23 (m, 4H, Ar), 4.23 (q, J = 5.6 Hz, 2H,
CH2), 2.33 (s, 3H, CH3), 1.17 (t, J = 5.6 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
(ppm): 160.71, 145.50, 141.75, 140.15, 138.33, 136.89, 130.74, 129.31, 127.33, 126.95,
122.78, 61.02, 21.40, 14.38; HRMS (ESI-MS) m/z 387.1121 (M+H)+, C18H18N4O4SH+, calcd
387.1127.
4.1.2.2.
Ethyl
1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-
carboxylate (4b)
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Yield 75%; mp: 199oC; IR(KBr) (ν, cm-1): 3333, 3178 (m, N-H stretch), 1728 (s, C=O
1
stretch), 1335, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.91 (d, J =
8.8 Hz, 2H, Ar), 7.60 (d, J = 8.8 Hz, 2H, Ar), 7.55 (s, 2H, SO2NH2), 7.50-7.47 (m, 2H, Ar),
13
7.29 (t, J = 8.8 Hz, 2H, Ar), 4.24 (q, J = 7.2 Hz, 2H, CH2), 1.18 (t, J = 7.2Hz, 3H, CH3); C
1
NMR (100 MHz, DMSO-d6) δ (ppm): 162.88 (d, JCF = 246 Hz), 160.14, 145.09, 140.42,
3
4
137.65, 136.66, 132.95 (d, JCF = 9 Hz), 126.89, 126.49, 121.85 (d, JCF = 3 Hz), 115.43 (d,
2JCF = 22 Hz), 56.04, 13.87; HRMS (ESI-MS) m/z 391.0889 (M+H)+, C17H15FN4O4SH+,
calcd 391.0876.
4.1.2.3.
Ethyl
1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-1,2,3-triazole-4-
carboxylate (4c)
Yield 76%; mp: 208oC; IR(KBr) (ν, cm-1): 3263, 3186 (m, N-H stretch), 1713 (s, C=O
1
stretch), 1335, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (d, J =
8.4 Hz, 2H, Ar), 7.60 (d, J = 8.4 Hz, 2H, Ar), 7.53-7.51 (m, 4H, Ar, SO2NH2), 7.45 (d, J =
8.4 Hz, 2H, Ar), 4.24 (q, J = 7.2 Hz, 2H, CH2), 1.17 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100
MHz, DMSO-d6) δ (ppm): 160.54, 145.61, 140.65, 138.02, 137.16, 135.40, 132.79, 128.85,
127.38, 126.95, 124.88, 61.13, 14.34; HRMS (ESI-MS) m/z 407.0580 (M+H)+, 409.0555
(M+H+2)+, C17H15ClN4O4SH+, calcd 407.0581.
4.1.2.4.
Ethyl
1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-1,2,3-triazole-4-
carboxylate (4d)
Yield 81%; ; mp: 227oC; IR(KBr) (ν, cm-1): 3371, 3271 (m, N-H stretch), 2982 (m, -
CH3stretch), 1713 (s, C=O stretch), 1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-
d6) δ (ppm): 7.92 (d, J = 8.4 Hz. 2H, Ar), 7.65 (d, J = 8.4 Hz, 2H, Ar), 7.61 (d, J = 8.4 Hz,
2H, Ar), 7.55 (s, 2H, SO2NH2), 7.38 (d, J = 8.4 Hz, 2H, Ar), 4.24 (q, J = 7.2 Hz, 2H, CH2),
1.17 (t, J = 7.2Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 160.09, 145.15,
140.26, 137.56, 136.66, 132.53, 131.32, 126.94, 126.51, 124.79, 123.76, 60.68, 13.89;
HRMS (ESI-MS) m/z 451.0075 (M+H)+, 453.0057 (M+H+2)+, C17H15BrN4O4SH+, calcd
451.0075.
4.1.2.5. Ethyl 1-[4-(aminosulfonyl)phenyl]-5-(pyridin-2-yl)-1H-1,2,3-triazole-4-carboxylate
(4e)
Yield 70%; mp: 221oC; IR(KBr) (ν, cm-1): 3248, 3202 (m, N-H stretch), 1736 (s, C=O
1
stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.55 (dd, J =
4.0 Hz, J = 0.8 Hz, 1H, py), 7.97 (dt, J = 8.0 Hz, J = 1.6 Hz, 1H, py), 7.88 (d, J = 8.8 Hz, 2H,
11

ACCEPTED MANUSCRIPT
Ar), 7.85 (d, J = 6.8 Hz, 1H, py), 7.58 (d, J = 8.8 Hz, 2H, Ar), 7.56 (s, 2H, SO2NH2), 7.49 (m,
1H, py), 4.24 (q, J = 7.2 Hz, 2H, CH2), 1.14 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 159.97, 149.51, 145.19, 144.96, 140.02, 138.00, 137.12, 136.82, 127.24,
126.89, 125.83, 124.83, 56.05, 13.82; HRMS (ESI-MS) m/z 374.0931 (M+H)+,
C16H15N5O4SH+, calcd 374.0923.
4.1.2.6. Ethyl 1-[4-(aminosulfonyl)phenyl]-5-(thiophen-2-yl)-1H-1,2,3-triazole-4-carboxylate
(4f)
Yield 75%; mp: 232oC; IR(KBr) (ν, cm-1): 3362, 3194 (m, N-H stretch), 1728 (s, C=O
1
stretch), 1335, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.97 (dd, J =
6.8 Hz, J = 1.6 Hz, 2H, Ar), 7.83 (dd, J = 4.8 Hz, J = 1.2, 1H, th), 7.70 (dd, J = 6.8 Hz, J =
1.6 Hz, 2H, Ar), 7.59 (s, 2H, SO2NH2), 7.36 (dd, J = 3.6 Hz, J = 1.2 Hz, 1H, th), 7.14 (dd, J =
4.8 Hz, J = 3.6 Hz, 1H, th), 4.29 (q, J = 7.2 Hz, 2H, CH2), 1.23 (t, J = 7.2 Hz, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6) δ (ppm): 160.55, 146.00, 138.19, 137.24, 135.83, 133.23,
131.56, 127.81, 127.38, 127.35, 124.12, 61.30, 14.40; HRMS (ESI-MS) m/z 379.0527
(M+H)+, C15H14N4O4S2H+, calcd 379.0534.
4.1.3. Synthesis of 1-[4-(aminosulfonyl)phenyl]-5-aryl-1H-1,2,3-triazole-4-carboxylic acids
(5a-5f)
General procedure: An aqueous solution of NaOH (10%, 10 mL) was added into the
appropriate 1,2,3-triazolic ester 4a-4f (1.00 mmol). The mixture was refluxed for 4-5 hrs.
Then cooled the solution and the mixture was neutralized with concd HCl in ice bath. The
crude white solid was precipitated out which was filtered off, washed with water, dried and
recrystallized with appropriate solvent.
4.1.3.1. 1-[4-(Aminosulfonyl)phenyl]-5-(p-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (5a)
Yield 84%; mp: 177oC; IR(KBr) (ν, cm-1): 3348, 3225 (m, N-H stretch), 2615 (br, O-H
stretch), 1713 (s, C=O stretch), 1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ
(ppm): 13.20 (s, br, 1H, COOH), 7.90 (d, J = 7.2 Hz, 2H, Ar), 7.59 (d, J = 7.6 Hz, 2H, Ar),
7.55 (s, 2H, SO2NH2), 7.27 (d, J = 7.6 Hz, 2H, Ar), 7.22 (d, J = 7.2 Hz, 2H, Ar), 2.32 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 162.19, 145.38, 141.46, 139.97, 138.44,
137.62, 130.73, 129.32, 127.28, 126.93, 123.09, 21.38; HRMS (ESI-MS) m/z 359.0822
(M+H)+, C16H14N4O4SH+, calcd 359.0814.
12

ACCEPTED MANUSCRIPT
4.1.3.2. 1-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid
(5b)
Yield 80%; mp: 187oC; IR(KBr) (ν, cm-1): 3333, 3256 (m, N-H stretch), 2523 (br, O-H
stretch), 1706 (s, C=O stretch), 1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ
(ppm): 13.18 (s, br, 1H, -COOH), 7.90 (dd, J = 6.8 Hz, J = 1.6 Hz, 2H, Ar), 7.58 (dd, J = 6.8
Hz, J = 1.6 Hz, 2H, Ar), 7.54 (s, 2H, SO2NH2), 7.50–7.45 (m, 2H, Ar,), 7.30-7.25 (m, 2H,
1
Ar); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 164.48 (d, JCF = 226 Hz), 162.09,145.56,
3
4
140.58, 138.23, 137.82, 133.24 (d, JCF = 8.7 Hz), 127.31, 122.25, (d, JCF = 3.2 Hz), 115.88
2
(d, JCF = 21.8 Hz); HRMS (ESI-MS) m/z 363.0560 (M+H)+, C15H11FN4O4SH+, calcd
363.0563.
4.1.3.3. 1-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid
(5c)
Yield 88%; mp: 177oC; IR(KBr) (ν, cm-1): 3340, 3232 (m, N-H stretch), 2650 (br, O-H
stretch), 1735 (s, C=O stretch), 1335, 1080 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ
(ppm): 13.25 (s, 1H, OH), 7.93 (d, J = 8.6 Hz, 2H, Ar), 7.61 (d, J = 8.6 Hz, 2H, Ar), 7.55 (s,
2H, SO2NH2), 7.51 (d, J = 8.4 Hz, 2H, Ar), 7.45 (d, J = 8.4 Hz, 2H, Ar); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 162.06, 145.52, 140.39, 138.17, 137.91, 135.29, 132.81, 128.86, 127.38,
126.95, 125.18; HRMS (ESI-MS) m/z 379.0267 (M+H)+, 381.0236 (M+H+2)+,
C15H11ClN4O4SH+, calcd 379.0268.
4.1.3.4. 1-[4-(Aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylic acid
(5d)
Yield 79%; mp: 180oC; IR(KBr) (ν, cm-1): 3333, 3265 (m, N-H stretch), 2607 (br, O-H
stretch), 1744 (s, C=O stretch), 1335, 1111 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ
(ppm): 13.25 (s, br, 1H, COOH), 7.92 (d, J = 8.8 Hz, 2H, Ar), 7.64 (d, J = 8.4 Hz, 2H, Ar),
13
7.60 (d, J = 8.4 Hz, 2H, Ar), 7.54 (s, 2H, SO2NH2), 7.37 (d, J = 8.8 Hz, 2H, Ar); C NMR
(100 MHz, DMSO-d6) δ (ppm): 161.62, 145.06, 139.97, 137.70, 137.43, 132.56, 131.32,
126.93, 126.51, 125.11, 123.64; HRMS (ESI-MS) m/z 422.9757 (M+H)+, 424.9737
(M+H+2)+, C15H11BrN4O4SH+, calcd 422.9762.
4.1.3.5. 1-[4-(Aminosulfonyl)phenyl]-5-(pyridin-2-yl)-1H-1,2,3-triazole-4-carboxylic acid
(5e)
13

ACCEPTED MANUSCRIPT
Yield 94%; mp: 190oC; IR(KBr) (ν, cm-1): 3364, 3209 (m, N-H stretch), 2609 (br, O-H
stretch), 1705 (s, C=O stretch), 1335, 1157 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ
(ppm): 13.36 (s, br, 1H, COOH), 8.55-8.54 (m, 1H, py), 7.98-7.93 (m, 4H, py, Ar), 7.58-7.46
(m, 5H, py, Ar, SO2NH2); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 161.91, 149.87, 145.89,
145.31, 140.22, 138.60, 138.31, 137.26, 127.71, 127.30, 126.25, 125.16; HRMS (ESI-MS)
m/z 346.0611 (M+H)+, C14H11N5O4SH+, calcd 346.0610.
4.1.3.6. 1-[4-(Aminosulfonyl)phenyl]-5-(thiophen-2-yl)-1H-1,2,3-triazole-4-carboxylic acid
(5f)
Yield 89%; mp: 183oC; IR(KBr) (ν, cm-1): 3356, 3240 (m, N-H stretch), 2507 (br, O-H
stretch), 1713 (s, C=O stretch), 1358, 1173 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ
(ppm): 13.31 (s, br, 1H, COOH), 7.95 (d, J = 8.4 Hz, 2H, Ar), 7.80 (d, J = 4.4 Hz, 1H, th),
7.68 (d, 2H, J = 8.4 Hz, Ar), 7.58 (s, 2H, SO2NH2), 7.34 (d, J = 2.8 Hz, 1H, th), 7.14-7.12 (m,
1H, th); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 162.04, 145.90, 138.31, 137.98, 135.48,
133.04, 131.37, 127.80, 127.34, 127.33, 124.47; HRMS (ESI-MS) m/z 351.0222 (M+H)+,
C13H10N4O4S2H+, calcd 351.0221.
4.1.4. Synthesis of 4-(4-(hydroxymethyl)-5-aryl-1H-1,2,3-triazol-1-yl) benzenesulfonamides
(6a-6f)
General procedure: A solution of 1,2,3-triazolic ester 4a-4f (1.5 mmol) in dry tetrahydrofuran
(30 ml) cooled to 10-15o C was added drop-wise to a cold suspension of LiAlH4 (3.0 mmol)
in dry tetrahydrofuran (5 mL) with stirring under anhydrous condition. After 20 minutes of
stirring, the reaction mixture was refluxed for 2 hrs. After completion of reaction, the reaction
mixture was neutralized with aqueous solution of 1N HCl and extracted with ethyl acetate,
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was
recrystallized with ethanol.
4.1.4.1. 4-(4-(hydroxymethyl)-5-(p-tolyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (6a)
Yield 65%; mp: 223oC; IR(KBr) (ν, cm-1): 3371 (br, O-H stretch), 3232, 3163 (m, N-H
1
stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.91 (dd, J =
6.8 Hz, J = 1.6 Hz, 2H, Ar), 7.57-7.52 (m, 4H, Ar, SO2NH2), 7.29-7.22 (m, 4H, Ar), 5.36 (t, J
13
= 5.6 Hz, 1H, OH), 4.50 (d, J = 5.2 Hz, 2H, CH2), 2.33 (s, 3H, CH3); C NMR (100 MHz,
CDCl3) δ (ppm): 145.79, 144.92, 139.59, 139.12, 136.10, 129.97, 127.45, 126.16, 123.56,
54.37, 21.31; HRMS (ESI-MS) m/z 345.1023 (M+H)+, C16H16N4O3SH+, calcd 345.1021.
14

ACCEPTED MANUSCRIPT
4.1.4.2. 4-(4-(hydroxymethyl)-5-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl) benzenesulfonamide
(6b)
Yield 58%; mp: 215oC; IR(KBr) (ν, cm-1): 3350 (br, O-H stretch), 3310, 3225 (m, N-H
1
stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.94 (d, J =
8.4 Hz, 2H, Ar), 7.57 (d, J = 8.4 Hz, 2H, Ar), 7.53 (s, 2H, SO2NH2), 7.43 (dd, J = 8.4 Hz, J =
5.6 Hz, 2H, Ar), 7.34-7.30 (m, 2H, Ar), 5.64-5.17 (br, 1H, OH), 4.52 (s, 2H, CH2), 13C NMR
1
(100 MHz, DMSO-d6) δ (ppm): 163.25 (d, JCF = 246 Hz), 146.04, 145.01, 138.91, 135.16,
3
4
2
132.58 (d, JCF = 8.7 Hz), 127.49, 126.19, 123.02 (d, JCF = 3.2 Hz), 116.52 (d, JCF = 21.8
Hz), 54.38; HRMS (ESI-MS) m/z 349.0770 (M+H)+, C15H13FN4O3SH+, calcd 349.0770.
4.1.4.3. 4-(4-(hydroxymethyl)-5-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide
(6c)
Yield 62%; mp: 130oC; IR(KBr) (ν, cm-1): 3394 (br, O-H stretch), 3371, 3232 (m, N-H
1
stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.93 (d, J =
8.8 Hz, 2H, Ar), 7.62-7.50 (m, 6H, Ar, SO2NH2) 7.40 (d, J = 8.8 Hz, 2H, Ar), 5.40 (t, J = 5.2
Hz, 1H, OH), 4.54 (d, J = 5.2 Hz, 2H, CH2), 13C NMR (100 MHz, CDCl3) δ (ppm): 146.51,
145.10, 138.90, 134.94, 134.90, 131.97, 129.49, 127.51, 126.62, 125.51, 54.40; HRMS (ESI-
MS) m/z 365.0473 (M+H)+, 367.0445 (M+H+2)+, C15H13ClN4O3SH+, calcd 365.0475.
4.1.4.4. 4-(4-(hydroxymethyl)-5-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide
(6d)
Yield 60%; ; mp: 120oC; IR(KBr) (ν, cm-1): 3375 (br, O-H stretch), 3364, 3225 (m, N-H
1
stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.93 (dd, J =
6.8 Hz, J = 2 Hz, 2H, Ar), 7.69 (dd, J = 6.4 Hz, J = 2 Hz, 2H, Ar), 7.58 (dd, J = 6.8 Hz, J = 2
Hz, 2H, Ar), 7.54 (s, 2H, SO2NH2), 7.32 (dd, J = 6.4 Hz, J = 2 Hz, 2H, Ar), 5.42 (t, J = 5.6
Hz, 1H, OH), 4.53 (d, J = 5.2Hz, 2H, CH2), 13C NMR (100 MHz, DMSO-d6) δ (ppm):
146.10, 145.06, 138.82, 134.99, 132.41, 132.18, 127.55, 126.23, 125.86, 123.66, 54.38;
HRMS (ESI-MS) m/z 408.9988 (M+H)+, 410.9949 (M+H+2)+, C15H13BrN4O3SH+, calcd
408.9970.
4.1.4.5.
4-(4-(hydroxymethyl)-5-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide
(6e)
Yield 57%; mp: 220oC; IR(KBr) (ν, cm-1): 3464 (br, O-H stretch), 3325, 3171 (m, N-H
1
stretch), 1327, 1149 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.56 (d, J =
15

ACCEPTED MANUSCRIPT
4.4 Hz, 1H, py), 7.99 (dt, J = 7.6 Hz, J = 1.6 Hz, 1H, py), 7.91 (d, J = 8.8 Hz, 2H, Ar), 7.77
(d, J = 8.4 Hz, 1H, py), 7.55 (d, J = 8.8 Hz, 2H, Ar), 7.53 (s, 2H, SO2NH2), 7.47-7.44 (m, 1H,
py), 5.43 (t, J = 5.6 Hz, 1H, OH), 4.64 (d, J = 5.2Hz, 2H, CH2), 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 150.32, 146.88, 146.32, 144.81, 139.61, 137.92, 135.07, 127.28, 125.91,
125.76, 124.58, 54.59; HRMS (ESI-MS) m/z 332.0821 (M+H)+, C14H13N5O3SH+, calcd
332.0817.
4.1.4.6. 4-(4-(hydroxymethyl)-5-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide
(6f)
Yield 58%; mp: 222oC; IR(KBr) (ν, cm-1): 3464 (br, O-H stretch), 3240, 3171 (m, N-H
1
stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.97 (dd, J =
6.8 Hz, J = 2 Hz, 2H, Ar), 7.75 (dd, J = 5.2 Hz, J = 1.6 Hz, 1H, th), 7.67 (dd, J = 6.8 Hz, J = 2
Hz, 2H, Ar), 7.58 (s, 2H, SO2NH2), 7.33 (dd, J = 3.6 Hz, J = 1.2 Hz, 1H, th), 7.19 (dd, J = 5.2
Hz, J = 3.6 Hz, 1H, th), 5.44 (t, J = 5.2 Hz, 1H, OH), 4.59 (d, J = 5.2 Hz, 2H, CH2), NMR
(100 MHz, DMSO-d6) δ (ppm): 146.08, 145.67, 138.75, 131.09, 130.72, 130.57, 128.37,
127.50, 127.02, 125.82, 54.53; HRMS (ESI-MS) m/z 337.0426 (M+H)+, C13H12N4O3S2H+,
calcd 337.0429.
4.1.5.
Synthesis
of
4-[4-(hydrazinocarbonyl)-5-aryl-1H-1,2,3-triazol-1-
yl]benzenesulfonamides (7a-7f)
General procedure: The mixture of a suitable 1,2,3-triazolic ester 4a-4f (1.0 mmol) and
hydrazine hydrate (1.5 mmol) was dissolved in ethanol (12 mL). The reaction mixture was
refluxed for 10-12 hrs. Reaction was followed by thin layer chromatography (TLC). After the
completion of reaction, some of the solvent was removed under vacuum and allowed to cool
at room temperature. The obtained solid was filtered, dried at room temperature and
recrystallized from EtOH:THF (1:1) to afford the desired compound in good yield.
4.1.5.1. 4-[4-(hydrazinocarbonyl)-5-(p-tolyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide (7a)
Yield 80%; mp: 187oC; IR(KBr) (ν, cm-1): 3742, 3394, 3302, 3194 (m, N-H stretch), 1674 (s,
1
C=O stretch), 1335, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s,
ex, 1H, NH), 7.90 (d, J = 8.8 Hz, 2H, Ar), 7.58 (d, J = 8.8 Hz, 2H, Ar), 7.55 (s, 2H, SO2NH2),
7.25 (d, J =8 Hz, 2H, Ar), 7.20 (d, J = 8 Hz, 2H, Ar), 4.49 (s, br, ex, 2H, NH2), 2.32 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 159.77, 145.32, 139.80, 139.14, 138.72,
138.54, 130.79, 129.27, 127.35, 126.83, 122.92, 21.37.
16

ACCEPTED MANUSCRIPT
4.1.5.2.
4-[4-(hydrazinocarbonyl)-5-(4-fluorophenyl-1H-1,2,3-triazol-1-
yl]benzenesulfonamide (7b)
Yield 74%; ; mp: 215oC; IR(KBr) (ν, cm-1): 3749, 3410, 3317, 3186 (m, N-H stretch), 1674
1
(s, C=O stretch), 1327, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.92
(s, ex, 1H, NH), 7.91 (d, J = 6.0 Hz, 2H, Ar), 7.60-7.26 (m, 8H, SO2NH2, Ar), 4.50 (s, ex,
13
1
2H, NH2); C NMR (100 MHz, DMSO-d6) δ (ppm): 162.70 (d, JCF = 246 Hz), 159.11,
3
4
144.92, 138.73, 137.87, 137.48, 132.97 (d, JCF = 8 Hz), 126.90, 126.38, 121.96 (d, JCF = 4
2
Hz), 115.30 (d, JCF = 21 Hz); HRMS (ESI-MS) m/z 377.0829 (M+H)+, C15H13FN6O3SH+,
calcd 377.0832.
4.1.5.3.
4-[4-(hydrazinocarbonyl)-5-(4-chlorophenyl)-1H-1,2,3-triazol-1-
yl]benzenesulfonamide (7c)
Yield 81%; mp: 195oC; IR(KBr) (ν, cm-1): 3743, 3394, 3263, 3194 (m, N-H stretch), 1674 (s,
1
C=O stretch), 1335, 1173 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.92 (s,
ex, 1H, NH), 7.91 (d, J = 8.6 Hz, 2H, Ar), 7.59 (d, J = 8.6 Hz, 2H, Ar), 7.54 (s, 2H,
SO2NH2), 7.49 (d, J = 8.4 Hz, 2H, Ar), 7.40 (d, J = 8.4 Hz, 2H, Ar), 4.50 (s, ex, 2H, NH2);
13C NMR (100 MHz, DMSO-d6) δ (ppm): 159.47, 145.45, 139.29, 138.25, 137.74, 135.07,
132.87, 128.75, 127.40, 126.86, 124.99; HRMS (ESI-MS) m/z 393.0540 (M+H)+, 395.0512
(M+H+2)+, C15H13ClN6O3SH+, calcd 393.0536.
4.1.5.4.
4-[4-(hydrazinocarbonyl)-5-(4-bromophenyl)-1H-1,2,3-triazol-1-
yl]benzenesulfonamide (7d)
Yield 77%; mp: 215oC; IR(KBr) (ν, cm-1): 3734, 3456, 3348, 3271, 3225 (m, N-H stretch),
1682 (s, C=O stretch), 1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm):
9.93 (s, ex, 1H, NH), 7.91 (d, J = 8.8 Hz, 2H, Ar), 7.62-7.58 (m, 4H, Ar), 7.54 (s, 2H,
SO2NH2), 7.33 (d, J = 8.8 Hz, 2H, Ar), 4.49 (s, ex, 2H, NH2); 13C NMR (100 MHz, DMSO-
d6) δ (ppm): 159.03, 145.00, 138.81, 137.80, 137.35, 132.63, 131.23, 126.98, 126.43, 124.92,
123.44; HRMS (ESI-MS) m/z 437.0029 (M+H)+, 439.0005 (M+H+2)+, C15H13BrN6O3SH+,
calcd 437.0031.
4.1.5.5. 4-[4-(hydrazinocarbonyl)-5-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide
(7e)
Yield 68%; mp: 216oC; IR(KBr) (ν, cm-1): 3730, 3248, 3124 (m, N-H stretch), 1682 (s, C=O
1
stretch), 1350, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 10.01 (s, ex,
17

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1H, NH), 8.49 (d, J = 4 Hz, 1H, py), 7.97-7.85 (m, 4H, py, Ar), 7.57-7.54 (m, 4H, Ar,
SO2NH2), 7.47-7.44 (m, 1H, py), 4.54 (s, br, ex, 2H, NH2); 13C NMR (100 MHz, DMSO-d6)
δ (ppm): 159.39, 149.83, 145.76, 145.16, 139.90, 138.92, 137.67, 137.15, 127.73, 127.26,
126.23, 124.96; HRMS (ESI-MS) m/z 360.0873 (M+H)+, C14H13N7O3SH+, calcd 360.0879.
4.1.5.6.
4-[4-(hydrazinocarbonyl)-5-(thiophen-2-yl)-1H-1,2,3-triazol-1-
yl]benzenesulfonamide (7f)
Yield 74%; mp: 207oC; IR(KBr) (ν, cm-1): 3723, 3456, 3310, 3209 (m, N-H stretch), 1651 (s,
1
C=O stretch), 1391, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.93 (s,
ex, 1H, NH), 7.96 (d, J = 8.4 Hz, 2H, Ar), 7.78 (d, J = 5.2 Hz, 1H, th), 7.69 (d, J = 8.4 Hz,
2H, Ar), 7.60 (s, 2H, SO2NH2), 7.38 (d, J = 3.2 Hz, 1H, th), 7.11 (t, J = 5.2 Hz, 1H, th), 4.55
(s, br, ex, 2H, NH2); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 159.11, 145.50, 138.87,
137.95, 132.48, 132.23, 130.64, 127.27, 126.99, 124.26, 56.04 HRMS (ESI-MS) m/z
365.0491 (M+H)+, C13H12N6O3S2H+, calcd 365.0490.
4.1.6. Synthesis of 1-[4-(Aminosulfonyl)phenyl]-5-aryl-1H-1,2,3-triazole-4-carboxamides
(8a-8f)
General procedure: A mixture of aqueous ammonia solution (5-6 ml) and appropriate 1,2,3-
triazolic ester 4a-4f (1.00 mmol) was stirred at room temperature in a bunged flask for 24-26
hrs. The solid white coloured compound was precipitated out which was filtered off, washed
with cold water, dried and recrystallized from ethanol.
4.1.6.1. 1-[4-(Aminosulfonyl)phenyl]-5-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide (8a)
Yield 75%; mp: 277oC; IR(KBr) (ν, cm-1): 3472, 3371, 3333, 3209 (m, N-H stretch), 1675 (s,
1
C=O stretch), 1342, 1173 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.00 (s,
ex, 1H, NH/OH), 7.91 (d, J = 8 Hz, 2H, Ar), 7.59-7.54 (m, 5H, SO2NH2, NH/OH, Ar), 7.26
(d, J =8 Hz, 2H, Ar), 7.20 (d, J =8 Hz, 2H, Ar), 3.39 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 162.10, 145.32, 139.70, 139.60, 139.38, 138.58, 130.88, 129.20, 127.30,
126.93, 123.33, 21.38; HRMS (ESI-MS) m/z 358.0979 (M+H)+, C16H15N5O3SH+, calcd
358.0974.
4.1.6.2. 1-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-carboxamide
(8b)
18

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Yield 74%; mp: 230oC; IR(KBr) (ν, cm-1): 3391, 3209 (m, N-H stretch), 1675 (s, C=O
1
stretch), 1342, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.05 (s, ex,
1H, NH/OH), 7.91 (d, J = 8 Hz, 2H, Ar), 7.59-7.56 (m, 3H, Ar, NH/OH), 7.44-7.41 (m, 2H,
13
Ar), 7.32 (s, 2H, SO2NH2), 7.25 (m, 2H, Ar); C NMR (100 MHz, DMSO-d6) δ (ppm):
1
3
162.65 (d, JCF = 246 Hz), 161.51, 144.92, 139.25, 138.06, 37.89, 133.04 (d, JCF = 8 Hz),
4
2
126.84, 126.47, 122.14 (d, JCF = 3 Hz), 115.23 (d, JCF = 22 Hz); HRMS (ESI-MS) m/z
362.0715 (M+H)+, C15H12FN5O3SH+, calcd 362.0723.
4.1.6.3. 1-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-1,2,3-triazole-4-carboxamide
(8c)
Yield 74%; mp: 255oC; IR(KBr) (ν, cm-1): 3394, 3333, 3279, 3225 (m, N-H stretch), 1673 (s,
1
C=O stretch), 1342, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.06 (s,
ex, 1H, OH/NH), 7.92 (d, J = 8.6 Hz, 2H, Ar), 7.59 (d, J = 8.6 Hz, 2H, NH/OH, Ar), 7.53 (s,
2H, SO2NH2), 7.48 (d, J = 8.4 Hz, 2H, Ar), 7.41 (d, J = 8.4 Hz, 2H, Ar); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 161.94, 145.46, 139.83, 138.35, 138.29, 135.01, 132.94, 128.69, 127.37,
126.95, 125.20; HRMS (ESI-MS) m/z 378.0428 (M+H)+, 380.0401 (M+H+2)+,
C15H12ClN5O3SH+, calcd 378.0427.
4.1.6.4. 1-[4-(Aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxamide
(8d)
Yield 79%; mp: 265oC; IR(KBr) (ν, cm-1): 3456, 3394, 3279 (m, N-H stretch), 1672 (s, C=O
1
stretch), 1342, 1173 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.08 (s, ex,
1H, OH/NH), 7.91 (d, J = 8.4 Hz, 2H, Ar), 7.62-7.54 (m, 7H, Ar, SO2NH2, OH/NH), 7.33 (d,
13
J = 8.4 Hz, 2H, Ar); C NMR (100 MHz, DMSO-d6) δ (ppm): 161.49, 145.01, 139.36,
137.96, 137.84, 132.70, 131.17, 126.94, 126.53, 125.13, 123.37; HRMS (ESI-MS) m/z
421.9910 (M+H)+, 423.9889 (M+H+2)+, C15H12BrN5O3SH+, calcd 421.9922.
4.1.6.5. 1-[4-(Aminosulfonyl)phenyl]-5-(pyridin-2-yl)-1H-1,2,3-triazole-4-carboxamide (8e)
Yield 72%; mp: 220oC; IR(KBr) (ν, cm-1): 3456, 3356, 3232 (m, N-H stretch), 1643 (s, C=O
1
stretch), 1335, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.49 (d, J =
1.2 Hz, 1H, py), 8.15 (s, ex, 1H, NH/OH), 7.95-7.85 (m, 4H, py, Ar), 7.65 (s, ex, 1H,
NH/OH), 7.56-7.44 (m, 5H, py, Ar, SO2NH2); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
161.84, 149.63, 145.94, 145.16, 140.43, 138.91, 138.28, 137.07, 127.97, 127.24, 126.27,
124.93; HRMS (ESI-MS) m/z 345.0765 (M+H)+, C14H12N6O3SH+, calcd 345.0770.
19

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4.1.6.6. 1-[4-(Aminosulfonyl)phenyl]-5-(thiophen-2-yl)-1H-1,2,3-triazole-4-carboxamide (8f)
Yield 70%; mp: 150oC; IR(KBr) (ν, cm-1): 3456, 3394, 3302, 3225 (m, N-H stretch), 1659 (s,
1
C=O stretch), 1350, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 8.08 (s,
ex, 1H, NH/OH), 7.96 (d, J = 8.8 Hz, 2H, Ar), 7.76 (d, J =4.8 Hz, 1H, th), 7.68 (d, J = 8.8 Hz,
2H, Ar), 7.64 (s, ex, 1H, NH/OH), 7.59 (s, 2H, SO2NH2), 7.36 (d, J =2.8 Hz, 1H, th), 7.10
(dd, J =4.8 Hz, J = 4.0 Hz, 1H, th); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 161.52, 145.48,
139.33, 138.04, 133.07, 132.40, 130.62, 127.16, 127.04, 126.93, 124.41; HRMS (ESI-MS)
m/z 350.0381 (M+H)+, C13H11N5O3S2H+, calcd 350.0381.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content
and writing of this article.
Acknowledgement
The authors, Lalit Vats and Rajiv Kumar, are thankful to University Grants Commission,
New Delhi, India for the award of Junior Research Fellowship and for Senior Research
Fellowship respectively, and the other, Vikas Sharma, to the Council of Scientific and
Industrial Research, New Delhi, India for the award of Junior Research Fellowship.
20

ACCEPTED MANUSCRIPT
References
[1] B. Żołnowska, J. Sławiński, K. Szafrański, A. Angeli, C.T. Supuran, A. Kawiak, S.
Bartoszewska, Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1, 3, 5-
triazin-2-ylamino) guanidine derivatives: Inhibition of human carbonic anhydrase
cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and
XII, anticancer activity, and molecular modeling studies, Eur. J. Med. Chem. 143 (2018)
1931-1941.
[ 2 ] C. Capasso, C.T. Supuran, An overview of the alpha-, beta-and gamma-carbonic
anhydrases from Bacteria: can bacterial carbonic anhydrases shed new light on evolution
of bacteria?, J. Enzyme Inhib. Med. Chem. 30 (2015) 325-332.
[ 3 ] C.T. Supuran, C. Capasso, The η-class carbonic anhydrases as drug targets for
antimalarial agents, Expert Opin. Ther. Targets 19 (2015) 551-563.
[4] E. Licsandru, M. Tanc, I. Kocsis, M. Barboiu, C.T. Supuran, A class of carbonic
anhydrase I–selective activators, J. Enzyme Inhib. Med. Chem. 32 (2017) 37-46.
[5] M. Falsini, L. Squarcialupi, D. Catarzi, F. Varano, M. Betti, L. Di Cesare Mannelli, C.T.
Supuran, 3-Hydroxy-1 H-quinazoline-2, 4-dione as a New Scaffold To Develop Potent
and Selective Inhibitors of the Tumor-Associated Carbonic Anhydrases IX and XII, J.
Med. Chem. 60 (2017) 6428-6439.
[6] L. De Luca, F. Mancuso, S. Ferro, M.R. Buemi, A. Angeli, S. Del Prete, C. Capasso, C.T.
Supuran, R. Gitto, Inhibitory effects and structural insights for a novel series of
coumarin-based compounds that selectively target human CA IX and CA XII carbonic
anhydrases, Eur. J. Med. Chem. 143 (2018) 276-282.
[7] J. Slawinski, Z. Brzozowski, B. Zolnowska, K. Szafranski, A. Pogorzelska, D. Vullo, C.T.
Supuran, Synthesis of a new series of N 4-substituted 4-(2-aminoethyl)
benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic
isozymes I and II and transmembrane tumor-associated isozymes IX and XII, Eur. J.
Med. Chem. 84 (2014) 59-67.
[8] R. Perfetto, S. Del Prete, D. Vullo, G. Sansone, C. Barone, M. Rossi, C.T. Supuran, C.
Capasso, Biochemical characterization of the native α-carbonic anhydrase purified from
the mantle of the Mediterranean mussel, Mytilus galloprovincialis, J. Enzyme Inhib.
Med. Chem. 32 (2017) 632–639.
21

ACCEPTED MANUSCRIPT
[9] C.T. Supuran, Carbonic anhydrases: from biomedical applications of the inhibitors and
activators to biotechnological use for CO2 capture, J. Enzyme Inhib. Med. Chem. 28
(2013) 229-230.
[10] W.M. Eldehna, M.F. Abo-Ashour, A. Nocentini, P. Gratteri, I.H. Eissa, M. Fares, O.E.
Ismael, H.A. Ghabbour, M.M. Elaasser, H.A. Abdel-Aziz, C.T. Supuran, Novel 4/3-((4-
oxo-5-(2-oxoindolin-3-ylidene) thiazolidin-2-ylidene) amino) benzenesulfonamides:
Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular
modelling studies, Eur. J. Med. Chem. 139 (2017) 250-262.
[11] B.B. Gao, A. lermont, S. Rook, S.J. Fonda, V.J. Srinivasan, M. Wojtkowski, J.G.
Fujimoto, R.L. Avery, P.G. Arrigg, S.E. Bursell, L.P. Aiello, E.P. Feener, Extracellular
carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability
through prekallikrein activation, Nat. Med. 13 (2007) 181-188.
[12 ] C.T. Supuran, Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors,
Metabolites 7 (2017) 48.
[13] N. Hen, M. Bialer, B. Yagen, A. Maresca, M. Aggarwal, A.H. Robbins, R. McKenna, A.
Scozzafava, C.T. Supuran, Anticonvulsant 4-aminobenzenesulfonamide derivatives with
branched-alkylamide moieties: X-ray crystallography and inhibition studies of human
carbonic anhydrase isoforms I, II, VII, and XIV, J. Med. Chem. 54 (2011) 3977-3981.
[14] M.Y. Mboge, B.P. Mahon, N. Lamas, L. Socorro, F. Carta, C.T. Supuran, R. McKenna,
Structure activity study of carbonic anhydrase IX: Selective inhibition with ureido-
substituted benzenesulfonamides, Eur. J. Med. Chem. 132 (2017) 184-191.
[15] C.T. Supuran, Carbonic anhydrases: novel therapeutic applications for inhibitors and
activators, Nat. Rev. Drug Discov. 7 (2008) 168-181.
[16] D. Neri, C.T. Supuran, Interfering with pH regulation in tumours as a therapeutic
strategy, Nat. Rev. Drug Discov. 10 (2011) 767-777.
[17 ] Z. Hou, B. Lin, Y. Bao, H. Yan, M. Zhang, X. Chang, X. Zhang, Z. Wang, G. Wei, M.
Cheng, Y. Liu, C. Guo, Dual-tail approach to discovery of novel carbonic anhydrase IX
inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the
active site, Eur. J. Med. Chem. 132 (2014) 1-10.
[18] T. Arslan, G. Celik, H. Celik, M. Senturk, N. Yaylı, D. Ekinci, Synthesis and Biological
Evaluation of Novel Bischalcone Derivatives as Carbonic Anhydrase Inhibitors, Archiv.
Der. Pharmazie 349 (2016) 741-748.
22

ACCEPTED MANUSCRIPT
[19] A. Maresca, C. Temperini, H. Vu, N.B. Pham, S.A. Poulsen, A. Scozzafava, R.J. Quinn,
C.T. Supuran, Non-Zinc Mediated Inhibition of Carbonic Anhydrases: Coumarins Are a
New Class of Suicide Inhibitors, J. Am. Chem. Soc. 131 (2009) 3057-3062.
[20] S. Kumar, M. Ceruso, T. Tuccinardi, C.T. Supuran, P.K. Sharma, Pyrazolylbenzo [d]
imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA
IX and XII, Bioorg. Med. Chem. 24 (2016) 2907-2913.
[21] P. Khloya, M. Ceruso, S. Ram, C.T. Supuran, P.K. Sharma, Sulfonamide bearing
pyrazolylpyrazolines as potent inhibitors of carbonic anhydrase isoforms I, II, IX and
XII, Bioorg. Med. Chem. Lett. 25 (2015) 3208-3212.
[22] P. Khloya, G. Celik, D. Vullo, C.T. Supuran, P.K. Sharma, 4-Functionalized 1, 3-
diarylpyrazoles bearing benzenesulfonamide moiety as selective potent inhibitors of the
tumor associated carbonic anhydrase isoforms IX and XII, Eur. J. Med. Chem. 76 (2014)
284-290.
[23] N. Chandak, M. Ceruso, C.T. Supuran, P.K. Sharma, Novel sulfonamide bearing
coumarin scaffolds as selective inhibitors of tumor associated carbonic anhydrase
isoforms IX and XII, Bioorg. Med. Chem. 24 (2016) 2882-2886.
[24] S. Işık, D. Vullo, S. Durdagi, D. Ekinci, M. Şentürk, A. Çetin, C.T. Supuran, Interaction
of carbonic anhydrase isozymes I, II, and IX with some pyridine and phenol
hydrazinecarbothioamide derivatives, Bioorg. Med. Chem. Lett. 25(2015) 5636-5641.
[25] E.A. Türkoğlu, M. Şentürk, C.T. Supuran, D. Ekinci, Carbonic anhydrase inhibitory
properties of some uracil derivatives, J. Enzyme Inhib. Med. Chem. 32 (2017) 74-77.
[26] S. Ram, G. Celik, P. Khloya, D. Vullo, C.T. Supuran, P.K. Sharma, Benzenesulfonamide
bearing 1, 2, 4-triazole scaffolds as potent inhibitors of tumor associated carbonic
anhydrase isoforms hCA IX and hCA XII, Bioorg. Med. Chem. 22 (2014) 1873-1882.
[27] S. Ram, M. Ceruso, P. Khloya, C.T. Supuran, P.K. Sharma, 4-Functionalized 1,3-
diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of
carbonic anhydrase isoforms hCA I, II, IX and XII, Bioorg. Med. Chem. 22 (2014) 6945-
6952.
[28] R. Kumar, V. Sharma, S. Bua, C.T. Supuran, P.K. Sharma, Synthesis and biological
evaluation
of
benzenesulphonamide-bearing
1,4,5-trisubstituted-1,2,3-triazoles
possessing human carbonic anhydrase I, II, IV, and IX inhibitory activity, J. Enzyme
Inhib. Med. Chem. 32 (2017) 1887-1894.
23

ACCEPTED MANUSCRIPT
[29] R. Kumar, S. Bua, S. Ram, S. Del Prete, C. Capasso, C.T. Supuran, P.K. Sharma,
Benzenesulfonamide bearing imidazothiadiazole and thiazolotriazole scaffolds as potent
tumor associated human carbonic anhydrase IX and XII inhibitors, Bioorg. Med. Chem.
25 (2017) 1286-1293.
[30] A. Nocentini, F. Carta, M. Ceruso, G. Bartolucci, C.T. Supuran, Click-tailed coumarins
with potent and selective inhibitory action against the tumor-associated carbonic
anhydrases IX and XII, Bioorg. Med. Chem. 23 (2015) 6955-6966.
[31] C.T. Supuran, How many carbonic anhydrase inhibition mechanisms exist?, J. Enzyme
Inhib. Med. Chem. 31 (2016) 345-360.
[32] W.M. Eldehna, G.H. Al-Ansary, S. Bua, A. Nocentini, P. Gratteri, A. Altoukhy, H.
Ghabbour, H.Y. Ahmed, C.T. Supuran, Novel indolin-2-one-based sulfonamides as
carbonic anhydrase inhibitors: Synthesis, in vitro biological evaluation against carbonic
anhydrases isoforms I, II, IV and VII and molecular docking studies, Eur. J. Med. Chem.
127 (2017) 521-530.
[33] S. Akocak, N. Lolak, A. Nocentini, G. Karakoc, A. Tufan, C.T. Supuran, Synthesis and
biological evaluation of novel aromatic and heterocyclic bis-sulfonamide Schiff bases as
carbonic anhydrase I, II, VII and IX inhibitors, Bioorg. Med. Chem. 25 (2017) 3093-
3097.
[34] S. Angapelly, P.V. Sri Ramya, A. Angeli, S. Maria Monti, M. Buonanno, M. Alvala, M.
Arifuddin, Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent carbonic
anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA
IV inhibitors, Bioorg. Med. Chem. 25 (2017) 539-544.
[35] L.Y. Ma, L.P. Pang, B. Wang, M. Zhang, B. Hu, D.Q. Xue, K.P. Shao, B.L. Zhang, Y.
Liu, E. Zhang, H.M. Liu, Design and synthesis of novel 1,2,3-triazole-pyrimidine
hybrids as potential anticancer agents, Eur. J. Med. Chem. 86 (2014) 368-380.
[ 36 ] A. Grandane, M. Tanc, R. Zalubovskis, C.T. Supuran, 6-Triazolyl-substituted
sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic
anhydrases IX and XII, Bioorg. Med. Chem. Lett. 24 (2014) 1256-1260.
[37] A.A. Ali, D. Gogoi, A.K. Chaliha, A.K. Buragohain, P. Trivedi, P.J. Saikia, P.S. Gehlot,
A. Kumar, V. Chaturvedi, D. Sarma, Synthesis and biological evaluation of novel
1,2,3-triazole derivatives as anti-tubercular agents, Bioorg. Med. Chem. 27 (2017)
3698-3703.
24

ACCEPTED MANUSCRIPT
[38] P. Kumar, N. Chandak, P. Kaushik, C. Sharma, D. Kaushik, K.R. Aneja, P.K. Sharma,
Synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory–
antibacterial agents, Med. Chem. Res. 21 (2012) 3396-3405.
[39] S. Kumar, W. Namkung, A.S. Verkman, P.K. Sharma, Novel 5-substituted benzyloxy-2-
arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors,
Bioorg. Med. Chem. 20 (2012) 4237-4344.
[40] Y. Morimoto, F. Matsuda, H. Shirahama, Synthetic studies on virantmycin. 1. Total
synthesis of (±)-virantmycin and determination of its relative stereochemistry,
Tetrahedron 52 (1996) 10609-10630.
[41] J.M. Holub, K.O. Colin, A. Getzel, A. Argenti, M.A. Evans, D.C. Smith, G.A. Dalglish,
S. Rifat, D.L. Wilson, B.M. Taylor, U. Miott, J. Glersaye, K.S. Lal, B.J. McCranor, J.D.
Berkowitz, R.B. Miller, J.R. Lukens, K. Krumpe, J.T. Gupton, B.S. Burnham, Lipid-
Lowering Effects of Ethyl 2-Phenacyl-3-aryl-1H-pyrrole- 4-carboxylates in Rodents,
Molecules 9 (2004) 134-157.
[42] T. Rogez-Florent, S. Meignan, C. Foulon, P. Six, A. Gros, C. Bal-Mahieu, P. Depreux,
New selective carbonic anhydrase IX inhibitors: synthesis and pharmacological
evaluation of diarylpyrazole-benzenesulfonamides, Bioorg. Med. Chem. 21 (2013) 1451-
1464.
[43 ] D. Kumar, V. Judge , R. Narang, S. Sangwan, E.De Clercq, J. Balzarini, B. Narasimhan,
Benzylidene/2-chlorobenzylidene hydrazides: Synthesis, antimicrobial activity, QSAR
studies and antiviral evaluation, Eur. J. Med. Chem. 45 (2010) 2806-2816.
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Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing
benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX
inhibitors
Lalit Vats, Vikas Sharma, Andrea Angeli, Rajiv Kumar, Claudiu T. Supuran, Pawan K. Sharma
Research Highlights
•
•
•
•
Synthesis of a library of thirty novel 4-functionalized 1,5-diaryl-1,2,3-triazoles
containing benzenesulfonamide moiety is disclosed.
All of the synthesized compounds were assayed as inhibitors of carbonic anhydrase
isoforms hCA I, II, IV and IX.
Most of the compounds showed promising inhibition potential for carbonic anhydrase
isoforms hCA I, II and IV.
Heteroaryl derivatives were found to be less effective inhibitors as compared to p-
substituted phenyl derivatives.