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

Article abstract of DOI:10.1080/14756366.2017.1367775

A library of benzenesulphonamides incorporating 1,2,3-triazole rings functionalised with ester, carboxylic acid, carboxamide, carboxyhydrazide, and hydroxymethyl moieties were synthesised. The carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity of th

Full text of DOI:10.1080/14756366.2017.1367775

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
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
Rajiv Kumar, Vikas Sharma, Silvia Bua, Claudiu T. Supuran & Pawan K.
Sharma
To cite this article: Rajiv Kumar, Vikas Sharma, Silvia Bua, Claudiu T. Supuran & Pawan
K. Sharma (2017) 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, Journal of Enzyme Inhibition and Medicinal Chemistry, 32:1, 1187-1194, DOI:
10.1080/14756366.2017.1367775
To link to this article: http://dx.doi.org/10.1080/14756366.2017.1367775
© 2017 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Published online: 11 Sep 2017.
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Date: 14 September 2017, At: 04:42

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2017
VOL. 32, NO. 1, 1187–1194
https://doi.org/10.1080/14756366.2017.1367775
RESEARCH PAPER
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
Rajiv Kumara, Vikas Sharmaa, Silvia Buab, Claudiu T. Supuranb and Pawan K. Sharmaa
b
aDepartment of Chemistry, Kurukshetra University, Kurukshetra, India; Neurofarba Department, Laboratorio di Chimica Bioinorganica, Sezione di
ꢀ
Scienze Farmaceutiche, Universita degli Studi di Firenze, Firenze, Italy
ABSTRACT
ARTICLE HISTORY
Received 19 July 2017
Accepted 11 August 2017
A library of benzenesulphonamides incorporating 1,2,3-triazole rings functionalised with ester, carboxylic
acid, carboxamide, carboxyhydrazide, and hydroxymethyl moieties were synthesised. The carbonic anhy-
drase (CAs, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) iso-
forms, hCA I, hCA II, hCA IV, and hCA IX. Among them, hCA II and IV are anti-glaucoma drug targets,
being involved in aqueous humour secretion within the eye. hCA I was inhibited with Ki’s ranging
between 8.3 nM and 0.8737 mM. hCA II, the physiologically dominant cytosolic isoform, was excellently
inhibited by these compounds, with Ki’s in the range of 1.6–9.4 nM, whereas hCA IV was effectively inhib-
ited by most of them, with Ki’s in the range of 1.4–55.3 nM. Thirteen of the twenty sulphonamides were
found to be excellent inhibitors of tumour associated hCA IX with Ki’s ꢀ 9.5 nM. Many of the new com-
pounds reported here showed low nM inhibitory action against hCA II, IV, and IX, isoforms involved in
glaucoma and some tumours, making them interesting candidates for further medicinal chemistry/pharma-
cologic studies.
KEYWORDS
1,2,3-Triazoles; benzenesul-
phonamide; carbonic
anhydrase; isoforms I, II, IV,
IX; acetazolamide
Introduction
Recently our research group has reported some fused
1,2,4-triazoles and 4-functionalised pyrazoles bearing benzenesul-
phonamide as selective inhibitors of CA IX and XII22–24. Further
1,2,3-triazole ring containing compounds are gaining interest in
diverse therapeutic areas like antiproliferative,25 antitubercular,
antimicrobial26–28, anticancer29,30, anti-HIV31, antifungal, antibacter-
ial32, anti-inflammatory33, antiobesity34, antiviral35, etc., as well as
in several DNA-alkylating, crosslinking agents36,37, and b-lactamase
inhibitors38. Also some 1,2,3-triazole ring containing selective CAIs
have been reported (1–3)39,40. Motivated by these findings and
continuing our interest in the design of various classes of hetero-
Carbonic anhydrases (CAs, EC 4.2.1.1) belong to family of zinc met-
alloenzymes found in variety of organisms, including higher verte-
brates and humans1–3. As all the seven families of CAs known to
date (a, b, c, d, f, g, and Õ-class)4–6 are involved in the reversible
hydration–dehydration of carbon dioxide and bicarbonate ions,
therefore, play vital roles in various important physiological proc-
esses, such as respiration, electrolyte secretion in variety of tis-
sues/organs, biosynthetic reactions (i.e. lipogenesis, glucogenesis,
and ureagenesis), bone resorption, calcification, etc.1,2,7,8. However,
several studies demonstrated that abnormal levels or activities of
these enzymes have been associated with various human diseases.
Out of the sixteen isoforms of human associated a-class of CAs,
some isoforms are involved in pertinent pathologies, such as glau-
coma9, epilepsy10, obesity11, altitude sickness,1 retinitis pigmen-
tos1 cancer12–15, etc. Therefore, carbonic anhydrase inhibitors
(CAIs) have applications as therapeutic agents, such as antiglau-
coma, antiobesity, antidiuretic, antiepileptic, anti-altitude sickness,
antipain, and anti-infective agents1,16–20. However, designing and
synthesising isoform-selective inhibitors are a challenging task for
obtaining a drug with minimum side effect.
cyclic based compounds of potential medicinal interest22–24,41–46
,
we turned our attention towards the synthesis of a small library of
novel 4-functionalised 1-aryl-5-alkyl/aryl-1,2,3-triazoles (4a–4d,
5a–5d, 6a–6d, 7a–7d, and 8a–8d) bearing a primary sulphona-
mide group on the phenyl ring at N-1 position of 1,2,3-triazole
scaffold with different functionalities at C-4, such as ester, carbox-
ylic acid, carboxamide, hydrazinocarbonyl, and hydroxymethyl
(Figure 1) in order to investigate their carbonic anhydrases inhib-
ition against isoforms hCA I, II, IV, and IX.
Primary sulphonamide bearing heterocyclic compounds form a
part of potent CAIs in which binding group binds to the Zn(II) ion
as anion in a tetrahedral geometry. A large number of drugs
belonging to this class, like acetazolamide (AZA), methazolamide
Materials and methods
General
All the commercially available chemicals were used without further
(MZA), ethoxzolamide (EZA), dorzolamide (DZA), etc., are in clinical purification. All the solvents were dried and/or purified according
use from past many years targeting different therapeutic areas21
.
to standard procedures prior to use. All the reactions were
CONTACT Pawan K. Sharma
Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Universita degli Studi di Firenze, Sesto Fiorentino,
Firenze, Italy
pksharma@kuk.ac.in
Department of Chemistry, Kurukshetra University, Kurukshetra, India; Claudiu T. Supuran
claudiu.supuran@unifi.it
ꢀ
ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri-
bution, and reproduction in any medium, provided the original work is properly cited.

1188
R. KUMAR ET AL.
Figure 1. Some clinically used sulphonamide based drugs and 1,2,3-triazole ring containing CA inhibitors.
monitored by thin layer chromatography (TLC) on TLC silica gel on J ¼ 2.0 Hz, 2H, Ar), 7.61 (s, 2H, SO2NH2), 4.37 (q, J ¼ 7.2 Hz, 2H,
F254 aluminium plates using a mixture of chloroform and methanol CH2), 2.58 (s, 3H, –CH3), 1.35 (t, J ¼ 7.2 Hz, 3H, CH3); 13C NMR
as eluent while UV lamp was used to visualise the spots. Melting (100 MHz, DMSO-d6) d (ppm): 160.92, 145.31, 139.48, 137.47,
points were determined in open capillaries in an electrical melting 136.08, 127.14, 125.98, 60.50, 14.12, 9.73; HRMS (ESI-MS) m/z
333.0640 (M þ Na)þ, C12H14N4O4SNaþ, calcd 333.0634.
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
Ethyl 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-1,2,3-triazole-4-
carboxylate (4b)
Yield 75%; dirty white solid; mp: 184 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3371,
were registered at 100 MHz, using deuterated dimethyl sulphoxide
(DMSO-d6) as solvent, and tetramethylsilane (TMS) as internal
standard at room temperature. Chemical shifts are reported as d
values in parts per million (ppm) downfield from TMS. High reso-
lution 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 a doublet of a doublet (ddd),
doublet of triplet (dt), triplet (t), quartet (q), multiplet (m),
3263, 3061 (m, N–H stretch), 1704 (s, C¼O stretch), 1342, 1159 (s,
SO2 stretch); 1H NMR (400 MHz, CDCl3) d (ppm):): 7.96 (dd,
J ¼ 7.2 Hz, J ¼ 1.2 Hz, 2H, Ar), 7.56–7.48 (m, 5H, Ar), 7.32 (dd,
J ¼ 8.4 Hz, J ¼ 1.2 Hz, 2H, Ar), 7.06 (s, 2H, SO2NH2), 4.33 (q,
J ¼ 7.2 Hz, 2H, CH2), 1.28 (t, J ¼ 7.2 Hz, 3H, CH3); 13C NMR (100 MHz,
exchangeable proton (ex) for NMR assignments and strong (s),
medium (m), broad (br) for IR assignments. The coupling constants
are expressed in hertz (Hz).
CDCl3) d (ppm): 165.33, 149.56, 145.64, 142.84, 141.97, 135.02,
134.95, 133.38, 132.17, 130.08, 130.05, 65.94, 18.81; HRMS (ESI-MS)
m/z 395.0785 (M þ Na)þ, C17H16N4O4SNaþ, calcd 395.0789.
Synthesis of ethyl 1-[4-(aminosulfonyl)phenyl]-5-(alkyl/aryl)-1H-
1,2,3-triazole-4-carboxylate (4a–4d)
Ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-1,2,3-
triazole-4-carboxylate (4c)
General procedure:
A mixture of appropriate b-diketoester
Yield 74%; pale yellow solid; mp: 176 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3364,
3271 (m, N–H stretch), 2970 (m, –CH3 stretch), 1713 (s, C¼O
11a–11d (2.00 mmol) and piperidine (5 mol%) dissolved in 3 ml
DMSO were heated at 70 ꢁC in silicon oil bath for 5 min followed
by addition of 4-azidobenzenesulphonamide (2.02 mmol). After
addition, reaction mixture was allowed to stir at 70 ꢁC for 4–6 h.
Reaction was monitored through thin-layer chromatography. After
completion, reaction mixture was poured into water after cooling
to afford required product 4a–4d. The crude product thus
obtained was recrystalised with ethanol.
1
stretch), 1342, 1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) d
(ppm): 7.93 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.59 (d, J ¼ 8.8 Hz,
2H, Ar), 7.54 (s, 2H, SO2NH2), 7.32 (d, J ¼ 8.8 Hz, 2H, Ar), 6.97 (dd,
J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 4.23 (q, J ¼ 7.2 Hz, 2H, CH2), 3.77 (s,
3H, –CH3), 1.18 (t, J ¼ 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-
d6) d (ppm): 160.31, 160.26, 144.94, 141.09, 137.89, 136.28, 131.88,
126.82, 126.37, 116.99, 113.72, 60.46, 55.21, 13.89; HRMS (ESI-MS)
m/z 403.1072 (M þ H)þ, C18H18N4O5SHþ, calcd 403.1076.
Ethyl 1-[4-(aminosulfonyl)phenyl]-5-methyl-1H-1,2,3-triazole-4-
carboxylate (4a)
Ethyl 1-[4-(aminosulfonyl)phenyl]-5-(2-naphthyl)-1H-1,2,3-
triazole-4-carboxylate (4d)
stretch),1335, 1165 (s, SO2stretch); 1H NMR (400 MHz, DMSO-d6) d Yield 92%; dirty white solid; mp: 180 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3325,
(ppm): 8.08 (dd, J ¼ 8.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.88 (dd, J ¼ 8.8 Hz, 3240 (m, N–H stretch), 1728 (s, C¼O stretch), 1335, 1165 (s, SO2
Yield 91%; white solid; mp: 212 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3302, 3070
(m, N–H stretch), 2924 (m, –CH3 stretch), 1728 (s, C¼O

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1
1189
stretch); 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.07 (d, J ¼ 8.4 Hz, stretch), 1335, 1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) d
1H, Ar), 8.00 (d, J ¼ 8.0 Hz, 1H, Ar), 7.78 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz,
2H, Ar), 7.65 (dd, J ¼ 7.2 Hz, J ¼ 1.2 Hz, 1H, Ar),7.58 (d, J ¼ 8.8 Hz,
3H, Ar), 7.54 (dd, J ¼ 8.0 Hz, J ¼ 1.2 Hz, 1H, Ar),7.48 (dt, J ¼ 8.4 Hz,
J ¼ 1.6 Hz, 1H, Ar), 7.45–7.43 (m, 3H, Ar, SO2NH2), 4.04–4.00 (m, 2H,
CH2), 0.81 (t, J ¼ 7.6 Hz, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6) d
(ppm): 159.80, 145.04, 139.66, 138.14, 137.71, 132.67, 131.10,
130.40, 129.42, 128.41, 127.33, 126.73, 126.42, 125.66, 125.06,
124.32, 123.12, 60.29, 13.25; HRMS (ESI-MS) m/z 423.1124 (M þ H)þ,
C21H18N4O4SHþ, calcd 423.1127.
(ppm): 12.98 (s, br, 1H, COOH), 8.04 (d, J ¼ 8.4 Hz, 1H, Ar), 7.97 (d,
J ¼ 8.0 Hz, 1H, Ar), 7.76 (dd, J ¼ 8.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.66 (dd,
J ¼ 7.6 Hz, J ¼ 1.2 Hz, 1H, Ar), 7.58–7.39 (m, 8H, Ar, SO2NH2); 13C
NMR (100 MHz, DMSO-d6) d (ppm): 161.28, 144.94, 139.32, 138.88,
137.83, 132.67, 131.06, 130.29, 129.48, 128.42, 127.30, 126.66,
126.40, 125.61, 125.11, 124.32, 123.39; HRMS (ESI-MS) m/z
395.0800 (M þ H)þ, C19H14N4O4SHþ, calcd 395.0814.
Synthesis of 1-[4-(aminosulfonyl)phenyl]-5-alkyl/aryl-1H-1,2,3-
triazole-4-carboxamide (6a–6d)
Synthesis of 1-[4-(aminosulfonyl)phenyl]-5-alkyl/aryl-1H-1,2,3-
triazole-4-carboxylic acid (5a–5d)
General procedure: A solution of appropriate 1,2,3-triazolic ester
4a–4d (1.29 mmol) in cold concentrated aq. ammonia solution
(3 ml) was stirred for 22 h in a stoppered flask. The white precipi-
tates of carboxamide derivatives 6a–6d thus obtained were fil-
tered, washed with excess of cold water, dried at 120 ꢁC and
recrystallised from ethanol.
General procedure: An appropriate 1,2,3-triazolic ester 4a–4d was
dissolved in 20% aq NaOH solution (5 ml) and refluxed for 4 h.
Then cooled the solution to room temperature, added ice to it
and neutralised with concd HCl which resulted into the precipita-
tion of a white solid. The solid was filtered off, washed with water,
dried and recrystallised from appropriate solvent which afforded
the pure products 5a–5d.
1-[4-(Aminosulfonyl)phenyl]-5-methyl-1H-1,2,3-triazole-4-carboxa-
mide (6a)
Yield 74%; white solid; mp: 314–316 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3456,
3356, 3271 (m, N–H stretch), 1674 (s, C¼O stretch), 1333, 1173 (s,
SO2 stretch); 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.06 (dd,
J ¼ 8.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.94 (s, ex, 1H, OH/NH), 7.87 (dd,
J ¼ 8.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.52–7.49 (m, ex, 3H, OH/NH,
SO2NH2), 2.57 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6) d (ppm):
162.59, 145.10, 138.47, 137.72, 137.01, 127.10, 125.80, 9.31; HRMS
1-[4-(Aminosulfonyl)phenyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic
acid (5a)
Yield 94%; white solid; mp: 198 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3348, 3225
(m, N–H stretch), 3078 (br, O–H stretch), 2905 (m, –CH3 stretch),
1697 (s, C¼O stretch),1334, 1150 (s, SO2 stretch); 1H NMR
(400 MHz, DMSO-d6) d (ppm): 13.24 (s, br, 1H, –COOH), 8.07 (d,
J ¼ 8.4 Hz, 2H, Ar), 7.87 (d, J ¼ 8.4 Hz, 2H, Ar), 7.62 (s, 2H, SO2NH2),
2.56 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6) d (ppm): 162.42, (ESI-MS) m/z 282.0656 (M þ H)þ, C10H11N5O3SHþ, calcd 282.0661.
145.24, 139.22, 137.63, 136.83, 127.16, 125.94, 9.74; HRMS (ESI-MS)
m/z 305.0325 (M þ Na)þ, C10H10N4O4SNaþ, calcd 305.0321.
1-[4-(Aminosulfonyl)phenyl]-5-phenyl-1H-1,2,3-triazole-4-carboxa-
mide (6b)
1-[4-(Aminosulfonyl)phenyl]-5-phenyl-1H-1,2,3-triazole-4-carboxylic
Yield 76%; pale yellow solid; mp: 210 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3479,
acid (5b)
3379, 3178, 3101 (m, N–H stretch), 1674 (s, C¼O stretch), 1335,
Yield 85%; white solid; mp: 156 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3379, 3263
1
1157 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) d (ppm): 8.03 (s,
(m, N–H stretch), 3063 (br, O–H stretch),1713 (s, C¼O stretch),
ex, 1H, OH/NH), 7.88 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.58–7.54
(m, 5H, Ar, SO2NH2, OH/NH), 7.42–7.37 (m, 5H, Ar); 13C NMR
(100 MHz, DMSO-d6) d (ppm): 162.00, 145.35, 139.71, 139.33,
138.48, 131.00, 130.02, 128.57, 127.26, 126.91, 126.24; HRMS (ESI-
MS) m/z 366.0629 (M þ Na)þ, C15H13N5O3SNaþ, calcd 366.0635.
1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) d (ppm):
12.66 (s, br, 1H, –COOH), 7.90 (dd, J ¼ 6.8 Hz, J ¼ 1.6 Hz, 2H, Ar),
7.59–7.57 (m, 4H, Ar, SO2NH2), 7.45–7.40 (m, 5H, Ar); 13C NMR
(100 MHz, DMSO-d6) d (ppm): 162.12, 145.41, 141.41, 138.33,
137.72, 130.84, 130.29, 128.71, 127.27, 126.92, 126.16; HRMS (ESI-
MS) m/z 367.07473 (M þ Na)þ, C15H12N4O4SNaþ, calcd 367.0477.
1-[4-(Aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-1,2,3-triazole-
4-carboxamide (6c)
1-[4-(Aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-1,2,3-triazole-
4-carboxylic acid (5c)
Yield 76%; white solid; mp: 280–282 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3441,
3325, 3240, 3101 (m, N-H stretch), 2916 (m, –CH3 stretch), 1690 (s,
C¼O stretch), 1342, 1165 (s, SO2 stretch); 1H NMR (400 MHz,
DMSO-d6) d (ppm): 7.95 (s, 1H, OH/NH), 7.90 (dd, J ¼ 6.8 Hz,
J ¼ 2.0 Hz, 2H, Ar), 7.58–7.53 (m, 5H, OH/NH, Ar, SO2NH2), 7.29 (d,
J ¼ 8.8 Hz, 2H, Ar), 6.94 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 3.77 (s,
3H, –CH3); 13C NMR (100 MHz, DMSO-d6) d (ppm): 161.64, 160.03,
144.77, 138.93, 138.69, 138.15, 131.98, 126.79, 126.33, 117.40,
113.60, 55.17; HRMS (ESI-MS) m/z 396.0754 (M þ Na)þ,
C16H15N5O4SNaþ, calcd 396.0743.
Yield 98%; dirty white solid; mp: 148–150 ꢁC; IR(KBr) (ꢀ, cmꢂ1):
3333, 3242 (m, N–H stretch), 3055 (br, O–H stretch), 2905 (m, –CH3
1
stretch), 1705 (s, C¼O stretch), 1335, 1165 (s, SO2 stretch); H NMR
(400 MHz, DMSO-d6) d (ppm): 13.02 (s, br, 1H, –COOH), 7.90 (d,
J ¼ 8.8 Hz, 2H, Ar), 7.56 (d, J ¼ 8.8 Hz, 2H, Ar), 7.55 (s, 2H, SO2NH2),
7.30 (d, J ¼ 8.8 Hz, 2H, Ar), 6.95 (d, J ¼ 8.8 Hz, 2H, Ar), 3.77 (s, 3H,
–CH3); 13C NMR (100 MHz, DMSO-d6) d (ppm): 161.69, 160.16,
144.85, 140.75, 137.98, 137.01, 131.85, 126.78, 126.32, 117.31,
113.72, 55.18; HRMS (ESI-MS) m/z 397.0577 (M þ Na)þ,
C16H14N4O5SNaþ, calcd 397.0582.
1-[4-(Aminosulfonyl)phenyl]-5-(2-naphthyl)-1H-1,2,3-triazole-4-car-
boxamide (6d)
1-[4-(Aminosulfonyl)phenyl]-5-(2-naphthyl)-1H-1,2,3-triazole-4-car-
boxylic acid (5d)
Yield 75%; white solid; mp: 278–280 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3472,
3364, 3217, 3063 (m, N–H stretch), 1682 (s, C¼O stretch), 1350,
Yield 93%; pale yellow solid; mp: 198–200 ꢁC; IR(KBr) (ꢀ, cmꢂ1):
3356, 3256 (m, N–H stretch), 3078 (br, O–H stretch), 1690 (s, C¼O 1165 (s, SO2 stretch); 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.03

1190
R. KUMAR ET AL.
(d, J ¼ 8.8 Hz, 2H, OH/NH, Ar), 7.97 (d, J ¼ 8.0 Hz, 1H, Ar), 7.76 (d, 1H NMR (400 MHz, DMSO-d6) d (ppm): 9.53 (s, ex, 1H, NH), 8.04 (d,
J ¼ 8.8 Hz, 2H, Ar), 7.62–7.36 (m, 10H, Ar, SO2NH2, OH/NH); 13C J ¼ 8.0 Hz, 1H, Ar), 7.98 (d, J ¼ 8.0 Hz, 1H, Ar), 7.76 (d, J ¼ 8.8 Hz, 2H,
NMR (100 MHz, DMSO-d6) d (ppm): 161.10, 144.86, 140.91, 137.94, Ar), 7.63 (d, J ¼ 7.2 Hz, 1H, Ar), 7.58–7.44 (m, 7H,Ar, SO2NH2), 7.35
137.25, 132.71, 131.17, 130.07, 129.54, 128.36, 127.09, 126.64, (d, J ¼ 8.4 Hz, 1H, Ar), 4.45 (s, ex, 2H, NH2); 13C NMR (100 MHz,
126.30, 125.55, 125.09, 124.45, 123.58; HRMS (ESI-MS) m/z DMSO-d6) d (ppm): 159.26, 145.30, 140.74, 138.42, 137.31, 133.22,
416.0805 (M þ Na)þ, C19H15N5O3SNaþ, calcd 416.0794.
131.73, 130.67, 130.19, 128.90, 127.66, 127.20, 126.84, 126.01,
125.61, 124.94, 123.88; HRMS (ESI-MS) m/z 431.0894 (M þ Na)þ,
C19H16N6O3SNaþ, calcd 431.0903.
Synthesis of 4-[4-(hydrazinocarbonyl)-5-alkyl/aryl-1H-1,2,3-
triazol-1-yl]benzenesulphonamide (7a)
Synthesis of 4-(4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-
yl)benzenesulphonamide (8a–8d)
General procedure: A solution of appropriate 1,2,3-triazolic ester
4a–4d (1.93 mmol) and hydrazine hydrate (5.81 mmol) in ethanol
(15 ml) was refluxed for 10–12 h. The reaction was monitored General procedure: Appropriate 1,2,3-triazolic ester 4a–4d
through thin-layer chromatography. After completion, reaction (3.22 mmol) was dissolved in dry tetrahydrofuran (20 ml) and a sus-
mixture was concentrated and allowed to cool to room tempera- pension of LiAlH4 (6.44 mmol) in dry tetrahydrofuran (5 ml) was
ture. Solid thus obtained was filtered and crystallised from slowly added under anhydrous conditions. After 20 min of reaction
EtOH:THF (1:1) to afford the desired compounds 7a–7d in good at 20 ꢁC, reaction mixture was refluxed for 2 h. After completion of
yields.
the reaction, an aqueous solution of HCl 1 N was added dropwise
until a neutral pH. The reaction mixture was concentrated under
reduced pressure; the residue was taken into ethyl acetate and
washed with water and brine. The organic layer was dried over
MgSO4 and concentrated under reduced pressure. The residue was
recrystalised in ethanol.
4-[4-(Hydrazinocarbonyl)-5-methyl-1H-1,2,3-triazol-1-yl]benzenesul-
phonamide (7a)
Yield 92%; white solid; mp: 216–218 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3325,
3178, 3078, 3016 (m, N–H stretch), 1670 (s, C¼O stretch), 1342,
1
1165 (s, SO2 stretch); H NMR (400 MHz, DMSO-d6) d (ppm): 9.79 (s,
4-(4-(Hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)benzenesulpho-
ex, 1H, NH), 8.06 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.88 (dd,
J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.57 (s, 2H, SO2NH2), 4.50 (s, ex, 2H, namide (8a)
NH2), 2.58 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6) d (ppm): Yield 55%; pale yellow solid; mp: 184 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3495
160.00, 145.06, 137.79, 137.69, 136.40, 127.11, 125.72, 9.21; HRMS (br, O–H stretch), 3294, 3186, 3086 (m, N–H stretch), 1336, 1157 (s,
(ESI-MS) m/z 319.0576 (M þ Na)þ, C10H12N6O3SNaþ, calcd 319.0590. SO2 stretch); 1H NMR (400 MHz,DMSO-d6) d (ppm): 8.05 (dd,
J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.85 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar),
7.58 (s, 2H, SO2NH2), 5.20 (t, ex, J ¼ 5.6 Hz, 1H, OH), 4.59 (d,
J ¼ 5.6 Hz, 2H, CH2), 2.39 (s, 3H, CH3); 13C NMR (100 MHz,DMSO-d6)
4-[4-(Hydrazinocarbonyl)-5-phenyl-1H-1,2,3-triazol-1-yl]benzenesul-
phonamide (7b)
d (ppm): 145.71, 144.96, 139.01, 132.34, 127.65, 125.56, 54.68, 8.95.
Yield 70%; white solid; mp: 206 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3402, 3317,
3186, 3094 (m, N–H stretch), 1668 (s, C¼O stretch), 1335, 1157 (s,
1
4-(4-(Hydroxymethyl)-5-phenyl-1H-1,2,3-triazol-1-yl)benzenesulpho-
SO2 stretch); H NMR (400 MHz, DMSO-d6) d (ppm): 9.88 (s, ex, 1H,
NH), 7.89 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.58 (dd, J ¼ 6.8 Hz, namide (8b)
J ¼ 2.0 Hz, 2H, Ar), 7.54 (s, 2H, SO2NH2), 7.42–7.38 (m, 5H, Ar), 4.49 Yield 68%; pale yellow solid; mp: 174–176 ꢁC; IR(KBr) (ꢀ, cmꢂ1):
(s, ex, 2H, NH2); 13C NMR (100 MHz, DMSO-d6) d (ppm): 159.67, 3325 (br, O–H stretch), 3225, 3171, 3070 (m, N–H stretch), 1342,
145.35, 139.22, 138.69, 138.45, 130.93, 130.10, 128.64, 127.31, 1157 (s, SO2 stretch); 1H NMR (400 MHz, CDCl3) d (ppm): 7.97 (d,
126.82, 125.99; HRMS (ESI-MS) m/z 381.0640 (M þ Na)þ, J ¼ 8.8 Hz, 2H, Ar), 7.48–7.44 (m, 5H, Ar, SO2NH2), 7.37–7.35 (m, 2H,
C15H14N6O3SNaþ, calcd 381.0745.
Ar), 7.28 (d, J ¼ 7.2 Hz, 2H, Ar), 5.25 (s, ex, 1H, OH), 4.65 (s, 2H,
CH2); 13C NMR (100 MHz, CDCl3) d (ppm): 150.68, 149.26, 143.74,
140.40, 134.54, 134.33, 133.81, 132.11, 131.06, 129.72, 59.36.
4-[4-(Hydrazinocarbonyl)-5-(4-methoxyphenyl)-1H-1,2,3-triazol-1-
yl]benzenesulphonamide (7c)
Yield 70%; white solid; mp: 170–172 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3333,
4-(4-(Hydroxymethyl)-5-(4-methoxyphenyl)-1H-1,2,3-triazol-1-
3232, 3103 (m, N-H stretch), 1659 (s, C¼O stretch), 1335, 1165 (s, yl)benzenesulphonamide (8c)
SO2 stretch);1H NMR (400 MHz, DMSO-d6) d (ppm): 9.80 (s, ex, 1H, Yield 69%; yellow solid; mp: 180–182 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3481
NH), 7.91 (dd, J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 7.57 (d, J ¼ 8.8 Hz, 2H, (br, O–H stretch), 3295 (m, N–H stretch), 2916 (m, –CH3 stretch),
Ar), 7.53 (s, 2H, SO2NH2), 7.29 (d, J ¼ 8.8 Hz, 2H, Ar), 6.94 (dd, 1342, 1142 (s, SO2 stretch); 1H NMR (400 MHz, CDCl3) d (ppm):
J ¼ 6.8 Hz, J ¼ 2.0 Hz, 2H, Ar), 4.48 (s, ex, 2H, NH2), 3.76 (s, 3H, 7.99–7.95 (m, 2H, Ar), 7.48–7.44 (m, 2H, Ar), 7.30–7.25 (m, 4H, Ar,
–CH3); 13C NMR (100 MHz, DMSO-d6) d (ppm): 160.10, 159.34, SO2NH2), 6.96–6.92 (m, 2H, Ar), 5.22 (t, J ¼ 5.6 Hz, 1H, OH), 4.63 (d,
144.78, 138.46, 138.13, 138.08, 131.90, 126.85, 126.24, 117.22, J ¼ 5.6 Hz, 2H, CH2), 3.85 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) d
113.69, 55.20; HRMS (ESI-MS) m/z 389.1026 (M þ H)þ, (ppm): 165.14, 150.34, 149.16, 143.87, 140.36, 135.92, 132.09,
C16H16N6O4SHþ, calcd 389.1032.
129.70, 122.94, 119.31, 60.14, 59.41.
4-[4-(Hydrazinocarbonyl)-5-(2-naphthyl)-1H-1,2,3-triazol-1-yl]benze- 4-(4-(Hydroxymethyl)-5-(2-naphthyl)-1H-1,2,3-triazol-1-yl)benzene-
nesulphonamide (7d)
sulphonamide (8d)
Yield 72%; white solid; mp: 156 ꢁC; IR(KBr) (ꢀ, cmꢂ1): 3279, 3063 Yield 71%; dirty white solid; mp: 212–214 ꢁC; IR(KBr) (ꢀ, cmꢂ1):
(m, N–H stretch), 1659 (s, C¼O stretch), 1327, 1165 (s, SO2 stretch); 3431 (br, O–H stretch), 3295 (m, N–H stretch), 1335, 1157 (s, SO2

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1191
stretch); 1H NMR (400 MHz, CDCl3) d (ppm): 8.02 (dd, J ¼ 6.8 Hz,
J ¼ 2.4 Hz, 1H, Ar), 7.94 (d, J ¼ 6.0 Hz, 1H, Ar), 7.76 (d, J ¼ 8.4 Hz, 2H,
Ar), 7.58–7.57 (m, 2H, Ar), 7.53–7.49 (m, 1H, Ar), 7.42–7.38 (m, 4H,
Ar), 7.27 (s, 2H, SO2NH2), 5.11 (t, J ¼ 5.2 Hz, 1H, OH), 4.48 (ddd,
J ¼ 58.4 Hz, J ¼ 12.4 Hz, J ¼ 5.2 Hz, 2H, CH2); 13C NMR (100 MHz,
CDCl3) d (ppm):152.24, 149.19, 143.80, 138.52, 138.23, 136.38,
135.34, 134.64, 133.53, 132.28, 131.96, 131.53, 130.37, 129.40,
128.73, 128.67, 59.26.
Table 1. Inhibitory potency data for compounds 4a–4d, 5a–5d, 6a–6d, 7a–7d,
and 8a–8d against isozymes hCAI, hCA II, hCA IV, and hCA IX.
Ki (nM)a
Compound
R
hCA I
hCA II
hCA IV
hCA IX
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
8d
AZA
–CH3
–C6H5
4-C6H4–OCH3
2-Naphthyl
–CH3
9.1
245.5
63
68.2
9.6
645.7
489.1
56.2
8.3
69.1
873.7
771.7
15.1
73.7
91.2
82.5
354.2
78.9
811.8
213.5
250
3.2
6
3.5
5.1
4.5
6.6
9.5
40
7.1
8.5
45.9
42.3
4.2
9.5
28.3
6.8
6.7
9.3
26.1
8.1
7.2
30.6
58.7
5.8
7.8
25.8
6.1
5.8
1.6
97.9
9
8.9
1.9
9.1
6.2
6
5
269.4
55.3
2.4
4.1
211.9
1.4
1.7
4
227.8
22.7
4
–C6H5
4-C6H4–OCH3
2-Naphthyl
–CH3
Results and discussion
–C6H5
Chemistry
4-C6H4–OCH3
2-Naphthyl
–CH3
The synthetic route adopted for the synthesis of 4-functionalised
1,2,3-triazole compounds (4a–4d, 5a–5d, 6a–6d, 7a–7d, and
8a–8d) is outlined in Scheme 1. 1,2,3-Triazole-4-carboxylates
4a–4d, the supreme compounds to carry out the complete con-
version, were synthesised by reactions of 4-azidobenzenesulphona-
mide (10) with differently substituted b-ketoesters (11a–11d) in
the presence of organic base. 4-Azidobenzenesulphonamide (10)
in turn was prepared from sulphanilamide (9) via diazotisation fol-
lowed by treatment with sodium azide47. After the synthesis, 1,2,3-
triazole-4-carboxylates 4a–4d were converted to corresponding
carboxylic acids 5a–5d by hydrolysis with a strong base and
7.6
38
–C6H5
4-C6H4–OCH3
2-Naphthyl
–CH3
–C6H5
4-C6H4–OCH3
2-Naphthyl
5.6
1.6
58.9
9.4
4
2
359.6
8.4
1.9
1.9
8.1
12.1
74
AZA: acetazolamide (reference compound).
aMean from three different assays, by a stopped flow technique (errors were in
the range of 5–10% of the reported values).
O
N3
NH2
OEt
R
O
O
(i), (ii)
(iii)
N
+
N
R
OEt
N
H2NO2S
SO2NH2
SO2NH2
9
10
11a-11d
4a-4d
O
O
R
R
NH2
OH
H2NO2S
N
H2NO2S
N
N
N
N
N
6a-6d
5a-5d
O
R
N
OEt
H2NO2S
N
N
(
v
4a-4d
i
i
)
O
R
R
NHNH2
OH
H2NO2S
N
N
H2NO2S
N
N
N
N
7a-7d
8a-8d
4,5,6,7,8,11
a
b
c
d
R
-CH3
-C6H5
4-C6H4-OCH3
2-Naphthyl
Scheme 1. Synthetic pathway to the sulphonamides 4a–4d, 5a–5d, 6a–6d, 7a–7d, and 8a–8d. Reagents and conditions: (i) HCl, NaNO2, H2O, 0 ꢁC, 15 min; (ii) NaN3,
0 ꢁC, 30 min; (iii) Piperidine, DMSO, 70 ꢁC, 4 h; (iv) NaOH, reflux, 3 h then H3Oþ; (v) NH3 solution, stir, 22 h; (vi) NH2NH2.H2O, EtOH, reflux, 10–12 h; (vii) LiAlH4, dry THF,
reflux, 2 h then H3Oþ.

1192
R. KUMAR ET AL.
corresponding carboxamide derivatives 6a–6d by treatment with
ammonia solution. 1,2,3-Triazole-4-hydrazinocarbonyl derivatives
7a–7d were obtained by treating their corresponding esters
4a–4d with hydrazine hydratein ethanol while 1,2,3-triazole-4-
hydroxymethyl derivatives 8a–8d were prepared by treating esters
4a–4d with lithium aluminium hydride48 (Scheme 1).
ii. Nearly all the newly synthesised compounds (4a–4d, 5a–5d,
6a–6d, 7a–7d, and 8a–8d) showed better inhibitory potential
in low nanomolar range with Ki ꢀ 9.4 nM except three com-
pounds namely 5b, 7b, and 8a against the most abundant
isoform hCA II as compared to standard drug AZA (Ki
¼12.1 nM). Some of the tested compounds mainly 5-CH3
derivatives (4a, 5a, and 6a) and two other compounds (7d
and 8c) exhibited inhibitory potency (Ki ꢀ 4 nM) several times
better than AZA (Table 1).
iii. All the tested compounds except some 5-CH3 derivatives
namely 5a, 6a, 7a, and 8a showed excellent inhibition poten-
tial with Ki in the range of 1.4–55.3 nM against membrane
bound isoform, hCA IV as compared to standard drug AZA.
Most of the compounds (4a–4d, 5c–5d, 6b–6d, 7c–7d, and
8b–8d) have their inhibitory potency (Ki ꢀ 8.4 nM) several
folds superior than AZA (Ki ꢀ 74 nM) against hCA IV which is
one of the drug target for designing antiglaucoma drugs
(Table 1).
iv. In general, all the tested compounds except few (4c, 5b, 5c,
6b, 7b, 8a, and 8b) have shown better activity profile
(Ki ꢀ 9.5 nM) against tumour associated membrane bound
isozyme hCA IX as compared to reference drug AZA (Ki
¼25.8 nM). It is significant to mention here that, in the
broader sense, derivatives with 5-CH3and 5-(naphtha-2-yl)
substitution have shown better activity as compared to other
derivatives (Table 1).
v. Interestingly compounds possessing rather bulky scaffolds
were milder inhibitors of cytosolic isoform hCA I, over other
isoforms (hCA II, IV, and IX) and is mainly due to the fact that
the active site cavity of hCA I is smaller than other isozymes
hCA II, IV and IX, because of the presence of two His residues
(i.e. His 200 and His 67)50. Overall comparison of activity, in
terms of SAR, reveals that all the compounds except deriva-
tives with 5-CH3 group were better selective for hCA II and
IV over hCA I in the broader sense. Therefore, these com-
pounds can be important candidates for designing antiglau-
coma drugs. However, their good activity against both hCA II
and hCA IX suggests that structure of compounds needs fur-
ther modification for getting better selectivity for tumour
associated hCA IX over hCA II.
The structures of all the newly synthesised compounds (4a–4d,
5a–5d, 6a–6d, 7a–7d, and 8a–8d) were characterised by a rigor-
ous analysis of their IR, 1H NMR and 13C NMR spectral data.
Structures were further confirmed by their HRMS data. In FT-IR, a
strong characteristic absorption band for C¼O stretch was
observed in the range 1704–1728 cmꢂ1 for 1,2,3-triazole-4-carboxy-
lates 4a–4d, 1690–1713 cmꢂ1 for 1,2,3-trazole-4-carboxylic acids
5a–5d, 1674–1690 cmꢂ1 for 1,2,3-triazole-4-carboxamides 6a–6d
and 1659–1670 cmꢂ1 for 1,2,3-triazole-4-hydrazinocabonyl deriva-
tives 7a–7d while no such absorption band was observed in 1,2,3-
triazole-4-hydroxymethyl compounds 8a–8d showing the com-
plete reduction of ester group to hydroxymethyl group. The NMR
spectra of ethyl esters of 1,2,3-triazole-4-caboxylic acids 4a–4d dis-
played a quartet in the range d 4.37–4.00 ppm of two protons and
a triplet in the range d 0.81–1.35 ppm of three protons for ethyl
group. Conversion of ester compounds 4a–4d to the correspond-
ing carboxylic acids 5a–5d was confirmed by
a downfield
exchangeable singlet around d 13.00 ppm due to COOH with dis-
appearance of signals due to ethyl group protons. Similarly, 1,2,3-
triazole-4-carboxamides 6a–6d were characterised by two
exchangeable singlets in the range of d 7.94–8.04 ppm and
7.52–7.54 ppm corresponding to NH and OH protons, target 1,2,3-
triazole-4-hydrazinocarbonyls 7a–7d showed two exchangeable
singlets in the range d 9.53–9.88 ppm due to NH proton and d
4.45–4.50 ppm due to NH2 protons whereas 1,2,3-triazole-4-hydrox-
ymethyl compounds 8a–8d displayed
a
triplet around
d
5.11–5.25 ppm of OH and a doublet around d 4.48–4.65 ppm of
CH2 protons. The presence of sulphonamide group in all the target
4-functionalised 1,2,3-triazole compounds (4–8) was evident from
a broad singlet, exchangeable in D2O, appearing in the range d
7.44–7.56 ppm.
CA inhibition
All the newly synthesised 4-functionalised 1,2,3-triazole com-
pounds (4a–4d, 5a–5d, 6a–6d, 7a–7d, and 8a–8d) were evaluated
against cytosolic isoenzymes hCA I & hCA II and membrane bound
isoenzymes hCA IV & hCA IX for their CA inhibition potential by
using stopped-flow CO2hydrase assay method49 and acetazola-
mide (AZA) was chosen as reference drug for the assay. In general,
all the assayed compounds have shown significant inhibitory
action against the reported isoforms, with low nanomolar inhib-
ition constant (Ki). Inhibition data of the compounds as given in
Conclusions
In this paper, we report a series of twenty novel compounds of 4-
functionalised 1-aryl-5-alkyl/aryl-1,2,3-triazole compounds (4a–4d,
5a–5d, 6a–6d, 7a–7d, and 8a–8d) bearing a primary sulphona-
mide group on the phenyl ring at N-1 position of 1,2,3-triazole
scaffold with different functionalities at C-4, such as ester, carbox-
ylic acid, carboxamide, hydrazinocarbonyl, and hydroxymethyl
which were evaluated against four isozymes, hCA I, II, IV, and IX.
Most of the compounds performed better against aforementioned
isoforms showing low nanomolar potency as compared to refer-
ence drug acetazolamide. Out of twenty newly synthesised com-
pounds, seventeen compounds (except 5 b, 7 b, and 8a) showed
low nanomolar affinity (Ki ꢀ 9.4 nM) for hCA II, sixteen compounds
except the derivatives with 5-CH3 substitution have displayed
excellent activity (Ki ꢀ 55.3 nM) for hCA IV and thirteen compounds
(except 4c, 5 b, 5c, 6 b, 7 b, 8a, and 8 b) have shown better activ-
ity (Ki ꢀ 9.5) for hCA IX while most of compounds with bulkier
substitution at C-5 were medium to weaker inhibitors of hCA I
with Ki values in the range of 56.2–873.7 nM. In short, reported
compounds have shown remarkable activity against hCA I, II, IV,
and IX isoforms from which it can be concluded that 1,2,3-triazoles
Table
1 let the following insights regarding CAs inhibitory
properties.
i. The cytosolic isoform hCA I was in general significantly inhib-
ited by all the newly synthesised compounds (4a–4d, 5a–5d,
6a–6d, 7a–7d, and 8a–8d) with Ki in the range 8.3 nM–0.8737
mM (Table 1). It is pertinent to mention that 5-CH3 substituted
derivatives of newly synthesised compounds except 8a were
most effective inhibitors of hCA I with Ki ꢀ 15.1nM as com-
pared to corresponding 5-aryl derivatives. At the same time
some compounds namely 5b, 5c, 6c, 6d, 8a, and 8c showed
weaker inhibition potential as compared to reference drug
AZA (Ki ¼250nM) against hCA I that is off-target while inhibit-
ing hCA II and IV in glaucoma and hCA IX in tumours.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1193
scaffold deserve to be investigated further as a novel scaffold for
CAIs.
against breast cancer cell lines. Bioorg Med Chem
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expression of tumor-associated carbonic anhydrases. Cancer
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One of the authors (Rajiv Kumar) is grateful to University Grants
Commission, New Delhi, India, for the award of Senior Research
Fellowship and the other (Vikas Sharma) to the Council of
Scientific and Industrial Research, New Delhi, India, for the award
of Junior Research Fellowship.
17. Scozzafava A, Supuran CT, Carta F. Antiobesity carbonic
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Disclosure statement
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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