Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors

Article abstract of DOI:10.1016/j.ejmech.2018.06.021

In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF₃ (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-7j were prepared in one pot manner via enaminone intermediate using novel methodology. All the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of edema related isoform hCA I with their inhibition constant (K_i) ranging from 30.1 to 86.8 nM as compared to standard drug acetazolamide (AAZ) with K_i = 250 nM. Further it was found that most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b, 7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition potential (K_i < 50 nM). Against glaucoma associated hCA IV, compound 7d was found to be better inhibitor (K_i = 52.4 nM) than AAZ (K_i = 74 nM) while against tumor associated hCA IX, all the compounds have shown moderate inhibition potential. Present study have added one more step in exploring the 1,2,3-triazlole moiety in the medicinal field.

Full text of DOI:10.1016/j.ejmech.2018.06.021

Accepted Manuscript
Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as
potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
Rajiv Kumar, Lalit Vats, Silvia Bua, Claudiu T. Supuran, Pawan K. Sharma
PII:
S0223-5234(18)30512-9
10.1016/j.ejmech.2018.06.021
EJMECH 10491
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 9 February 2018
Revised Date: 5 June 2018
Accepted Date: 7 June 2018
Please cite this article as: R. Kumar, L. Vats, S. Bua, C.T. Supuran, P.K. Sharma, Design and
synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase
isoforms I, II, IV and IX inhibitors, European Journal of Medicinal Chemistry (2018), doi: 10.1016/
j.ejmech.2018.06.021.
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ACCEPTED MANUSCRIPT
Design and synthesis of novel benzenesulfonamide containing 1,2,3-
triazoles as potent human carbonic anhydrase isoforms I, II, IV and
IX inhibitors
Rajiv Kumar, Lalit Vats, Silvia Bua, Claudiu T. Supuran, Pawan K. Sharma
Graphical Abstract
O
H
Ar
H2NO2S
N
N
N
N3
NH2
7a-7j
O
X
+
Ar
O
F3C
X
SO2NH2
SO2NH2
=
-
C
O
Ar
C
F3
N
N
H2NO2S
N
8a-8j
7a-7j, 8a-8j Ki (nM) ≤ 86.8 against hCA I
7b, 7d-7e, 8d-8f, 8j Ki (nM) < 50 against hCA II
7b-7e, 8d-8f Ki (nM) ≤ 95.8 against hCA IV
7d-7f, 8a, 8d-8f, 8i Ki (nM) ≤ 48.2 against hCA IX

ACCEPTED MANUSCRIPT
Design and synthesis of novel benzenesulfonamide containing 1,2,3-
triazoles as potent human carbonic anhydrase isoforms I, II, IV and
IX inhibitors
Rajiv Kumara, Lalit Vatsa, Silvia Buab, Claudiu T. Supuranb*, Pawan K. Sharmaa*
aDepartment of Chemistry, Kurukshetra University, Kurukshetra-136119, India.
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
In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic
derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide
at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized
and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four
human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized
via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-
7j were prepared in one pot manner via enaminone intermediate using novel methodology. All
the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of
edema related isoform hCA I with their inhibition constant (Ki) ranging from 30.1-86.8 nM as
compared to standard drug acetazolamide (AAZ) with Ki = 250 nM. Further it was found that
most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b,
7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition
potential (Ki < 50 nM). Against glaucoma associated hCA IV, compound 7d was found to be
better inhibitor (Ki = 52.4 nM) than AAZ (Ki = 74 nM) while against tumor associated hCA IX,
all the compounds have shown moderate inhibition potential. Present study have added one more
step in exploring the 1,2,3-triazlole moiety in the medicinal field.
1

ACCEPTED MANUSCRIPT
Keywords: 1,2,3-Triazoles, Benzenesulfonamide, Carbonic anhydrase isoforms I, II, IV, IX,
Acetazolamide, Enaminones.
2

ACCEPTED MANUSCRIPT
1. Introduction
Compounds having 1,2,3-triazole scaffold have received considerable attention due to their
association with diverse biological activities including anticancer [1,2], antimicrobial [3],
antiproliferative [4], antimalarial [5], antibacterial [6], antitubercular [7] etc. In addition, primary
sulfonamides constitute an important pharmacophore in many leading classes of drugs with
several types of pharmacological activities [8-12]. Acetazolamide (AAZ), methazolamide
(MZA), ethoxzolamide (EZA), celecoxib (CLX) etc. (Fig. 1) are well known clinically used
drugs bearing sulfonamide groups cutting across different therapeutic areas [13,14]. These are
also established as strong carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, but may have many
side effects. Carbonic anhydrases, widespread zinc metalloenzymes, mainly known to catalyze
-
the reversible hydration of carbon dioxide to bicarbonate and protons (CO2 + H2O ↔ HCO3 +
H+) [15,16], exist in seven unrelated gene families known till date: the α, β, γ, δ, ζ, η and ɵ-CAs
[17-19]. Various CA isoforms play vital roles in many physiological processes like respiration,
electrolyte secretion in variety of tissues/organs, biosynthetic reactions (i.e. lipogenesis,
glucogenesis and ureagenesis), bone resorption, calcification etc. [20,21]. However the
overexpression and sluggishness of various CA isoforms are responsible for many diseases in
mammals. Out of sixteen human associated α-CA isoforms, hCA I is involved in retinal and
cerebral edema while hCA II is associated with glaucoma, edema, epilepsy, and altitude sickness
[16,22]. Overactivity of hCA IV is associated with glaucoma, retinitis pigmentosa and stroke
while hCA IX, a transmembrane isoform, is over-expressed in many tumors, and known to be
associated with cancer progression [16,23,24]. Therefore, selective inhibition of some isoforms
over others is highly desired for targeting particular therapeutic areas with minimum side effects.
Recently our group reported some benzenesulfonamide bearing 1,4,5-trisubstituted-1,2,3-triazole
scaffolds (1-5) as hCA I, II, IV and IX inhibitors (Fig. 1) [25]. Most of these 1,2,3-triazole
derivatives have shown excellent inhibitory potency against hCA isoforms II, IV and IX.
Furthermore, 1,2,3-triazole ring bearing sulfocoumarin 6 (Fig. 1) and other derivatives have been
reported as potent isoform-selective inhibitors of tumor-associated carbonic anhydrases [26]. In
the light of these facts and inspired by our previous work in the field of designing various classes
of heterocyclic compounds of potential medicinal interest [27-35], we planned to synthesize
some novel 5-substituted 4-aroyl-1-aryl-1,2,3-triazoles 7a-7j and 8a-8j bearing primary
sulfonamide group on the phenyl ring at N-1position and -CF3/-H group at C-5 position of 1,2,3-
3

ACCEPTED MANUSCRIPT
triazole ring for evaluating their CA inhibitory profile against isoforms hCA I, II, IV and IX (Fig.
1).
O
O
N N
S
N
S
N
N
SO2NH2
SO2NH2
CH3
NH
N
SO2NH2
S
O
AAZ
MZA
EZA
H2NO2S
N
N
N
F3C
N
N
R
CO2Et/COOH/CONH2/CONHNH2/CH2OH
SO2NH2
1
2
3
4
5
CLX
CF3
O
O
F3C
N
H
Ar
Ar
N
H2NO2S
N
N
H2NO2S
N
N
N
N
O
O
N
S
O
6
7a-7j
8a-8j
Fig. 1. Some clinically used sulfonamide/sulfocoumarin based drugs and derivatives incorporating the1,2,3-triazole
ring (1-6),together with the designed sulfonamides 7-8 acting as CA inhibitors
2. Results and discussion
2.1.Chemistry
All the novel 1,2,3-triazoles were synthesized using 4-azidobenzenesulfonamide (12) according
to the reaction sequence depicted in Scheme 1. 4-Azidobenzenesulfonamide (12) was
synthesized from sulfanilamide (11) by its diazotization followed by treatment with sodium azide
[36]. It is pertinent to mention here that 4-aroyl-1-aryl-1,2,3-triazoles 7a-7j were synthesized in
one pot manner by using a novel variant of the classical click chemistry. First, various methyl
ketone derivatives 9a-9j were refluxed for 12-14 hrs in N,N-dimethylformamide dimethyl acetal
(DMF-DMA) reagent/solvent resulting into formation of key intermediates, enaminones 10a-10j.
After evaporating the excess of reagent/solvent, enaminones 10a-10j (without isolating), were
treated with 4-azidobenzenesulfonamide (12) in DMSO solvent resulting into formation of the
target 1,2,3-triazole derivatives 7a-7j via [3+2] cycloaddition reaction in high yields. 5-
4

ACCEPTED MANUSCRIPT
Trifluoromethyl substituted 1,2,3-triazole derivatives 8a-8j were synthesized by treatment of 4-
azidobenzenesulfonamide (12) with variously substituted trifluoro-1,3-diketones 13a-13j by
using organic base piperidine according to earlier reported method [37]. Aryl substituted 1,3-
diketones 13a-13j, in turn, were synthesized by reacting various methyl ketones 9a-9j with ethyl
trifluoroacetate by using sodium ethoxide base [38] as shown in Scheme 1.
O
O
DMF-DMA, reflux
12-14 hrs
Ar
N
Ar
O
DMSO, 90oC
8-10 hrs
Ar
Ar
9a-9j
10a-10j
H2NO2S
N
N
N
NH2
N3
7a-7j
(i) HCl, NaNO2, H2O, 0oC
(ii) NaN3, 0oC
O
SO2NH2
F3C
SO2NH2
Piperidine, DMSO
70oC, 4-6 hrs
11
12
H2NO2S
N
N
N
(i) CF3COOC2H5, NaOEt,
dry Benzene
8a-8j
O
O
O
Ar
Ar
CF3
(ii) H3O+
9a-9j
13a-13j
7-10,
13
a
b
c
d
e
f
g
h
i
j
4-Me 4-MeO 4-F 4-Cl 4-Br
C6H4
2-
2-
2-
2-
Ar
C6H5
C6H4 C6H4 C6H4 C6H4 naphthyl picolinyl thienyl furyl
Scheme 1. Synthetic pathway of target 1,2,3-triazoles 7a-7j and 8a-8j.
1
13
The spectral data (IR, H NMR, C NMR and HRMS) of target compounds 7a-7j and 8a-8j
were in full agreement with the proposed structures. 1,2,3-Triazoles 7a-7j showed strong
absorption bands at 1620-1659 cm-1 corresponding to carbonyl (C=O) stretching in IR spectra
while compounds 7a-7j showed a characteristic singlet around δ ~ 9.70 ppm for triazolic ring
1
proton (C5-H) in H NMR spectra. Further, a characteristic signal around δ ~ 184 ppm due to
carbonyl carbon was observed in 13C NMR spectra of 1,2,3-triazoles 7a-7j. In IR-spectra,
compounds 8a-8j showed strong carbonyl (C=O) stretching bands around 1651-1697 cm-1 which
is slightly higher than band obtained in compounds 7a-7j definitely due to the presence of –CF3
group in 8a-8j in place of –H at C-5 position of triazolic ring. This fact is further supported by
5

ACCEPTED MANUSCRIPT
1
the absence of singnal in compounds 8a-8j at around δ ~ 9.70 ppm as appeared in 7a-7j in H
NMR spectra. In 13C NMR spectra, 1,2,3-triazoles 8a-8j showed a characteristic signal around δ
~ 184 ppm due to carbonyl carbon along with two other characteristic quartets with 1JCF ~ 268 Hz
and 2JCF ~ 41.3 Hz centering around δ ~ 118 ppm and δ ~ 184 ppm respectively. Further, all the
newly synthesized compounds exhibited sharp absorption bands in their FT-IR spectra at ~ 1342
cm-1 and ~ 1165 cm-1 for SO2 stretching while SO2NH2 group resonated around δ ~ 7.66 ppm as
sharp singlet integrating for two protons in 1H NMR spectra.
2.2. CA inhibition studies
All the newly synthesized 1,2,3-triazoles 7a-7j and 8a-8j were screened for their CA inhibition
potential by stopped-flow, CO2 hydrase assay method [39] against 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). Table 1 presents the results of their CA
inhibition profile as compared to the clinically used acetazolamide (AAZ) as reference drug.
(i) The cytosolic isoform, hCA I (edema related) was, in general, strongly inhibited by all the
newly synthesized 1,2,3-triazoles 7a-7j and 8a-8j with inhibition constant (Ki) in the range
30.1-86.8 nM as compared to standard drug AAZ (Ki = 250 nM). General comparison of the
activities of compounds of two series (7a-7j and 8a-8j) revealed that the compounds 8a-8j
with –CF3 group were slightly more effective against CA isoform hCA I than compounds 7a-
7j with –H group at C-5 position of 1,2,3-triazole ring (Table 1).
(ii) The inhibition potential of newly synthesized 1,2,3-triazoles 7a-7j and 8a-8j against hCA II
(cytosolic isoform) was less satisfactory as all the twenty compounds (7a-7j and 8a-8j) were
less effective as hCA II inhibitors with Ki value ≥ 23 nM as compared to AAZ (Ki = 12 nM).
Amongst the 4-substituted phenyls with electron donating groups, it was observed that
compounds with –H group (7a-7c) were found to be better inhibitors than compounds with –
CF3 group at C-5 position (8a-8c). On the other hand, amongst the haloderivatives, the
compounds with –CF3 group (8d-8f) were found to be better inhibitors than compounds with
–H group at C-5 position (7d-7f) of hCA II (Table 1). However, inhibition potential of other
compounds against isoform hCA II was inconsistent.
6

ACCEPTED MANUSCRIPT
(iii) Against isoform hCA IV (associated with glaucoma) the inhibition potential of some newly
synthesized 1,2,3-triazoles 7b-7e, 8d-8f with Ki ≤ 95.8 nM was comparable to standard drug
AAZ (Ki = 74 nM) while the compound 7d was even better inhibitor (Ki = 52.4 nM).
However inhibition potential of other compounds was not satisfactory against hCA IV.
General comparison of inhibitory potency of series 7a-7j and 8a-8j, showed that the
compounds 7a-7j with –H group were slightly more effective than compounds 8a-8j with –
CF3 group at C-5 position against CA isoform hCA IV with few exceptions (Table 1).
(iv)The tumor associated target isoform hCA IX was moderately inhibited by compounds 7a-7j
and 8a-8j, with Ki’s in the range of 27.3 nM – 0.361 µM as compared to standard drug AAZ
(Ki = 25 nM). However, in general, it was observed that some compounds with electron
withdrawing substituents i.e. 7d-7f & 8d-8f and two others 8a & 8i were found to be better
inhibitors (Ki ≤ 48.2 nM) of hCA IX as compared to remaining compounds of both series
(Table 1).
(v) Overall comparison of activity, in terms of structure activity relationship (SAR), revealed
that compounds with electron withdrawing substituents i.e. 7d-7f & 8d-8f were better
inhibitors of hCA I, hCA II, hCA IV and hCA IX isoforms in the broader sense. Further,
study of inhibitory potency of compounds with heteroaryl substituents (7h-7j & 8h-8j)
revealed that these were more potent inhibitors of isoforms hCA I & II over hCA IV & IX as
shown in Table 1.
(vi)Selective inhibition is necessary for CA inhibitors to act as potential drugs targeting
particular therapeutic area with minimal side effects. Although, the tested compounds did not
show strong selectivity against a specific hCA isoform yet the study of recent papers on
1,2,3-triazole moiety from our group [25,40] and the current work, suggests that compounds
with haloaroyl substituents at C-5 position along with bulkier groups at C-4 position of 1,2,3-
triazole ring could be designed for selective inhibition.
Table 1. Inhibitory potency data for compounds 7a-7j and 8a-8j against CA isoforms hCA I, hCA II, hCA IV,
and hCA IX
Ki (nM)a
Compounds
R
hCA I
67.7
hCA II
67.1
hCA IV
914.4
hCA IX
136.5
C6H5
7a
7

ACCEPTED MANUSCRIPT
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
2-picolinyl
2-thienyl
2-furyl
65.2
36.5
69.8
83.6
39.1
61.9
57.3
79.7
66.5
30.1
54.4
42.4
51.2
86.8
34.2
42.5
37.2
64.5
42.6
250
40.3
51.3
48.8
40.4
80
84.9
80.2
324
145.2
47.8
7b
7c
7d
7e
7f
52.4
79.4
27.3
326.2
369.5
389.3
419.2
341.1
918.5
772.5
242.3
82.3
44.7
61.4
63.9
180.2
84.5
94.8
55.4
61.9
23
127.2
182.1
361.6
217.3
39.8
7g
7h
7i
7j
C6H5
8a
8b
8c
8d
8e
8f
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
2-picolinyl
2-thienyl
2-furyl
144.4
140.7
38.1
31.1
48.9
55.3
67.3
59
95.8
48.2
87.7
35.8
320.9
294.7
555.7
618.1
74
248.1
155.6
45.4
8g
8h
8i
35.8
12
189.6
25
8j
AAZ
-
AAZ = acetazolamide (reference compound).
a
Mean from 3 different assays, by a stopped flow technique (errors were in the range of ±5-10% of the reported
values).
3. Conclusion
Two series of twenty novel compounds 7a-7j and 8a-8j containing 1,2,3-triazole scaffold have
been synthesized, characterized and investigated for their inhibition potential against four of the
isoforms of α-class of carbonic anhydrases comprising cytosolic, ubiquitous isoforms hCA I & II
8

ACCEPTED MANUSCRIPT
as well as the transmembrane isoforms, hCA IV & IX. The activity profile revealed that all the
newly synthesized compounds were moderate inhibitors of hCA II, IV and IX. However, all the
newly synthesized compounds 7a-7j and 8a-8j showed excellent CAs inhibitory profile (Ki ≤
86.8 nM) against hCA I (edema related) as compared to standard drug acetazolamide ( Ki = 250
nM). Although, most of tested compounds have shown weaker inhibition potential as compared
to standard drug AAZ against hCA II yet compounds 7b, 7d-7e, 8d-8f, 8j (mostly with electron
withdrawing substituents) were good inhibitors (Ki < 50 nM). Against glaucoma associated hCA
IV, compound 7d was found to be better inhibitor (Ki = 52.4 nM) than AAZ while against tumor
associated isoform hCA IX, all the tested compounds have shown weaker inhibition potential.
Overall comparison of activity of all the novel 1,2,3-triazoles, 7a-7j and 8a-8j, revealed that
compounds with electron withdrawing substituents, in broader sense, were more effective as CA
inhibitors.
4. Experimental protocols
4.1. 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 reactions were
monitored by 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
1
13
pellet technique. H NMR spectra were recorded on 400 MHz, while C 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. In NMR data, ‘tr’ is used for triazolic
ring. Multiplicities are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
doublet of doublet (dd), doublet of triplet (dt), triplet of triplet (tt), exchangeable proton (ex) for
NMR assignments and strong (s), medium (m), broad (br) for IR assignments. The coupling
constants are expressed in hertz (Hz).
9

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4.2. Synthesis of 4-(4-Aroyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7a-7j)
General procedure: A mixture of appropriately substituted aryl methyl ketone (4 mmol) and
DMF-DMA (20 mmol) was refluxed for 8-12 hrs and monitored by TLC. After complete
consumption of substituted methyl ketone, the mixture was subjected to rotary evaporation under
reduced pressure to remove the excess of DMF-DMA and the liberated methanol. After that
DMSO (6-8 mL) and 4-azidobenzenesulfonamide (4 mmol) were added to reaction mixture.
After addition, reaction mixture was allowed to stir at 90o C for 8-10 hrs in silicon oil bath. After
completion, reaction mixture was poured into water to afford required product (7a-7j). Crude
product thus obtained was recrystalized with ethanol.
4.2.1. 4-(4-Benzoyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7a)
o
Yield 78%; white solid; mp: 224-226 C; IR(KBr) (ν, cm-1): 3356, 3263 (m, N-H stretch), 1643
1
(s, C=O stretch), 1335, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.71 (s,
1H, tr), 8.29-8.27 (m, 4H, Ar), 8.07 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H, Ar), 7.75 (t, J = 7.2 Hz, 1H,
Ar), 7.66-7.62 (m, 2H, Ar), 7.59 (s, 2H, SO2NH2); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
185.51, 147.71, 144.98, 138.58, 136.91, 134.01, 130.46, 129.15, 128.90, 127.92, 121.61; HRMS
(ESI-MS) m/z 351.0577 (M+Na)+, C15H12N4O3SNa+, calcd 351.0522.
4.2.2. 4-(4-(4-Methylbenzoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7b)
o
Yield 86%; white solid; mp: 242-244 C; IR(KBr) (ν, cm-1): 3371, 3248 (m, N-H stretch), 1636
1
(s, C=O stretch), 1327, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.66 (s,
1H, tr), 8.27 (d, J = 8.4 Hz, 2H, Ar), 8.21 (d, J = 8.0 Hz, 2H, Ar), 8.07 (d, J = 8.4 Hz, 2H, Ar),
13
7.59 (s, 2H, SO2NH2), 7.42 (d, J = 8.0 Hz, 2H, Ar), 2.43 (s, 3H, CH3); C NMR (100 MHz,
DMSO-d6) δ (ppm): 184.90, 147.92, 144.95, 144.95, 138.60, 134.31, 130.64, 129.70, 128.69,
127.92, 121.55, 21.73; HRMS (ESI-MS) m/z 365.0694 (M+Na)+, C16H14N4O3SNa+, calcd
365.0679.
4.2.3. 4-(4-(4-Methoxybenzoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7c)
o
Yield 88%; pale yellow solid; mp: 232-234 C; IR(KBr) (ν, cm-1): 3294, 3178 (m, N-H stretch),
1
1643 (s, C=O stretch), 1327, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
9.64 (s, 1H, tr), 8.36 (d, J = 8.8 Hz, 2H, Ar), 8.27 (d, J = 8.8 Hz, 2H, Ar), 8.08 (d, J = 8.8 Hz, 2H,
10

ACCEPTED MANUSCRIPT
Ar), 7.59 (s, 2H, SO2NH2), 7.14 (d, J = 8.8 Hz, 2H, Ar), 3.89 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 183.53, 164.04, 148.21, 144.92, 138.62, 133.02, 129.49, 128.50, 127.92,
121.51, 114.46, 56.10; HRMS (ESI-MS) m/z 381.0664 (M+Na)+, C16H14N4O4SNa+, calcd
381.0628.
4.2.4. 4-(4-(4-Fluorobenzoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7d)
o
Yield 90%; pale yellow solid; mp: 218-220 C; IR(KBr) (ν, cm-1): 3364, 3263 (m, N-H stretch),
1
1636 (s, C=O stretch), 1311, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
9.72 (s, 1H, tr), 8.43-8.40 (m, 2H, Ar), 8.27 (d, J = 8.8 Hz, 2H, Ar), 8.07 (d, J = 8.8 Hz, 2H, Ar),
7.59 (s, 2H, SO2NH2), 7.47 (t, J = 8.8 Hz, 2H, Ar); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
1
3
183.85, 165.72 (d, JCF = 251.1 Hz), 147.72, 145.03, 138.54, 133.56 (d, JCF = 9.6 Hz), 128.98,
2
127.93, 121.93, 116.26 (d, JCF = 21.7 Hz), 111.24; HRMS (ESI-MS) m/z 347.0536 (M+1),
C15H11FN4O3S, calcd 347.0536.
4.2.5. 4-(4-(4-Chlorobenzoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7e)
o
Yield 88%; pale yellow solid; mp: 254-256 C; IR(KBr) (ν, cm-1): 3364, 3240 (m, N-H stretch),
1
1636 (s, C=O stretch), 1335, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
9.73 (s, 1H, tr), 8.33 (d, J = 8.4 Hz, 2H, Ar), 8.27 (d, J = 8.8 Hz, 2H, Ar), 8.07 (d, J = 8.8 Hz, 2H,
13
Ar), 7.72 (d, J = 8.4 Hz, 2H, Ar), 7.57 (s, 2H, SO2NH2); C NMR (100 MHz, DMSO-d6) δ
(ppm):184.23, 147.58, 145.06, 139.00, 138.52, 135.52, 132.35, 129.30, 129.06, 127.92, 121.62;
HRMS (ESI-MS) m/z 363.024/365.0209 (M+1)/(M+3), C15H11ClN4O3S, calcd 363.024/365.024.
4.2.6. 4-(4-(4-Bromobenzoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7f)
o
Yield 83%; white solid; mp: 256-258 C; IR(KBr) (ν, cm-1): 3333, 3240 (m, N-H stretch), 1636
1
(s, C=O stretch), 1327, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.73 (s,
1H, tr), 8.27 (d, J = 8.8 Hz, 2H, Ar), 8.24 (d, J = 8.4 Hz, 2H, Ar), 8.07 (d, J = 8.8 Hz, 2H, Ar),
7.86 (d, J = 8.4 Hz, 2H, Ar), 7.58 (s, 2H, SO2NH2); 13C NMR (100 MHz, DMSO-d6) δ
(ppm):184.43, 147.56, 145.05, 138.52, 135.85, 132.44, 132.26, 129.08, 128.23, 127.94, 121.61;
HRMS (ESI-MS) m/z 406.9735/408.9711 (M+1)/(M+3), C15H11BrN4O3S, calcd
406.9735/408.9735.
4.2.7. 4-(4-(2-Naphthoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7g)
11

ACCEPTED MANUSCRIPT
o
Yield 85%; light brown solid; mp: 228-230 C; IR(KBr) (ν, cm-1): 3364, 3263 (m, N-H stretch),
1
1620 (s, C=O stretch), 1311, 1149 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
9.76 (s, 1H, tr), 9.04 (s, 1H, Ar), 8.30 (d, J = 8.4 Hz, 2H, Ar), 8.24-8.19 (m, 2H, Ar), 8.14-8.05
(m, 4H, Ar), 7.73 (t, J = 7.2 Hz, 1H, Ar), 7.67 (t, J = 7.6 Hz, 1H, Ar), 7.60 (s, 2H, SO2NH2); 13C
NMR (100 MHz, DMSO-d6) δ (ppm): 185.35, 147.81, 145.00, 138.62, 135.65, 134.22, 132.88,
132.48, 130.37, 129.47, 128.96, 128.83, 128.20, 127.96, 127.55, 125.51, 121.61; HRMS (ESI-
MS) m/z 379.0787 (M+1), C19H14N4O3S, calcd 379.0787.
4.2.8. 4-(4-Picolinoyl-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7h)
o
Yield 81%; light brown solid; mp: 238-240 C; IR(KBr) (ν, cm-1): 3302, 3202 (m, N-H stretch),
1
1659 (s, C=O stretch), 1335, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
9.87 (s, 1H, tr), 8.84 (d, J = 4.8 Hz, 1H, Ar), 8.28 (d, J = 8.8 Hz, 2H, Ar), 8.18 (d, J = 7.6 Hz, 1H,
Ar), 8.12 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H, Ar), 8.08 (d, J = 8.8 Hz, 2H, Ar), 7.76 (dd, J = 7.2 Hz, J
13
= 1.2 Hz, 1H, Ar), 7.60 (s, 2H, SO2NH2); C NMR (100 MHz, DMSO-d6) δ (ppm): 183.50,
153.45, 149.74, 144.91, 144.72, 138.63, 138.31, 130.41, 128.32, 127.95, 123.98, 121.68; HRMS
(ESI-MS) m/z 330.0583 (M+1), C14H11N5O3S, calcd 330.0583.
4.2.9. 4-(4-(2-Thienylcarbonyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7i)
o
Yield 83%; light brown solid; mp: 258-260 C; IR(KBr) (ν, cm-1): 3310, 3232 (m, N-H stretch),
1
1620 (s, C=O stretch), 1327, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
9.73 (s, 1H, tr), 8.63 (s, 1H, Ar), 8.28 (d, J = 8.8 Hz, 2H, Ar), 8.20 (t, J = 4.0 Hz, 1H, Ar), 8.08
(d, J = 8.8 Hz, 2H, Ar), 7.59 (s, 2H, SO2NH2), 7.39 (d, J = 4.0 Hz, 1H, Ar); 13C NMR (100 MHz,
DMSO-d6) δ (ppm):176.78, 147.45, 145.03, 142.25, 138.56, 137.08, 136.51, 129.49, 128.27,
127.92, 121.60; HRMS (ESI-MS) m/z 357.0099 (M+Na)+, C13H10N4O3S2Na+, calcd 357.0087.
4.2.10. 4-(4-(2-Furoyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (7j)
Yield 80%; light brown solid; mp: 198 oC; IR(KBr) (ν, cm-1): 3310, 3232 (m, N-H stretch), 1620
1
(s, C=O stretch), 1327, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm): 9.72 (s,
1H, tr), 8.27 (d, J = 8.4 Hz, 2H, Ar), 8.19 (s, 1H, Ar), 8.11-8.06 (m, 3H, Ar), 7.59 (s, 2H,
SO2NH2), 6.87 (d, J = 2.0 Hz, 1H, Ar); 13C NMR (100 MHz, DMSO-d6) δ (ppm):171.15, 150.45,
12

ACCEPTED MANUSCRIPT
149.16, 146.31, 144.53, 138.10, 127.68, 127.47, 122.56, 121.12, 113.04; HRMS (ESI-MS) m/z
341.0353 (M+Na)+, C13H10N4O4SNa+, calcd 341.0315.
4.3. Synthesis of 4-[4-aroyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide (8a-
8j)
General procedure: 4-Azidobenzenesulfonamide (4.04 mmol) was dissolved in DMSO (4 mL) in
a 50 mL round bottom flask. Thereafter, the appropriate aryl 1,3-diketones (4.04 mmol) and
organic base, piperidine (5 mol %) were added to the reaction mixture. After addition, the
reaction mixture was stirred at 70o C in silicon oil bath for 4-6 hrs and progress of reaction was
monitored through thin layer chromatography. After completion, reaction mixture was poured
into water after cooling to afford desired product (8a-8j) which was filtered and recrystalized
with ethanol.
4.3.1. 4-[4-Benzoyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide (8a)
o
Yield 75%; pale yellow solid; mp: 140-142 C; IR(KBr) (ν, cm-1): 3356,3263 (m, N-H stretch),
1
1651 (s, C=O stretch), 1350, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
8.16-8.12 (m, 4H, Ar), 8.02 (d, J = 8.4 Hz, 2H, Ar), 7.80 (tt, J = 7.2 Hz, J = 1.2 Hz, 1H, Ar),
13
7.67-7.63 (m, 4H, Ar, SO2NH2); C NMR (100 MHz, DMSO-d6) δ (ppm): 185.40, 146.64,
2
145.07, 137.30, 135.54, 134.60, 130.33, 128.81, 128.74 (q, JCF = 41.4 Hz), 127.14, 127.08,
118.83 (q, 1JCF = 268.8 Hz); HRMS (ESI-MS) m/z 419.0377 (M+Na)+, C16H11F3N4O3SNa+, calcd
419.0396.
4.3.2. 4-[4-(4-Methylbenzoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide
(8b)
o
Yield 78%; dirty white solid; mp: 138-140 C; IR(KBr) (ν, cm-1): 3380, 3277 (m, N-H stretch),
1
1659 (s, C=O stretch), 1358, 1149 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
8.13 (d, J = 8.8 Hz, 2H, Ar), 8.04-8.00 (m, 4H, Ar), 7.67 (s, 2H, SO2NH2), 7.45 (d, J = 8.0 Hz,
2H, Ar), 2.45 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 184.91, 146.64, 145.55,
2
145.26, 137.33, 133.08, 130.50, 129.43, 128.47 (q, JCF = 41.3 Hz), 127.16, 127.08, 118.87 (q,
1JCF = 268.7 Hz), 55.38; HRMS (ESI-MS) m/z 411.0723 (M+Na)+, C17H13F3N4O3SNa+, calcd
411.0733.
13

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4.3.3. 4-[4-(4-Methoxybenzoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide
(8c)
o
Yield 84%; white solid; mp: 142-144 C; IR(KBr) (ν, cm-1): 3317, 3240 (m, N-H stretch), 1651
(s, C=O stretch), 1358, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14-8.11
(m, 4H, Ar), 8.01 (d, J = 8.4 Hz, 2H, Ar), 7.66 (s, 2H, SO2NH2), 7.16 (d, J = 8.8 Hz, 2H, Ar),
3.91 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 183.58, 164.44, 146.60, 145.46,
2
1
137.34, 132.94, 128.36, 128.23 (q, JCF = 41.3 Hz), 127.14, 127.07, 118.90 (q, JCF = 268.6 Hz),
21.31; HRMS (ESI-MS) m/z 449.0488 (M+Na)+, C17H13F3N4O4SNa+, calcd 449.0502.
4.3.4.
4-[4-(4-Fluorobenzoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide
(8d)
Yield 89%; yellow solid; mp: 118-120 oC; IR(KBr) (ν, cm-1): 3310, 3256 (m, N-H stretch), 1659
(s, C=O stretch), 1358, 1157 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (d, J
= 8.8 Hz, 2H, Ar), 8.01 (d, J = 8.8 Hz, 2H, Ar), 7.93 (d, J = 9.2 Hz, 2H, Ar), 7.68 (s, 2H,
13
SO2NH2), 7.03 (d, J = 9.2 Hz, 2H, Ar); C NMR (100 MHz, DMSO-d6) δ (ppm): 181.96,
2
154.39, 146.42, 146.12, 137.35, 132.77, 127.43 (q, JCF = 41.0 Hz), 127.11, 127.00, 123.37,
1
118.99 (q, JCF = 266.63 Hz), 112.39; HRMS (ESI-MS) m/z 415.0537 (M+1), C16H10F4N4O3S,
calcd 415.0410.
4.3.5.
4-[4-(4-Chlorobenzoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide
(8e)
Yield 72%; yellow solid; mp: 126-128 oC; IR(KBr) (ν, cm-1): 3356, 3271 (m, N-H stretch), 1666
(s, C=O stretch), 1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16 (dd,
J = 6.8 Hz, J = 2.0 Hz, 2H, Ar), 8.13 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H, Ar), 7.99 (d, J = 8.4 Hz, 2H,
13
Ar), 7.88 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H, Ar),7.66 (s, 2H, SO2NH2); C NMR (100 MHz,
DMSO-d6) δ (ppm): 184.10, 146.62, 144.70, 139.64, 137.25, 134.18, 132.16, 128.99, 129.01 (q,
1
2JCF = 41.3 Hz), 127.10, 127.04, 118.56 (q, JCF = 269.0 Hz); HRMS (ESI-MS) m/z 452.9987
(M+Na)+, C16H10ClF3N4O3SNa+, calcd 453.0006.
4.3.6. 4-[4-(4-Bromobenzoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide (8f)
14

ACCEPTED MANUSCRIPT
Yield 83%; yellow solid; mp: 126-128 oC; IR(KBr) (ν, cm-1): 3348, 3256 (m, N-H stretch), 1674
(s, C=O stretch), 1335, 1149 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.13 (dd,
J = 6.8 Hz, J = 2.0 Hz, 2H, Ar), 8.08 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H, Ar), 8.00 (d, J = 8.4 Hz, 2H,
13
Ar), 7.74 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H, Ar),7.66 (s, 2H, SO2NH2); C NMR (100 MHz,
DMSO-d6) δ (ppm): 184.35, 146.66, 144.73, 137.29, 134.55, 132.22, 131.98, 129.99, 129.07 (q,
1
2JCF = 41.3 Hz), 127.14, 127.08, 118.76 (q, JCF = 268.9 Hz); HRMS (ESI-MS) m/z 496.9494
(M+Na)+, C16H10BrF3N4O3Na+, calcd 496.9501.
4.3.7. 4-[4-(2-naphthoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide (8g)
o
Yield 77%; pale yellow solid; mp: 168-170 C; IR(KBr) (ν, cm-1): 3564, 3250 (m, N-H stretch),
1
1697 (s, C=O stretch), 1366, 1149 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
8.82 (s, 1H, Ar), 8.17-8.04 (m, 8H, Ar), 7.78-7.67 (m, 4H, Ar, SO2NH2); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 185.27, 146.66, 145.24, 137.33, 135.59, 133.73, 132.94, 131.84, 129.83,
2
129.578, 128.68, 128.69 (q, JCF = 41.3 Hz), 127.84, 127.37, 127.16, 127.12, 124.36, 118.88 (q,
1JCF = 268.7 Hz); HRMS (ESI-MS) m/z 469.0534 (M+Na)+, C20H13F3N4O3SNa+, calcd 469.0553.
4.3.8. 4-(4-picolinoyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide (8h)
o
Yield 85%; brown solid; mp: 182-184 C; IR(KBr) (ν, cm-1): 1682 (s, C=O stretch), 1358, 1142
(s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.79 (d, J = 4.4 Hz, 1H, Ar), 8.23 (d, J
= 8.0 Hz, 1H, Ar), 8.17 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H, Ar), 8.13 (d, J = 8.4 Hz, 2H, Ar), 8.03 (d,
J = 8.4 Hz, 2H, Ar), 7.82-7.79 (m, 1H, Ar),7.69 (s, 2H, SO2NH2); 13C NMR (100 MHz, DMSO-
2
d6) δ (ppm):186.15, 152.23, 149.58, 146.70, 144.52, 138.07, 137.07, 128.71, 128.41 (q, JCF
=
1
42.0 Hz), 127.26, 127.16, 123.96, 118.90 (q, JCF = 268.0 Hz); HRMS (ESI-MS) m/z 420.0390
(M+Na)+, C15H10F3N5O3S Na+, calcd 420.0349.
4.3.9. 4-[4-(2-Thienylcarbonyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide
(8i)
o
Yield 87%; pale yellow solid; mp: 206-208 C; IR(KBr) (ν, cm-1): 3325, 3225 (m, N-H stretch),
1
1636 (s, C=O stretch), 1342, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) δ (ppm):
8.33 (dd, J = 4.0 Hz, J = 1.2 Hz, 1H, Ar), 8.28 (dd, J = 5.2 Hz, J = 1.2 Hz, 1H, Ar), 8.12 (dd, J =
6.8 Hz, J = 2.0 Hz, 2H, Ar), 8.00 (d, J = 8.4 Hz, 2H, Ar), 7.66 (s, 2H, SO2NH2), 7.41-7.39 (m,
15

ACCEPTED MANUSCRIPT
13
1H, Ar); C NMR (100 MHz, DMSO-d6) δ (ppm): 176.24, 146.65, 144.69, 141.41, 138.08,
2
1
137.71, 137.41, 129.18, 128.88 (q, JCF = 41.6 Hz), 127.59, 127.18, 118.75 (q, JCF = 269.0 Hz);
HRMS (ESI-MS) m/z 424.9957 (M+Na)+, C14H9F3N4O3S2Na+, calcd 424.9960.
4.3.10. 4-[4-(2-furoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide (8j)
Yield 77%; brown solid; mp: 184-186 oC; IR(KBr) (ν, cm-1): 3333, 3209 (m, N-H stretch), 1651
(s, C=O stretch), 1335, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26 (d, J
= 0.8 Hz, 1H, Ar), 8.12 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H, Ar), 7.98 (d, J = 8.8 Hz, 2H, Ar), 7.90 (d,
J = 3.6 Hz, 1H, Ar), 7.65 (s, 2H, SO2NH2), 6.89 (dd, J = 3.6 Hz, J = 0.8 Hz, 1H, Ar); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 170.76, 150.42, 150.35, 146.65, 144.27, 137.35, 128.88 (q, 2JCF
1
= 41.6 Hz), 127.16, 127.05, 124.65, 118.74 (q, JCF = 268.9 Hz), 113.33; HRMS (ESI-MS) m/z
409.0173 (M+Na)+, C14H9F3N4O4SNa+, calcd 424.1089.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and
writing of this article.
Acknowledgements
Two of the authors (Rajiv Kumar, Lalit Vats) are grateful to University Grants Commission,
New Delhi, India for the award of Senior Research Fellowship and Junior Research Fellowship.
Authors are also thankful to Materials Research Centre, MNIT Jaipur for providing HRMS
facility.
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[16] V. Alterio, A.D. Fiore, K. D’Ambrosio, C.T. Supuran, G.D. Simone, Multiple Binding
Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15
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[18] C.T. Supuran, C. Capasso, The η-class carbonic anhydrases as drug targets for antimalarial
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[20] R. Perfetto, S. Del Prete, D. Vullo, G. Sansone, C. Barone, M. Rossi, C.T. Supuran, C.
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[21] C.T. Supuran, Carbonic anhydrases: from biomedical applications of the inhibitors and
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[22] C.T. Supuran, Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors.
Metabolites 7 (2017) 48.
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[23] 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.
[24] 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
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[25] R. Kumar, V. Sharma, S. Bua, C.T. Supuran, P.K. Sharma, Synthesis and biological
evaluation of benzenesulfonamide-bearing 1,4,5-trisubstituted-1,2,3-triazoles possessing
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[26] K. Tars, D. Vullo, A. Kazaks, J. Leitans, A. Lends, A. Grandane, R. Zalubovskis, A.
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[27] S. Ram, G. Celik, P. Khloya, D. Vullo, C.T. Supuran, P.K. Sharma, Benzenesulfonamide
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[31] 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,
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and XII, Bioorg. Med. Chem. 24 (2016) 2907-2913.
[33] R. Kumar, S. Bua, S. Ram, S. Del Prete, C. Capasso, C.T. Supuran, P.K. Sharma,
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tumor associated human carbonic anhydrase IX and XII inhibitors, Bioorg. Med. Chem. 25
(2017) 1286-1293.
[34] 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.
[35] 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.
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3‐Triazoles, Chem. Eur. J. 17 (2011) 3584-3587.
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[40] 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, Eur. J. Med. Chem. 150 (2018) 678-686.
20

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Design and synthesis of novel benzenesulfonamide containing 1,2,3-
triazoles as potent human carbonic anhydrase isoforms I, II, IV and
IX inhibitors
Rajiv Kumar, Lalit Vats, Silvia Bua, Claudiu T. Supuran, Pawan K. Sharma
Research Highlights
•
Twenty novel benzenesulfonamide containing 1,2,3-triazoles were designed and
synthesized.
•
•
Newly synthesized compounds were assayed against hCA isoforms I, II, IV and IX.
Inhibition results were promising as compared to antitumor drug acetazolamide.
•
•
All the tested compounds showed excellent, low nanomolar affinity for hCA I.
Most of the newly synthesized compounds were moderate inhibitors of hCA II, IV and IX.