Isatin: A privileged scaffold for the design of carbonic anhydrase inhibitors

Article abstract of DOI:10.1080/14756366.2016.1235042

The isatin scaffold is the constitutive fragment of several natural and synthetic bioactive molecules. Albeit several benzene sulphonamide-based carbonic anhydrase inhibitors (CAIs) have been reported, only recently isatin benzene sulphonamides have been

Full text of DOI:10.1080/14756366.2016.1235042

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Isatin: a privileged scaffold for the design of
carbonic anhydrase inhibitors
Claudia Melis, Rita Meleddu, Andrea Angeli, Simona Distinto, Giulia Bianco,
Clemente Capasso, Filippo Cottiglia, Rossella Angius, Claudiu T. Supuran &
Elias Maccioni
To cite this article: Claudia Melis, Rita Meleddu, Andrea Angeli, Simona Distinto, Giulia Bianco,
Clemente Capasso, Filippo Cottiglia, Rossella Angius, Claudiu T. Supuran & Elias Maccioni
(2016): Isatin: a privileged scaffold for the design of carbonic anhydrase inhibitors, Journal of
Enzyme Inhibition and Medicinal Chemistry, DOI: 10.1080/14756366.2016.1235042
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Date: 26 October 2016, At: 04:12

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2016
http://dx.doi.org/10.1080/14756366.2016.1235042
RESEARCH ARTICLE
Isatin: a privileged scaffold for the design of carbonic anhydrase inhibitors
Claudia Melisa, Rita Meleddua, Andrea Angelib, Simona Distintoa, Giulia Biancoa, Clemente Capassoc,
Filippo Cottigliaa, Rossella Angiusd, Claudiu T. Supuranb and Elias Maccionia
b
aDepartment of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy; Dipartimento NEUROFARBA, Sezione di Scienze
c
ꢀ
Farmaceutiche, Universita degli Studi di Firenze, Sesto Fiorentino, Florence, Italy; Istituto di Bioscienze e Biorisorse, CNR, Napoli, Italy;
dLaboratorio NMR e Tecnologie Bioanalitiche, Sardegna Ricerche, Pula, CA, Italy
ABSTRACT
ARTICLE HISTORY
Received 9 August 2016
Revised 6 September 2016
Accepted 6 September 2016
Published online 25 October
2016
The isatin scaffold is the constitutive fragment of several natural and synthetic bioactive molecules. Albeit
several benzene sulphonamide-based carbonic anhydrase inhibitors (CAIs) have been reported, only
recently isatin benzene sulphonamides have been studied and proposed as CAIs. In this study we have
designed, synthesised, and evaluated the biological activity of a series of differently substituted isatin-
based benzene sulphonamides which have been designed for the inhibition of carbonic anhydrase iso-
forms. The activity of all the synthesised compounds was evaluated towards human carbonic anhydrase I,
II, IX, and XII isozymes. Our results indicate that the nature and position of substituents on the isatin ring
can modulate both activity and isozyme selectivity.
KEYWORDS
Antitumour agents;
carbonic anhydrase
inhibitors; isatin hybrid
molecules
Introduction
effect is an attractive target for medicinal chemists, for the treat-
ment of multifactorial pathologies such as cancer41–43. On the
basis of the above and with the aim to achieve structure-activity
relationships on isatin derived CAIs, we have designed and
The isatin nucleus could be considered as a privileged scaffold for
the design of biologically active agents. The discovery and opti-
misation of isatin-based therapeutic agents have consistently
attracted the interest of medicinal chemists and the chemistry, the
biological properties and the therapeutic potential of isatin-based
agents has been recently reviewed1. Several biological activities
could be achieved by decoration of the isatin scaffold such as
synthesised
a series of new 4-{[5–(2-oxo-2,3-dihydro-1H-indol-
3-ylidene)-3-methyl-4-oxo-1,3-thiazolidin-2-ylidene]amino}benzene-1-
sulphonamides as potential inhibitors of the tumour associated CA
isoforms IX and XII.
anti-cancer2–7, anti-oxidant6, HIV reverse transcriptase inhibition8,9
neuroprotective10, anti-fungal11,12 anti-bacterial13,14 and anti-
,
,
Methods
diabetic15. Moreover, the isatin ring has been pointed out as an
essential part of anticancer hybrid molecules16,17. Recently, the
design of isatin-based carbonic anhydrase inhibitors (CAIs) has
been reported10,11,18–20. It is common knowledge that carbonic
anhydrase isozyme family is involved in several physiological
and/or pathological metabolic pathways21–26. They catalyse the
simple reaction of the reversible hydration of carbon dioxide to
bicarbonate and protons27, which is essential for the regulation of
the different chemical species connected with CO2 in the body
and its transport across biological membranes such as the inter-,
intra- and extra-cellular spaces25,28. Not surprisingly several CAIs
have been reported and their therapeutic potential has been
directed towards different pathologies29–31 (Figure 1).
Materials and apparatus
Starting materials and reagents were obtained from commercial
suppliers and were used without purification. All melting points
were determined on a Stuart SMP11 melting points apparatus
(Stone, UK) and are uncorrected. Electron ionisation mass spectra
were obtained by
a Fisons QMD 1000 mass spectrometer
(Danvers, MA) (70 eV, 200 mA, ion source temperature 200 ꢀC).
Samples were directly introduced into the ion source. Found mass
values are in agreement with theoretical ones. Melting points,
yield of reactions and the analytical data of derivatives are
reported in Table 1.
1H-NMR (Table 2) were registered on a Bruker 400 MHz spec-
trometer (Billerica, MA) or on a Varian 500 MHz (Palo Alto, CA)
Within CAIs, benzene-sulphonamides are widely represente-
d
32–35and their binding on carbonic anhydrase investigated36. (Table 2). All samples were measured in DMSO. Chemical shifts are
Benzene-sulphonamides are versatile scaffold that can be effi- reported referenced to the solvent in which they were measured.
ciently substituted to achieve isozyme specificity17,19,20,35,37–39. In Coupling constants J are expressed in hertz (Hz). Elemental analy-
ses were obtained on
a Perkin–Elmer 240 B microanalyser
this respect, the specific targeting of the tumour associated CA
isoforms IX and XII represents an innovative and specific approach
for the treatment of tumours23,40,41. Furthermore, the identification
of hybrid molecules, containing both the isatin scaffold and the
(Waltham, MA). Analytical data of the synthesised compounds are
in agreement within 0.4% of the theoretical values. TLC chroma-
tography was performed using silica gel plates (Merck F 254,
Billerica, MA), spots were visualised by UV light.
benzene-sulphonamide moiety, with
a multi-pharmacological
CONTACT Rita Meleddu
rita.meleddu@unica.it
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, Cagliari 09124, Italy;
Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Universita degli Studi di Firenze, Via Ugo Schiff, 6
ꢀ
Claudiu T. Supuran
claudiu.supuran@unifi.it
50019 Sesto Fiorentino, Florence, Italy
ß 2016 Informa UK Limited, trading as Taylor & Francis Group

2
C. MELIS ET AL.
Figure 1. Carbonic anhydrase inhibitors in clinical use: (1) acetazolamide, (2) (methazolamide, (3) ethoxzolamide, (4) dichlorphenamide, (5) dorzolamide, (6) brinzolamide,
and (7) topiramate.
Table 1. Chemical, analytical, and physical data of derivatives EMAC 10020.
O
O
CH
3
N
HN
S
N
O
R
S
NH
2
O
C–H–N
M.P. ꢀC
Yield %
Mass fragments
ꢁ
Compound
R
R.F.
Calc.
Found
EMAC 10020 a
EMAC 10020 c
EMAC 10020 d
EMAC 10020 l
EMAC 10020 m
EMAC 10020 n
EMAC 10020 o
ꢁ
H
0.52
0.38
0.42
0.50
0.65
0.51
0.69
C, 52.16; H, 3.40; N, 13.52
C, 48.16; H, 2.92; N, 12.48;
C, 49.99; H, 3.03; N, 12.96;
C, 53.26; H, 3.76; N, 13.08;
C, 49.99; H, 3.03; N, 12.96;
C, 47.30; H, 2.72; N, 11.61;
C, 43.82; H, 2.66; N, 11.36;
C, 52.19; H, 3.39; N, 13.50
C, 48.19; H, 2.90; N, 12.46;
C, 50.01; H, 3.00; N, 12.93;
C, 53.29; H, 3.73; N, 13.05;
C, 50.00; H, 3.01; N, 12.95;
C, 47.33; H, 2.70; N, 11.59;
C, 43.85; H, 2.64; N, 11.33;
320d
320-1
310-2
320-2
288d
314d
320d
38
71
66
67
43
41
75
414; 386; 373
448; 420; 407
432; 404; 391
428; 400; 387
432; 404; 391
482; 454; 441
492; 464; 451
5-Cl
5-F
5-CH3
7-F
5-CF3
7-Br
R.F. values were obtained on silica gel plates using a mixture of ethyl acetate/n-hexane 2/1.
Biological activity
(10%) and the stacking gel (3%) contained SDS (0.1%), respect-
ively. Activities of CA isoenzymes were determined according to a
method by Verporte et al.45 The increase in absorbance of reaction
medium was spectrophotometrically recorded at 348 nm. Also, the
quantity of protein was determined at 595 nm according to the
Bradford method46. Bovine serum albumin was used as standard
protein. The IC50 values were obtained from activity (%) versus
compounds plots47. For calculation of KI values, three different
concentrations were used. The Lineweaver–Burk curves were
drawn and calculations were realised47. The biological data are
reported in Table 3.
Carbonic anhydrase inhibition assay
The purification of cytosolic CA isoenzymes (CA I and CA II) were
previously described with
a simple one-step method by a
Sepharose-4B-L tyrosine-sulphanilamide affinity chromatography44
.
The protein quantity in the column effluents was determined
spectrophotometrically at 280 nm. Sodium dodecyl sulphate-
polyacrylamide gel electrophoresis (SDS-PAGE) was applied with a
R
Bio-Rad Mini Gel system Mini-PROTEINV system (Hercules, CA), Bio-
Rad Laboratories, Inc., China after purification of both CA isoen-
zymes. Briefly, it was performed in acrylamide for the running

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
3
Table 2. 1H NMR and 13C NMR data of derivatives EMAC 10020.
Compound
1H NMR d (ppm)
EMAC 10020 a
EMAC 10020 c
EMAC 10020 d
EMAC 10020 l
EMAC 10020 m
EMAC 10020 n
EMAC 10020 o
1H NMR (500 MHz, DMSO-d6) d (ppm): 3.32- 3.36 (3H, s, CH3, N-CH3); 7.05- 7.09 (1H, s, CH, Isat.); 6.91-6.93 (1H, d, J ¼ 7.6 Hz, CH, Isat.); 7.20
(2H, d, CH, J ¼ 8.8 Hz, 4-SO2NH2 phenyl); 7.35- 7.39 (3H, m, CH þ NH2, Isat.þ SO2NH2)7.86- 7.89 (2H, d, CH, J ¼ 8.8 Hz, 4-SO2NH2 phenyl);
8.84- 8.86 (1H, d, CH, J ¼ 8 Hz, Isat.); 11.20 (1H, s, NH, Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm): 29.10, 109.93, 120.10, 121.46, 123.55,
127.19, 128.05, 124.30, 130.80, 132.37, 140.16, 140.98, 150.52, 154.32, 165.46, 168.40.
1H NMR (500 MHz, DMSO-d6) d (ppm): 3.29- 3.37 (3H, s, CH3, N-CH3); 6.93- 6.95 (1H, d, CH, J ¼ 8.5 Hz, 5-Cl Isat.); 7.16- 7.20 (2H, d, CH,
J ¼ 8.5 Hz, 4-SO2NH2 phenyl); 7.33 (2H, s, NH2, SO2NH2); 7.41- 7.43 (1H, d, CH, Jo ¼ 8.5 Hz, Jm¼ 2, 5 Hz -Cl Isat.); 7.86- 7.88 (2H, d, CH,
J ¼ 8.5 Hz, 4-SO2NH2 phenyl); 8,89 (1H, d, CH, J ¼ 2 Hz, 5-Cl Isat.); 11.32 (1H, s, NH, 5-Cl Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm):
28.88, 111.47, 121.23, 121.41, 123.79, 125.81, 127.10, 127.31, 131.08, 132.55, 140.32, 141.89, 150.32, 153.96, 165.44, 168.05.
1H NMR (400 MHz, DMSO-d6) d (ppm): 3.33 (3H, s, CH3, N-CH3); 6.88 (1H, m, CH, 5-F Isat.); 7.18- 7.22 (2H, d, CH, J ¼ 8.4 Hz, 4-SO2NH2 phenyl);
7.22-7.25 (1H, d, CH, 5-F Isat.); 7.37 (2H, s, NH2, SO2NH2); 7.87- 7.90 (2H, d, CH, J ¼ 8.8 Hz, 4-SO2NH2 phenyl); 8.58 (1H, m, CH, 5-F Isat.);
11.20 (1H, s, NH, 5-F Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm): 28.91, 111.08, 114.54, 118.16, 120.70, 121.38, 124.46, 127.28, 132.35,
140.34, 150.35, 154.06, 156.30, 158.63, 165.58, 168.35.
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.30 (3H, s, CH3, 5-CH3 Isat.); 3.30- 3.35 (3H, s, CH3, N-CH3); 6.79 (1H, d, CH, 5-CH3 Isat.); 7.16-7.19
(3H, m, CH, 4-SO2NH2 phenyl þ5-CH3 Isat); 7.33 (2H, s, NH2, SO2NH2); 7.87 (2H, d, CH, J ¼ 8 Hz, 4-SO2NH2 phenyl); 8.67 (1H, s, CH, 5-CH3
Isat.); 11.05 (1H, s, NH, 5-CH3 Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm): 21.14, 29.12, 109.94, 120.06, 121.47, 123.50, 127.20, 128.03,
130.12, 130.70, 132.36, 140.15, 140.97, 150.52, 154.32, 165.45, 168.39.
1H NMR (500 MHz, Acetone-d6) d (ppm): 3.48 (3H, s, CH3, N-CH3); 7.13-7.15(1H, m, 7-F Isat.); 7.21-7.23 (2H, d, CH, J ¼ 8.5 Hz, 4-SO2NH2 phe-
nyl); 7.25-7.29 (3H, m, CH þ NH2,7-F Isat.þ SO2NH2), 7.96 (2H, d, CH, J ¼ 8.5 Hz, 4-SO2NH2 phenyl); 8.85 (1H, d, CH, J ¼ 8 Hz, 7-F Isat.);
10.43 (1H, s, NH, 7-F Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm): 28.91, 111.10, 114.54, 118.16, 120.70, 121.38, 122.90, 125.90, 127.28,
132.35, 150.35, 154.06, 156.30, 162.90, 165.58, 168.35.
1H NMR (400 MHz, Acetone-d6) d (ppm): 3.35 (3H, s, CH3, N-CH3); 7.04- 7.08 (1H, m, CH, 5-CF3 Isat.); 7.12 (2H, d, CH, J ¼ 8.5 Hz, 4-SO2NH2
phenyl); 7.27- 7.31 (1H, t, CH, J ¼ 8 Hz, 5-CF3 Isat.); 7.31 (2H, weak s, NH2, SO2NH2); 7.99 (2H, d, CH, J ¼ 8.5 Hz, 4-SO2NH2 phenyl); 8.67
(1H, d, CH, J ¼ 8 Hz, 5-CF3 Isat.); 11.67 (1H, NH, 5-CF3 Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm): 29.13, 109.95, 120.07, 121.47, 123.50,
124.60, 127.20, 128.04, 130.12, 130.71, 132.36, 140.16, 140.97, 150.53, 154.32, 165.45, 168.39.
1H NMR (500 MHz, DMSO-d6) d (ppm): 3.34 (3H, s, CH3, N-CH3); 6.99- 7.02 (1H, t, CH, J ¼ 8 Hz, 7-Br Isat); 7.19- 7.20 (2H, d, CH, J ¼ 8.5 Hz,
4-SO2NH2 phenyl); 7.34 (2H, s, NH2, SO2NH2); 7.54- 7.55 (1H, d, J ¼ 8 Hz, CH, 7-Br Isat.); 7.87- 7.89 (2H, d, CH, J ¼ 8.5 Hz, 4-SO2NH2 phenyl);
8.81- 8.83 (1H, d, CH, J ¼ 8 Hz, 7-Br. Isat.); 11.43 (1H, s, NH, 7-Br Isat.). 13C NMR (100 MHz, DMSO-d6) d (ppm): 29.02, 102.69, 121.45,
121.68, 123.37, 124.44, 126.71, 127.26, 132.79, 134.27, 140.30, 142.17, 150.38, 153.97, 165.31, 168.26.
General procedure for the synthesis of compound EMAC10020
anhydride (1,5 eq), and sodium acetate (2 eq) was refluxed over-
night in acetic acid. Once the reaction has come to completion
TLC (ethyl acetate/n-hexane 2/1) the hot suspension was filtered.
The obtained red/orange solid was washed with water.
Compounds EMAC 10020 were purified by column chromatog-
raphy on silica gel (ethyl acetate/n-hexane 2/1) to obtain the
desired compounds whose data are reported in Tables 1 and 2.
Synthesis of 1-methyl-3–(4-sulphamoylphenyl)thiourea1
4-Aminobenzensulphonamide (1 eq.) was refluxed in 2-propanol
until a clear solution is obtained. Then a solution of methylisothio-
cyanate (1 eq.) in 2-propanol was added dropwise. By adding the
isothiocyanate the solution became yellowish. The mixture was
stirred until reaction completion (5–6 h) monitored by TLC (ethyl
acetate/n-hexane 2/1). The reaction is allowed to cool down at r.t.
and the formation of a white foaming precipitate is observed,
which was filtered and crystallised from ethanol. White crystals;
Results and discussion
As a part of our ongoing research in the field of CAIs37 and to
achieve a better understanding of the structural requirements for
the selective inhibition of the different CA isoforms, we have syn-
thesised a series of 4-(3-methyl-4-oxo-5-(2-oxoindolin-3-ylidene)thia-
ꢀ
MW: 245.32 g/mol; yield: 65%; Mp: C 204–6
1H NMR (400 MHz, DMSO-d6) d (ppm): 3.15 (3H, s, CH3, N-CH3);
7.08 (d, 2H, CH, J ¼ 8.4, 4-SO2NH2 phenyl); 7.30 (2H, s, NH2,
SO2NH2); 7.80 (d, 2H, CH, J ¼ 8.4, 4-SO2NH2 phenyl); 10.01 (s,
2H,NH, thiourea).
zolidin-2-ylideneamino)-benzenesulphonamides
indicated
as
compounds EMAC 10020 a, c, d, l, m, n, and o. All the synthes-
ised compounds bear a differently substituted isatin scaffold
linked, by the interposition of a thiazolidinone spacer, to a ben-
zene-sulphonamide moiety, as zinc binder group. The synthesis of
compounds EMAC 10020 was performed as illustrated in Figure 2.
The procedure consists of two steps. The first step is the syn-
thesis of the 4-sulphamoylphenyl-thiourea derivative (1 of Figure
2) by simple reaction of the 4-aminobenzensulphonamide with
methylisothiocyanate. The second step of the synthetic route con-
sists of the formation of the thiazolidinone spacer2 which can be
obtained by reacting 1 with ethyl-bromoacetate. Desired com-
pounds were obtained by reacting compound 2 with the appropri-
ate isatin. We attempted to perform step two and three in a one
step one pot reaction, but our efforts only gave poor yields with
respect to the three step procedure which was therefore preferred.
Compounds EMAC 10020 were submitted to enzymatic assay to
evaluate their activity and selectivity towards human CA (hCA) iso-
zymes I, II, IX, XII. The results are illustrated in Table 3. As shown
in Table 3 some of the tested compounds could be considered as
hCA IX preferential inhibitors. However, the nature and position of
Synthesis of 4-(4-oxo-1,3-thiazolidin-2-ylidene)aminobenzene-1-
sulphonamide2
An ethanol solution of 1 (1.70 eq.), ethyl bromoacetate (1.90 eq)
and anhydrous sodium acetate (6.9 eq.) was refluxed under vigor-
ous stirring till the completion of the reaction (16–20 h), TLC (ethyl
acetate/n-hexane 2/1). Then the solution was cooled to 0 ꢀC, and
the formed precipitate filtered under vacuum and crystallised from
water.
White powder; MW: 285.34 g/mol; yield: 86%; Mp: 179–180 ꢀC
1H NMR (400 MHz, DMSO-d6) d (ppm): 3.17 (3H, s, CH3, N-CH3);
4.06 (s, 2H, CH2, thiazol.); 7.10 (d, 2H, CH, J ¼ 8.4, 4-SO2NH2 phenyl);
7.31 (2H, s, NH2, SO2NH2); 7.80 (d, 2H, CH, J ¼ 8.4, 4-SO2NH2 phenyl).
Synthesis of 4-(3-methyl-4-oxo-5-(2-oxoindolin-3-ylidene)thiazoli-
din-2-ylideneamino)benzene-sulphonamides EMAC 10020
A mixture of 4-(3-methyl-4-oxothiazolidin-2-ylideneamino)benzene-
sulphonamide (1 eq), the opportune isatin derivative (1 eq), acetic the substituents on the isatin scaffold played a crucial role in

4
C. MELIS ET AL.
Table 3. Inhibition data towards hCA I, II, IX, and XII of compounds EMAC 10020.
KI (nM)
Compound
Structure
hCA I
95.5
hCA II
40.7
hCA IX
40.1
hCA XII
841
EMAC 10020 a
EMAC 10020 c
EMAC 10020 d
958
8300
274
55.7
50.7
865
50.3
85.0
EMAC 10020 l
87.6
79.1
3.0
440
EMAC 10020 m
EMAC 10020 n
44.3
945
139
4.1
90.7
873
5720
2660
EMAC 10020 o
Acetazolamide
877
250
8780
12
126
25
824
5.7
Figure 2. Synthetic pathway to compounds EMAC 10020. Reagents and conditions: (i) 2-propanol, methyl isothiocyanate; (ii) ethanol, ethyl bromoacetate, dry sodium
acetate; (iii) R-isatin, acetic anhydride, dry sodium acetate, acetic acid.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
5
determining the activity and the isozyme selectivity. In the case of
compound EMAC 10020 a, bearing an un-substituted isatin,
almost no selectivity can be observed, but for a very poor activity
towards XII isozyme. With respect to isozyme IX, the introduction
of an electron withdrawing (EW) group (compounds EMAC 10020
c, EMAC 10020 d, and EMAC 10020 n) in the position 5 of the
isatin lead to a decrease of activity, albeit some selectivity towards
hCA IX could be observed for compound EMAC 10020 c.
However, the isosteric replacement of the chlorine atom and of
the trifluoro-methyl moiety by a methyl group lead to an increase
of activity (KI 3.0 nM) and selectivity. According to these prelimin-
ary results, in the case hCA IX, the presence of an EW group in
the position 5 of the isatin is not tolerated while the introduction
of an electron donating substituent in the same position is benefi-
cial for the activity and selectivity. Also in the case of compound
EMAC 10020 m, bearing a fluorine atom in the position 7 of the
isatin ring, a good activity (KI 4.1 nM) and selectivity towards hCA
IX was observed. Conversely the introduction of a bulkier EW
group in the position 7 of the isatin scaffold, as for compound
EMAC 10020 o, leads to a decrease of activity towards all iso-
zymes. All together these data corroborate the hypothesis that the
hybridisation of isatin scaffold with the benzene-sulphonamide
moiety could be advantageous for the design of new therapeutic
agents targeting the tumour associated hCA IX isoform.
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capto-1, 2, 4-triazoles. Int J Chem Sci 2015;13:613–24.
14. Roopan SM, Khan FRN, Selvan NT. Synthesis of 1-[(2-chloro-
quinolin-3-yl)methyl]indoline-2,3-dione derivatives as poten-
tial antimicrobials. J Pharm Res 2010;3:950–2.
15. Wang G, Peng Z, He D, Yan C, Liu W, inventors; Jishou
University, Peop. Rep. China. assignee. Coumarin-isatin type
compound useful in treatment of diabetes mellitus and its
preparation patent CN105237521A; 2016.
Conclusions
We have synthesised a small library of isatin/benzene-sulphona-
mides hybrids for the inhibition of hCA isoforms. The activity of
the newly synthesised derivatives has been evaluated towards
hCA I, II, IX, and XII. Compounds EMAC 10020 c, EMAC 10020 l,
and EMAC 10020 m could be considered as preferential hCA IX
inhibitors. Our data indicated that the nature and the position of
the substituents play a crucial role in tuning activity and selectivity
towards hCA isozyme. Overall these data support the hypothesis
that isatin hybrid molecules could represent a valuable starting
point for the design of active and selective hCAIs.
Acknowledgements
The authors wish to acknowledge the “Ufficio Valorizzazione dei
Risultati della Ricerca” of Sardegna Ricerche Technological Park,
Pula (CA) – Italy.
Disclosure statement
16. Havrylyuk D, Zimenkovsky B, Vasylenko O, et al. Synthesis of
new 4-thiazolidinone-, pyrazoline-, and isatin-based conju-
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
gates with promising antitumor activity.
J Med Chem
2012;55:8630–41.
17. Ibrahim HS, Abou-Seri SM, Tanc M, et al. Isatin-pyrazole ben-
zenesulfonamide hybrids potently inhibit tumour-associated
carbonic anhydrase isoforms IX and XII. Eur J Med Chem
2015;103:583–93.
18. Ozgun DO, Yamali C, Gul HI, Taslimi P, Gulcin I, Yanik T,
et al. Inhibitory effects of isatin Mannich bases on carbonic
anhydrases, acetylcholinesterase, and butyrylcholinesterase. J
Enzyme Inhib Med Chem 2016. [Epub ahead of print]. doi:
10.3109/14756366.2016.1149479.
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