Sulfonamide bearing pyrazolylpyrazolines as potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII

Article abstract of DOI:10.1016/j.bmcl.2015.05.096

Abstract A series of pyrazolylpyrazolines was designed, synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against cytosolic human (h) isozymes hCA I and hCA II as well as transmembrane tumor associated isozymes, hCA IX and hCA XII. All the tested compounds exhibited an excellent CA activity profile against hCA I, hCA II and hCA XII when compared to the reference drug acetazolamide (AZA). Compounds 6d, 6f and 7a-7f have exhibited better inhibition profile against hCA XII (K_i = 0.47-5.1 nM) as compared with AZA (K_i = 5.7 nM) especially, compounds 6a, 7a, 7c and 7d which were nearly 10-fold better than reference drug. Against hCA II, all of the tested compounds were better than the standard drug especially compounds 6c, 6d, 7c and 7d (K_i = 1.1-1.7 nM) were many fold better inhibitors than AZA (K_i = 12.1 nM). In addition, they acted as selective CA inhibitors of isoform hCA XII over the physiological isoform hCA I.

Full text of DOI:10.1016/j.bmcl.2015.05.096

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3208–3212
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Sulfonamide bearing pyrazolylpyrazolines as potent inhibitors
of carbonic anhydrase isoforms I, II, IX and XII
a,
Poonam Khloya a, Mariangela Ceruso b, Sita Ram a, Claudiu T. Supuran b, , Pawan K. Sharma
⇑
⇑
a Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India
b Università 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
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyrazolylpyrazolines was designed, synthesized and evaluated for carbonic anhydrase (CA, EC
4.2.1.1) inhibitory activity against cytosolic human (h) isozymes hCA I and hCA II as well as transmem-
brane tumor associated isozymes, hCA IX and hCA XII. All the tested compounds exhibited an excellent
CA activity profile against hCA I, hCA II and hCA XII when compared to the reference drug acetazolamide
(AZA). Compounds 6d, 6f and 7a–7f have exhibited better inhibition profile against hCA XII (Ki = 0.47–
5.1 nM) as compared with AZA (Ki = 5.7 nM) especially, compounds 6a, 7a, 7c and 7d which were nearly
10-fold better than reference drug. Against hCA II, all of the tested compounds were better than the stan-
dard drug especially compounds 6c, 6d, 7c and 7d (Ki = 1.1–1.7 nM) were many fold better inhibitors than
AZA (Ki = 12.1 nM). In addition, they acted as selective CA inhibitors of isoform hCA XII over the physio-
logical isoform hCA I.
Received 23 January 2015
Revised 14 May 2015
Accepted 28 May 2015
Available online 14 June 2015
Keywords:
Pyrazoles
Carbonic anhydrase isoforms I, II, IX, XII
Acetazolamide
Ó 2015 Elsevier Ltd. All rights reserved.
Cancer indeed is one of the major health issues bothering
humankind. Although significant advances are increasingly being
made in fight against cancer, development of new effective thera-
peutic approaches is still highly desirable. The ongoing research
efforts in this field to diversify therapeutic interventions have led
biologists and chemists to focus their attention toward the drugs
which could target specific pathways of crucial importance in the
growth and development of tumors.1 In the past few years, several
new tumor cell targets have been identified which led to the emer-
gence of carbonic anhydrase isozymes as promising druggable tar-
get. Carbonic anhydrases (CAs, EC 4.2.1.1) belong to the family of
zinc metalloenzymes found in a diversity of organisms and primar-
ily responsible for catalyzing simple but fundamental reaction, CO2
hydration into bicarbonate and protons. Different CA isoforms play
vital roles in various crucial physiological processes such as respi-
ration, calcification, acid balance, bone respiration etc.2 CA isoen-
zymes are among the most studied proteins that find
applications as therapeutic agents such as antiglaucoma, antiobe-
sity, antidiuretic, antiepileptic, antialtitude sickness, antipain, anti-
infective, and antitumor agents or as diagnostic tools.3–7
Amongst 16 CA isoforms belonging to the a-class, hCA I and hCA
II have been recognized as cytosolic isozymes while hCA IX and
hCA XII are identified as tumor-associated, transmembrane car-
bonic anhydrase isozymes.8 hCA IX and hCA XII isoforms are
mainly involved in the regulation of pH dynamics in solid tumors.
Therefore, search for new heterocyclic lead compounds which
could selectively inhibit the tumor associated hCA IX and hCA XII
is increasingly gaining the attention of researchers with a view to
develop new anticancer therapies, with such a sulfonamide based
inhibitor, SLC-0111 entering in Phase I Clinical Trials this year.9,10
Aromatic or heterocyclic compounds containing primary sul-
fonamide group have been extensively studied as important scaf-
folds for the development of new carbonic anhydrase inhibitors
(CAIs). Some members of this interesting class of sulfonamide
derivatives such as acetazolamide (AZA), methazolamide (MZA),
ethoxzolamide (EZA), pazopanib etc. are widely used CAIs as clin-
ical drugs (Fig. 1). Literature survey indicates that pyrazole scaffold
has been an important pharmacophore and privileged nucleus pre-
sent in various novel CA inhibitors (1–4)11–14 as shown in Figure 1.
Recently, we have reported 4-functionalized pyrazoles (5) as
potent inhibitors of the tumor associated CA isozymes hCA IX
and hCA XII over off-target cytosolic isozymes hCA I and hCA II.15
This promoted us to enhance the repertoire of 4-functionalized
pyrazoles for evaluation as novel CAIs.
⇑
Corresponding authors. Tel./fax: +39 055 4573005 (C.T.S.); tel.: +91
9416457355; fax: +91 1744 238277 (P.K.S.).
E-mail addresses: claudiu.supuran@unifi.it (C.T. Supuran), pksharma@kuk.ac.in
(P.K. Sharma).
Encouraged by the low nanomolar potencies of 4-functional-
ized pyrazoles15 as CAIs and as a part of our ongoing research
http://dx.doi.org/10.1016/j.bmcl.2015.05.096
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

P. Khloya et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3208–3212
3209
O
O
O
N
N
HN
N
N
N
N
S
S
S
SO2NH2
SO2NH2
SO2NH2
AZA
H2NO2S
MZA
EZA
H2NO2S
N
N
H2N
O
S
N
N
N
O
N
N
CF3
N
R
H3C
N
H
N
OH
Pazopanib
1
Celecoxib
HO
HO
O
Ph
N
Ph
O
O
O
N
N
N
N
N
OH
HN
HN
R
NC
H2N
SO2NH2
SO2NH2
4
2
3
Figure 1. Some CA inhibitors having pyrazole nucleus.
on heterocyclic compounds,16–24 of potential biological applica-
tions, we envisaged coupling the pyrazole and the pyrazoline
moieties in one molecular frame. Here we report a small library
of pyrazolylpyrazolines 6a–6f and 7a–7f and their CA evaluation
against a panel of selective two cytosolic isozymes (hCA I and
hCA II) as well as two transmembrane isozymes (hCA IX and
hCA XII) (Fig. 2).
It is pertinent to mention here that, to the best of our knowl-
edge, we have evaluated coupled pyrazole and pyrazoline moiety
in one molecular frame for the first time for CA inhibition profile.
The synthetic strategy employed to obtain the target com-
pounds 6a–6f and 7a–7f is depicted in Scheme 1.
Starting pyrazolone 9 was synthesized by the condensation of
ethyl
acetoacetate
with
4-hydrazinobezenesulfonamide
H2NO2S
N
N
R
CONH2/COOMe/CONHNH2
5
H2NO2S
H2NO2S
N
N
N
N
Cl
O
CH3
Cl
CH3
Non Bulky
group
N
N
H2NO2S
N
N
Bulky Group
R
R
7
6
Figure 2. Pyrazolylpyrazolines (6a–6f and 7a–7f) as CA inhibitors.

3210
P. Khloya et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3208–3212
hydrochloride (8).25 The pyrazolone 9 was then subjected to the
Vilsmeier–Haack chloroformylation reaction using DMF/POCl3 to
yield the corresponding 5-chloro-3-methyl-4-formylpyrazole with
protected sulfonamide group (10). It is pertinent to mention here
that under the Vilsmeier–Haack reaction conditions, the sulfon-
amide group of the benzenesulphonamide moiety also reacts with
Vilsmeier–Haack reagent and gets converted into N-[(dimethy-
lamino)methylidine]sulfonamide group. Having 5-chloro-3-
methyl-4-formylpyrazole (10) with protected sulfonamide group
in hand, the dimethylaminomethyl group was removed under
acidic conditions to afford the corresponding 5-chloro-3-methyl-
4-formylpyrazole (11) with free sulfonamide group. Chalcones 12
were prepared by using Claisen–Schmidt condensation reaction26
of 5-chloro-3-methyl-4-formylpyrazole (11) with appropriate ace-
tophenones. The final compounds, pyrazolylpyrazolines 6 were
obtained by the condensation of appropriate chalcones 12 with
4-hydrazinobenzenesulfonamide hydrochloride (8) in ethanol con-
taining catalytic amount of glacial acetic acid while compounds 7
were obtained by treating chalcones with hydrazine hydrate in
acetic acid solvent.
The structures of all the newly synthesized compounds (10, 11,
12a–12f, 6a–6f, and 7a–7f) were characterized by a rigorous anal-
ysis of their IR, 1H NMR and 13C NMR spectral data. IR spectrum of
compound 10 showed a strong characteristic absorption band at
1674 cmÀ1 corresponding to carbonyl (C@O) stretching while the
1H NMR spectrum of compound 10 showed a characteristic singlet
at d 9.92 for formyl proton and was further supported by the
appearance of a characteristic signal at d 184.6 in its 13C NMR.
The IR spectrum of compound 11 showed a strong absorption band
at 1682 cmÀ1 corresponding to carbonyl stretching, and two bands
in the region 1342 cmÀ1 and 1157 cmÀ1 attributed to SO2 stretch-
ing. The 1H NMR spectrum of compound 11 showed a broad sin-
glet, exchangeable in D2O, at
d 7.56 attributed to free
sulfonamide protons (SO2NH2). IR and 1H NMR spectrum of com-
pound 12 clearly indicated the deprotection of sulfonamide group.
The IR spectra of chalcones 12a–12f exhibited the characteristic
absorption band for C@O stretching at ꢀ1651 cmÀ1 while the vinyl
CH@CH appeared at 1288–1296 cmÀ1. The signals for vinyl protons
in compounds 12a–12f were found to be merged with aromatic
region in 1H NMR spectra. In general, the 1H NMR spectra of target
pyrazolylpyrazolines 6a–6f showed characteristic ABX pattern of
HC NO2S
N
H2NO2S
SO2NH2
N
N
N
N
(i)
(ii)
Cl
NHNH2.HCl
O
CHO
9
8
10
H2NO2S
R
N
(iv)
(iii)
N
N
N
H2NO2S
Cl
Cl
O
CHO
12
11
R
R
N
(v)
N
N
N
H2NO2S
N
N
Cl
O
Cl
12
(vi)
H2NO2S
H2NO2S
6
R
N
N
N
N
Cl
H2NO2S
O
7
6,7,12
R
a
H
b
CH3
c
d
F
e
Cl
f
Br
OCH3
Scheme 1. Synthesis of pyrazolylpyrazolines 6a–6f and 7a–7f. (i) ethyl acetoacetate, reflux; (ii) POCl3/DMF, 50–60 °C, stir 5–6 h; (iii) Conc. HCl, reflux; (iv) substituted
acetophenones, ethanol-water, 24 h; (v) 4-hydrazinobenzenesulfonamide 8, ethanol reflux; (vi) hydrazine hydrate, acetic acid, reflux.

P. Khloya et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3208–3212
3211
three protons of pyrazoline including two methylene protons at C-
4 and one methine proton at C-5 pyrazoline. In compounds 6a–6f,
methine proton (C5-H) of pyrazoline resonates at d 5.56–5.66 as a
doublet of doublet with coupling constants of 12.6 Hz and 6.3 Hz.
One of the methylene protons (C4-H) of pyrazoline appeared as a
doublet of doublet around d ꢀ4.02 with coupling constants
18.0 Hz and 12.6 Hz in compounds 6a–6f. The other methylene
proton (C4-H) could be found at ꢀd 3.36 merging in DMSO solvent
peak in pyrazolylpyrazolines 6a–6f and 7a–7f. The pyrazolylpyra-
zolines 7a–7f followed same ABX pattern as that of compounds
6a–6f. The structures of the pyrazolylpyrazolines 6a–6f and 7a–
7f were further supported by their 13C NMR spectrum which dis-
played a signal at ꢀd 54.0 due to C-5 pyrazoline while signal for
C-4 pyrazoline could be assigned at ꢀd 40.7, merging with DMSO
signal. The other protons appeared as expected in their 1H NMR
and 13C NMR spectra. Mass spectra of 6a–6f and 7a–7f showed
the molecular ion peak at M+1 which tallies to their molecular
formula.
All the newly synthesized pyrazolylpyrazolines 6a–6f and 7a–
7f were screened for their CA inhibition prolife by stopped-flow,
CO2 hydrase assay against hCA I, hCA II, hCA IX and hCA XII
enzymes.27 The inhibition data of tested compounds are reported
in Table 1.
The data from Table 1 clearly indicate that pyrazolylpyrazolines
6a–6f and 7a–7f act as strong inhibitors of isoforms hCA I, hCA II
and hCA XII. The following features could be extracted from the
data given in Table 1 regarding the CAs inhibitory properties of
pyrazolylpyrazoline derivatives:
(Ki = 0.17 nM), 7b (Ki = 0.54 nM), 7e (Ki = 0.26 nM) and 7f
(Ki = 0.30 nM) exhibited the inhibitory effect several fold
superior than AZA (Ki = 12.1 nM) for hCA II while five com-
pounds 6b, 6c, 6d, 7c and 7d were also found to be more
potent than AZA exhibiting potency in nanomolar range
with Ki 62 nM.
(3) All the tested compounds in both series of pyrazolylpyrazo-
lines 6a–6f and 7a–7f weakly inhibited tumor associated
isoform hCA IX except the compound 7d (R = F,
Ki = 6.9 nM) when compared to the standard drug AZA
(Ki = 25 nM).
(4) Tumor associated isoform hCA XII was strongly inhibited by
all the synthesized pyrazolylpyrazoline analogs 6a–6f and
7a–7f, except 6e, in nano molar and subnanomolar range
with Ki values 0.47–9.4 nM. Amongst all the tested com-
pounds, three analogs in the series of N-acetyl-substituted
pyrazolylpyrazolines
(7a–7f)
namely,
7a
(R = H,
Ki = 0.58 nM), 7c (R = OCH3, Ki = 0.54 nM) and 7d (R = F,
Ki = 0.57 nM) displayed inhibitory potential approximately
10-fold superior than AZA (Ki = 5.7 nM). Indeed, one com-
pound 6f (R = Br, Ki = 0.47 nM) in the series of N-benzenesul-
fonamide-substituted pyrazolylpyrazolines (6a–6f) was also
found to be more effective exhibiting 12-fold better CA inhi-
bition profile than the standard drug AZA. It can be con-
cluded from the Table 1 that the trend of CA inhibitory
potential
against
hCA
XII
was
found
to
be
6f < 7c < 7d < 7a < 6d < 7e < 7b and 7f with Ki 65.1 nM from
the most effective to the least effective compound.
(5) In general N-acetylsubstituted pyrazolylpyrazolines (7a–7f)
fared better in inhibiting hCA XII as compared to N-benzene-
sulfonamide substituted pyrazolylpyrazolines (6a–6f) indi-
cating that on a bulkier group at N-1 of pyrazoline is
detrimental to inhibition potency against hCA XII.
(6) Selectivity ratio for inhibiting the tumor-associated isoforms
(hCA IX and hCA XII) over the off-target cytosolic isoforms
(hCA I and hCA II) by compounds 6a–6f and 7a–7f has also
been presented in Table 2. It is evident that newly synthe-
sized compounds 6a–6f and 7a–7f showed better selectivity
ratio for tumor associated enzymes IX and XII with respect
to hCA I (Table 2). The entire series of compounds 6a–6f
and 7a–7f exhibited selectivity profile in the range of
160.4–0.32 for hCA IX and 1942.10–4.47 for hCA XII enzyme.
Compound 7d being the most efficient inhibitor of both
(1) The cytosolic isoform hCA I was in general significantly
inhibited by both series of pyrazolylpyrazolines 6a–6f and
7a–7f. The most effective compounds against the hCA I were
7a, 6f, 7e, 7b, and 6b arranged in a descending order from
the most effective to the least one with Ki 632.5 nM.
However, all the pyrazolylpyrazolines 6a–6f and 7a–7f were
found to be more potent than standard drug acetazolamide
(AZA) with Ki value <250 nM except two compounds 6d
(R = F) and 6e (R = Cl) having Ki values >250 nM.
(2) All the synthesized analogs in both series of pyrazolylpyra-
zolines displayed excellent inhibitory potential in nanomo-
lar and subnanomolar range with Ki values 0.17–10.9 nM
against the most abundant isoform hCA II. Out of all the
tested compounds,
four
compounds namely
7a
Table 1
Table 2
Carbonic anhydrase activity of pyrazolylpyrazolines 6a–6f and 7a–7f using a stopped-
flow, CO2 hydrase assay
Selectivity ratios for the inhibition of the tumor-associated isozymes hCA IX and hCA
XII over the cytosolic isozymes hCA I and hCA II for compounds
Compounds
R
Ki* (nM)
hCA IX
Inhibitors
R
Selectivity ratio*
hCA II/IX hCA I/XII
hCA I
hCA II
hCA XII
hCA I/IX
hCA II/XII
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
H
245
32.5
185
143
320
20.7
20.4
26.7
85.6
1107
23.3
149
250
10.9
0.6
1.5
1.4
3.1
71.6
70.7
52.4
44.7
32.9
44.4
63.1
67.1
56.9
6.9
9.4
7.1
5.9
3.0
55.7
0.47
0.58
4.0
0.54
0.57
3.9
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
H
3.42
0.45
3.53
3.19
9.72
0.46
0.32
0.39
1.50
160.40
0.75
2.21
10.0
0.15
0.01
0.02
0.03
0.09
0.12
0.01
0.01
0.02
0.24
0.01
0.01
0.4
26.06
4.47
31.35
47.66
5.74
44.04
35.17
6.67
158.51
1942.10
5.97
1.15
0.08
0.25
0.46
0.05
11.70
0.29
0.13
2.03
2.98
0.06
0.05
2.1
CH3
OCH3
F
Cl
Br
CH3
OCH3
F
Cl
Br
5.5
H
0.17
0.54
1.1
H
CH3
OCH3
F
Cl
Br
CH3
OCH3
F
Cl
Br
1.7
0.26
0.30
12.1
30.8
67.2
25
5.1
5.7
29.21
43.8
AZA
AZA
AZA = acetazolamide, reference compound, a standard sulfonamide CAI, is also
provided for comparison.
AZA = acetazolamide, reference compound, a standard sulfonamide CAI, is also
provided for comparison.
*
*
Mean from 3 different assays, errors were in the range of 5–10% of the
The Ki ratios are indicative of isozyme selectivity: a weak selective inhibitor is
reported value.
characterized by a low ratio value.

3212
P. Khloya et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3208–3212
2. (a) Supuran, C. T. J. Enzyme Inhib. Med. Chem. 2012, 27, 759; (b) Supuran, C. T. J.
isoforms hCA XII and IX, was about forty-five fold more
selective for hCA XII and sixteen-times more selective for
hCA IX over physiological isoform hCA I.
Enzyme Inhib. Med. Chem. 2013, 28, 229; (c) Capasso, C.; Supuran, C. T. J. Enzyme
Inhib. Med. Chem. 2014, 29, 379; (d) Thiry, A.; Dogne, J. M.; Masereel, B.;
Supuran, C. T. Trends Pharmacol. Sci. 2006, 27, 566.
3. (a) Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Supuran, C. T.; De Simone, G. Chem.
Rev. 2012, 112, 4421; (b) Carta, F.; Supuran, C. T. Expert Opin. Ther. Patents 2013,
23, 681.
4. Masini, E.; Carta, F.; Scozzafava, A.; Supuran, C. T. Expert Opin. Ther. Patents
2013, 23, 705.
5. Scozzafava, A.; Supuran, C. T.; Carta, F. Expert Opin. Ther. Patents 2013, 23, 725.
6. (a) Aggarwal, M.; Kondeti, B.; McKenna, R. Expert Opin. Ther. Patents 2013, 23,
717; (b) Maresca, A.; Vullo, D.; Scozzafava, A.; Manole, G.; Supuran, C. T. J.
Enzyme Inhib. Med. Chem. 2013, 28, 392; (c) Maresca, A.; Scozzafava, A.; Vullo,
D.; Supuran, C. T. J. Enzyme Inhib. Med. Chem. 2013, 28, 384; (d) Gieling, R. G.;
Parker, C. A.; De Costa, L. A.; Robertson, N.; Harris, A. L.; Stratford, I. J.; Williams,
K. J. J. Enzyme Inhib. Med. Chem. 2013, 28, 360; (e) Del Prete, S.; Vullo, D.; Fisher,
G. M.; Andrews, K. T.; Poulsen, S. A.; Capasso, C.; Supuran, C. T. Bioorg. Med.
Chem. Lett. 2014, 24, 4389.
7. Monti, S. M.; Supuran, C. T.; Simone, G. D. Expert Opin. Ther. Patents 2013, 23,
737.
8. Shin, H. J.; Bae Rho, S.; Chul Jung, S.; Han, I. O.; Oh, E. S.; Kim, J. Y. J. Cell Sci.
2014, 124, 1077.
9. Winum, J. Y.; Rami, M.; Scozzafava, A.; Montero, J. L.; Supuran, C. T. Med. Res.
Rev. 2008, 28, 445.
10. (a) Neri, D.; Supuran, C. T. Nature Rev. Drug Disc. 2011, 10, 767; (b) See more at
ClinicalTrails.gov: Safety Study of SLC-0111 in Subjects With Advanced Solid
Tumours—Full Text View—ClinicalTrials_gov.mht.
(7) A comparative study of N-benzenesulfonamide-substituted
pyrazolylpyrazolines 6a–6f and N-acetyl-substituted pyra-
zolylpyrazolines 7a–7f revealed that in general the N-
acetyl-substituted pyrazolylpyrazolines 7a–7f exhibited
better inhibitory potency against hCA IX, XII and II when
compared to the N-benzenesulfonamide-substituted pyra-
zolylpyrazolines (6a–6f).
In the present report, twelve novel pyrazolylpyrazolines 6a–6f
and 7a–7f were synthesized and screened for inhibition profile
against four human carbonic anhydrase isoforms. Most of the
tested compounds displayed excellent inhibitory potency in
nanomolar range against hCA I, hCA II and hCA XII when compared
to the reference drug acetazolamide. Some of the tested com-
pounds in series of pyrazolylpyrazolines 6a–6f and 7a–7f namely,
6d, 6f, 7a, 7b, 7c, 7d, 7e, and 7f exhibited low nanomolar Ki values
65 nM for hCA XII while nine compounds, 6b, 6c, 6d, 7a, 7b, 7c, 7d,
7e and 7f were found to be more potent exhibiting Ki values 62 nM
against hCA II. In addition, one compound 7d was more selective
for tumor associated isoforms hCA IX and XII over cytosolic isoform
hCA I. From the results it can be concluded that pyrazolylpyrazoli-
nes scaffold deserves to be investigated further as a novel scaffold
for CAIs.
11. Balseven, H.; Isgor, M. M.; Mert, S.; Alim, Z.; Beydemir, S.; Ok, S.; Kasimogullari,
R. Bioorg. Chem. 2013, 21, 21.
12. Rogez-Florent, T.; Meignan, S.; Foulon, C.; Six, P.; Gros, A.; Bal-Mahieu, C.;
Supuran, C. T.; Scozzafava, A.; Frederick, R.; Masereel, B.; Depreux, P.; Lansiaux,
A.; Goossens, J. F.; Gluszok, S.; Goossens, L. Bioorg. Med. Chem. 2013, 21, 1451.
13. Weber, A.; Casini, A.; Heine, A.; Kuhn, D.; Supuran, C. T.; Scozzafava, A.; Klebe,
G. J. Med. Chem. 2004, 47, 550.
14. Gluszok, S.; Frederick, R.; Foulon, C.; Klupsch, F.; Supuran, C. T.; Vullo, D.;
Scozzafava, A.; Gossens, J. F.; Masereel, B.; Depreux, P.; Goossens, L. Bioorg.
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Acknowledgements
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One of the authors (Poonam Khloya) is grateful to the Haryana
State Council for Science and Technology (HSCST), Panchkula
(Haryana), India and the other (Sita Ram) to the Council of
Scientific and Industrial Research, New Delhi, India for the award
of Senior Research Fellowships. The authors are thankful to
Sophisticated Analytical Instrument Facility, Central Drug
Research Institute, Lucknow for providing Mass spectra. Work from
CTS lab was financed by an EU project of the FP7 programme
(Metoxia).
20. Chandna, N.; Kumar, S.; Kaushik, P.; Kaushik, D.; Roy, S. K.; Gupta, G. K.; Jachak,
S. M.; Kapoor, J. K.; Sharma, P. K. Bioorg. Med. Chem. 2013, 21, 4581.
21. Chandna, N.; Chandak, N.; Kumar, P.; Kapoor, J. K.; Sharma, P. K. Green Chem.
2013, 15, 2294.
22. Sharma, P. K.; Kumar, S.; Kumar, P.; Kaushik, D.; Kaushik, Y.; Aneja, K. R. Eur. J.
Med. Chem. 2010, 45, 2650.
Supplementary data
23. Khloya, P.; Kumar, P.; Mittal, A.; Aggarwal, N. K.; Sharma, P. K. Org. Med. Chem.
Lett. 2013, 3, 9. http://dx.doi.org/10.1186/2191-2858-3-9.
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N. K.; Sharma, R. K.; Sharma, P. K.; Saso, L. J. Enzyme Inhib. Med. Chem. 2014, 76.
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Supplementary data (biological assay, experimental procedure
and spectroscopic characterization of compounds 6a–6f and 7a–
7f) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.bmcl.2015.05.096.
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