Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors

Article abstract of DOI:10.1002/ardp.202100028

A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives (5a–t) was synthesized and subjected for screening against the four physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA, and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX. Furthermore, among the two cytosolic isoforms, hCA II was more effectively inhibited as compared with hCA I. The most active compounds were 5o with K_i = 0.246 μM and 5p with K_i = 0.376 μM against hCA II, whereas compound 5f showed good inhibition against both hCA I and II with K_i = 0.493 and 0.4 μM, respectively. This class of underexplored sulfonamides may be used to design isoform-selective CA inhibitors targeting enzymes of medicinal chemistry interest.

Full text of DOI:10.1002/ardp.202100028

Received: 19 January 2021
Revised: 24 February 2021
Accepted: 26 February 2021
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DOI: 10.1002/ardp.202100028
F U L L P A P E R
Design and synthesis of benzenesulfonamide‐linked
imidazo[2,1‐b][1,3,4]thiadiazole derivatives as carbonic
anhydrase I and II inhibitors
1
1
1
2
Baijayantimala Swain | Kamtam Aashritha | Priti Singh | Andrea Angeli
|
1
1
3
Abhay Kothari | Dilep K. Sigalapalli | Venkata M. Yaddanapudi
|
2
1
Claudiu T. Supuran | Mohammed Arifuddin
1
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
Neurofarba Department, Sezione di ScienzeFarmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, Italy
2
3
Process Chemistry Process Technology, Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad,
Telangana, India
Correspondence:
Mohammed Arifuddin, Department of
Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research
Abstract
A novel series of imidazothiadiazole‐linked benzenesulfonamide derivatives (5a–t)
was synthesized and subjected for screening against the four physiologically and
pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA,
and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX.
Furthermore, among the two cytosolic isoforms, hCA II was more effectively in-
hibited as compared with hCA I. The most active compounds were 5o with
K = 0.246 µM and 5p with K = 0.376 µM against hCA II, whereas compound 5f
(
NIPER), Hyderabad, Telangana 500037, India.
Email: arifabib@gmail.com
Claudiu T. Supuran, Neurofarba Dept., Sezione
di ScienzeFarmaceutiche e Nutraceutiche,
Università degli Studi di Firenze, Via Ugo Schiff
6, 50019 Sesto Fiorentino, Florence, Italy.
Email: claudiu.supuran@unifi.it
i
i
i
showed good inhibition against both hCA I and II with K = 0.493 and 0.4 µM, re-
Present address
Mohammed Arifuddin, Department of
Chemistry, Anwar‐Ul‐Uloom College,
Hyderabad, Telangana, India.
spectively. This class of underexplored sulfonamides may be used to design isoform‐
selective CA inhibitors targeting enzymes of medicinal chemistry interest.
K E Y W O R D S
carbonic anhydrase, DABCO, hCA I and II isoforms, imidazothiadiazole, sulfonamide
1
|
INTRODUCTION
treatment of a range of disorders such as edema, glaucoma, obesity,
[7,8]
epilepsy, cancer, and osteoporosis.
Out of these 15 isoforms, hCA I
Carbonic anhydrase (CA; EC. 4.2.1.1) is a member of the zinc‐
and II are found in the cytosol of erythrocytes, the gastrointestinal
tract, kidneys, lung, brain, and most other tissues, being ubiquitous,
“house‐keeping” enzymes. The turnover rate of CA II is one of the
highest among all isoforms, and thus this isoform is one of the anti-
containing metalloenzyme family that catalyzes the reversible hydra-
−
+
tion of CO
2 3
to a bicarbonate anion (HCO ) and proton (H ), being
[1–3]
known as a pH‐regulating enzyme in most tissues.
Human carbonic
[9,10]
anhydrase (hCA) is subdivided into 15 different isoforms (hCA I to hCA
XIV) (CA XV is not expressed in primates) that are distributed in
different organs/tissues and are involved in various physiological
glaucoma drug targets together with hCA IV and XII.
The non-
substituted sulfonamido group‐containing sulfonamide derivatives,
especially the aromatic or heterocyclic sulfonamides, are specific and
[11,12]
[4–6]
processes.
These enzymes may be activated/inhibited for the
potent CA inhibitors.
A large number of sulfonamide‐based drugs
©
2021 Deutsche Pharmazeutische Gesellschaft
Arch Pharm. 2021;e2100028.
wileyonlinelibrary.com/journal/ardp
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https://doi.org/10.1002/ardp.202100028

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FIGURE 1 Classical carbonic anhydrase
inhibitors and structures of compounds i and ii
with anticancer and carbonic anhydrase
inhibition activity, respectively, and 5a–t
(present work)
such as acetazolamide (AAZ), methazolamide (MZA), ethoxzolamide
EZA), and dorzolamide (DZA) (Figure 1) are in clinical use for decades
chlorosulfonic acid at 110°C to afford the 3‐(chlorosulfonyl)benzoic
acids (2a–c), which were further treated with ammonium hydroxide
solution at 0°C to give the corresponding 3‐sulfamoylbenzoic acids
(3a–c). The obtained sulfonamide product was treated with thiosemi-
(
[13]
as diuretics, antiglaucoma, anticonvulsant, or antiobesity drugs.
In recent years, the imidazothiadiazole derivatives have been
studied in depth for their wide‐ranging biological activities, as they
possess antimicrobial, anticonvulsant, diuretic, anticancer, anti-
3
carbazide and POCl to undergo cyclodehydration, followed by cycli-
zation, to give 3‐(5‐amino‐1,3,4‐thiadiazol‐2‐yl)benzenesulfonamide
(4a–c), which was finally reacted with different substituted phenacyl
bromides in the presence of 1,4‐diazabicyclo[2,2,2]octane (DABCO),
known as an organic‐hindered base used to promote the ring cycliza-
tion, to give 3‐(6‐phenylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)benzenesul
[
14–16]
tubercular, analgesic, and anti‐inflammatory properties.
Imi-
dazothiadiazole derivative i (Figure 1) has been reported by Karki
[
17]
et al.
to possess anticancer activity and derivative ii (Figure 1) has
[
18]
been reported by Kumar et al.
as a potent tumor‐associated CA IX
[19]
and XII inhibitor. Motivated by these findings, we envisioned to
synthesize a novel series of imidazothiadiazole (5a–t) scaffolds
bearing 3‐functionalized benzenesulfonamide moiety and evaluated
them for CA inhibition potential against hCA I, II, VA, and XII.
fonamides as final products (5a–t) (shown in Table 1).
2.2
|
CA inhibition
The compounds synthesized (5a–t) were evaluated for their inhibitory
potency against the four physiologically and pharmacologically relevant
isoforms hCA I and II (cytosolic isoform), hCA VA (mitochondrial
isoform), and hCA IX (tumor‐associated transmembrane isoform), by a
2
2
|
RESULTS AND DISCUSSION
|
Chemistry
.1
2
stopped‐flow CO hydrase assay method. AAZ was taken as the
The synthesis of the target compounds (Scheme 1) was started with
standard drug. The following interpretations can be drawn from the
the reaction of commercially available benzoic acids (1a–c) with
inhibition data of the synthesized compounds given in Table 2.
SCHEME 1 Preparation of the target
compounds 5a–t as carbonic anhydrase
inhibitors

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TABLE 1 List of the synthesized compounds 5a–t as carbonic
anhydrase inhibitors
TABLE 2 The inhibitory potency data against isoforms hCA I, II,
VA, and IX for compounds 5a–t
a
Code
Structure
Code
5k
Structure
i
K (µM)
Compounds
hCA I
>100
0.684
>100
5.123
>100
0.493
9.747
0.928
>100
>100
>100
>100
>100
>100
9.686
1.249
>100
>100
>100
4.88
hCA II
6.786
0.650
3.867
1.608
6.486
0.406
3.616
0.839
0.935
9.151
4.934
7.002
0.529
5.782
0.246
0.376
3.714
2.635
6.582
0.855
0.012
hCA VA
7.170
0.975
7.916
6.310
6.576
>100
>100
>100
>100
6.588
>100
7.456
4.150
0.744
0.951
7.695
>100
>100
>100
6.100
0.063
hCA IX
4.591
6.977
>100
6.162
7.356
>100
>100
>100
>100
>100
>100
6.181
5.915
0.900
2.213
0.902
6.033
0.928
2.607
7.733
0.025
5
5
5
a
b
c
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
5l
5m
g
h
i
5d
5n
j
k
l
m
n
o
5
5
5
e
f
5o
5p
5q
5p
5
5
q
r
g
5s
5
t
AAZ
0.25
Abbreviation: hCA, human carbonic anhydrase.
5
5
5
h
5r
5s
5t
a
Mean from three different assays by a stopped‐flow technique (errors
were in the range of ±5–10% of the reported values).
with efficacy spanning from the low‐to‐moderate micromolar
i
range (K
i
= 0.246–9.1 µM). Among all these, eight compounds
= 0.246 µM for 5o,
.376 µM for 5p, 0.406 µM for 5f, 0.529 µM for 5m, 0.65 µM for
b, 0.839 µM for 5h, 0.855 µM for 5t, and 0.935 µM for 5i. The
ranging from
.6 to 9.1 µM. Compounds with –OMe and –Me substitutions on
displayed good inhibition potencies with K
i
0
5
j
remaining compounds showed low inhibition with K
i
1
either or both the benzene rings exhibited a better CA II
inhibitory activity as compared with the halogen‐containing deri-
vatives. It is also observed that the dihydroxy derivative with no
substitution on the benzenesulfonamide fragment (5f) showed
good inhibition than that of the substituted one (5l). However, the
•
The cytosolic isoform hCA I was not inhibited by most of the
compounds (K > 10,000 nM), except eight compounds that
showed low‐to‐moderate inhibition with K range of 0.5–9.6 µM.
Out of these, the most potent compounds are 5b (0.684 µM), 5f
0.493 µM), and 5g (0.928 µM).
i
4‐NO phenacyl bromide‐containing derivative with –OMe sub-
2
i
stitution on benzenesulfonamide part (5m) expressed good effi-
cacy than the one with no substitution (5g) and –Me substitution
(5s). From these observations, it can be clearly demonstrated that
the substitution pattern on both phenyl rings significantly affected
the inhibitory activity against the hCA II isoenzyme.
(
•
hCA II, the dominant physiological isoform, which is an anti-
glaucoma drug target, was inhibited by all the tested compounds,

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SWAIN ET AL.
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compounds 5o and 5p also showed a good docking score and more
protein–ligand interactions with the active site residues of hCA I.
Furthermore, compounds 5f, 5o, and 5p were docked against the
active site of hCA II, and the results showed good docking score and
interactions. Figure 4 illustrates the predicted binding mode and the
detailed protein–inhibitor interactions of compounds 5o and 5p with the
active site of hCA II. Compound 5o interacted with the active site of
2
hCA II by one hydrogen bond between the Thr200 and the SO group
with a distance of 2.18 Å. In addition, the nitrogen atom of the sulfo-
namide group formed a metal ion interaction with the zinc ion. Several
hydrophobic interactions were observed between compound 5o and the
active site residues, that is, Trp5, Val121, Phe131, Leu141, Val143,
FIGURE 2 Structure–activity relationship for the target carbonic
anhydrase inhibitors against human carbonic anhydrase (hCA)
isoforms
2
Leu198, Val207, and Trp209. The SO group of the compound 5p in-
teracted with hCA II by two H‐bonds with the active site residues
Thr199 (d = 2 Å) and Thr200 (d = 2.77 Å). Moreover, compound 5p
established a metal ion interaction with the zinc ion and also made
numerous hydrophobic interactions with the active site residues of hCA
II. From the molecular docking study, it was found that the synthesized
benzenesulfonamide‐linked imidazo[2,1‐b][1,3,4]thiadiazole derivatives
were well accommodated in the active pocket of hCA I and hCA II
receptors and also made favorable interactions with their key residues.
•
•
•
hCA VA, the antiobesity drug target, was not very susceptible to
inhibition, except 5b (0.9 µM), 5n (0.7 µM), and 5o (0.9 µM). Other
derivatives showed a very high micromolar inhibition constant
against the isoform.
The tumor‐associated isoform hCA IX was also not prone to in-
hibition by the compounds investigated here, except 5o, 5p, and
5
i
r with 0.9 µM K . All other compounds were much less potent and
exhibited high micromolar inhibitory potency against the isoform.
The structure–activity relationship drawn (Figure 2) from inhibi-
tion data showed that the compounds tested for CA inhibitory
activity were more selective toward hCA I and II over hCA VA and
hCA IX. Furthermore, while comparing with 4‐functionalized
benzenesulfonamide‐linked imidazothiadiazole (Figure 1), which
showed selectivity toward hCA IX and XII, the 3‐functionalized
benzenesulfonamides were selective toward hCA I and II.
3
|
CONCLUSION
A novel series of imidazothiadiazole‐linked benzenesulfonamide deri-
vatives (5a–t) was synthesized. The molecules were screened for their
CA inhibitory action against the four physiologically and pharmacolo-
gically related isoforms, namely the cytosolic isoforms hCA I and II, as
well as the mitochondrial isoform hCA VA and transmembrane tumor‐
associated isoforms, hCA IX. All the compounds showed good inhibi-
tion against hCA I and II over hCA VA and hCA IX. Considering the
selectivity, the compounds were more potent and efficient toward hCA
II as compared with hCA I. The most active compound was 5o with
2.3
|
Docking studies
K
i
= 0.246 µM against hCA II, whereas compound 5f showed good
The molecular docking study was carried out to explore the binding
mode of synthesized benzenesulfonamide‐linked imidazo[2,1‐b][1,3,4]
thiadiazole derivatives within the active site of hCA I and II. The
docking results along with the major interactions for 5f, 5o, 5p, and
AAZ with hCA I and hCA II enzymes are depicted in Table 3. As shown
in Figure 3, compound 5f interacted with the active site of hCA I by
two hydrogen bonds and two arene–arene (π–π) interactions. The
oxygen atom of sulfonamide moiety acted as a hydrogen bond acceptor
and formed two H‐bond interactions with Thr199 and His200 with a
distance of 1.72 and 2.71 Å, respectively. The nitrogen atom of sulfo-
namide moiety established a metal ion interaction with “Zn.” The
imidazo[2,1‐b][1,3,4]thiadiazole core and the benzene group attached
to the sulfonamide moiety established π–π interactions with the active
site residues Phe91 and His94, respectively. In addition, several hy-
drophobic interactions were observed between compound 5f and the
active site residues; for example, Phe91, Ala121, Leu131, Ala132,
Ala135, Leu141, Val143, Leu198, and Trp209 are the other residues
that stabilized the binding of 5f in the active site of hCA I. Similarly,
inhibition against both hCA I and II with K = 0.493 and 0.4 µM, re-
i
spectively. Furthermore, the compounds with –Me and –OMe sub-
stitution on both or each of the benzene ring expressed better
inhibition against hCA II isoform. It was also noticed that the dihydroxy
derivative with no substitution on the benzenesulfonamide fragment
(5f) showed good inhibition against hCA I and II. Hence, compounds 5o,
5p, and 5f could be taken as lead compounds for the further devel-
opment of potent and isoform‐selective CA inhibitors.
4
|
EXPERIMENTAL
|
Chemistry
4.1
4.1.1
|
General
The reported compounds were synthesized from commercially
available reagents without further purification. Solvents were

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FIGURE 3 (a) Docking pose of compound 5f (orange color stick) and (b) its ligand–protein interactions in the active site of human carbonic
anhydrase I (PDB ID: 1AZM). The red and purple dashed lines represent hydrogen bond and metal ion interactions, respectively. Green color tubes
indicate residues (Phe91, His94) involved in arene–arene (π–π) interaction with 5f. The zinc ion ligands (His94, 96, and 119) are not shown
distilled and dried using standard methods, wherever necessary,
before use. All the air‐ and moisture‐sensitive reactions were kept
under inert conditions using clean and dried glassware and syringe
technique to transfer solutions. Reactions progress was monitored
by thin‐layer chromatography (TLC) using Merck silica gel 60F‐254
plates. Column chromatography, on silica gel (60–120 mesh) using a
mixture of ethyl acetate and hexane as an eluent, was performed to
purify the synthesized molecules. Melting points were acquired on a
Stuart Digital Melting Point Apparatus/SMP 30 in open capillary
constants (J) in Hz. Multiplicities were described as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), and dd (doublet of
doublets). High‐resolution mass spectrometry (HRMS) was per-
formed with an Agilent QTOF mass spectrometer 6540 series in-
strument using the electrospray ionization (ESI) techniques at 70 eV.
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting Information.
1
tubes and were uncorrected. Nuclear magnetic resonance ( H NMR
4.1.2 General procedure for the synthesis of
|
3‐(5‐amino‐1,3,4‐thiadiazol‐2‐yl)benzene-
sulfonamides (4a–c)
13
and C NMR) spectra (see the Supporting Information) were re-
corded by using an Avance Bruker 500 MHz and 125 MHz spectro-
6
meter in dimethyl sulfoxide (DMSO)‐d as the solvent and
tetramethylsilane as the internal standard. Chemical shifts are re-
A stirred mixture of 3‐sulfamoylbenzoic acid (3a–c) (1 g), thiosemi-
presented as δ values in parts per million (ppm) and coupling
3
carbazide (1 equiv), and POCl (5 ml) was heated at 70°C for 30 min.
FIGURE 4 (a) Docking pose of compound 5o with human carbonic anhydrase (hCA) II; (b) docking pose of compound 5p with hCA II (PDB ID:
YYT). The red and purple dashed lines represent hydrogen bond and metal ion interactions, respectively. The sulphonamide (in the deprotonated
form) coordinates the zinc ion and the tails of the inhibitors participate in many favorable interactions with active site amino acid residues
4

SWAIN ET AL.
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−1
The reaction mixture was cooled to room temperature and water
127.7, 127.2, 123.8, 120.9, 111.7, 111.2; FTIR (cm ): 3307, 3139,
(
20 ml) was added. It was again heated at 70°C for 4 h. After com-
2983, 1696, 1347, 1158, 1257, 679; HRMS (ESI): m/z calc. for
+
+
+
pletion of the reaction (monitored by TLC), it was cooled and basified
to pH 8 by the dropwise addition of 50% NaOH with stirring. The
precipitate was filtered and recrystallized from ethanol to get 4a–c
with 65–70% yield.
16 4 2 2
C H12BrN O S [M+H] 434.9580 and found 436.9563 [M+2] .
3‐(6‐(4‐Chlorophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5d)
1
Orange solid, yield 56%, m.p. 258–260°C; H NMR (500 MHz,
6
DMSO‐d ) δ 8.87 (s, 1H), 8.39 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.05 (d,
4
.1.3
|
General procedure for the synthesis 3‐(6‐
J = 8.3 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.83 (t, J = 7.8 Hz, 1H), 7.61 (s,
13
phenylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamides (5a–t)
2H), 7.51 (d, J = 8.6 Hz, 2H); C NMR (125 MHz, DMSO‐d
6
) δ 160.6,
145.9, 145.2, 145.1, 133.0, 132.3, 131.1, 130.7, 130.4, 129.2, 126.9,
−1
1
26.7, 123.8, 123.1, 112.2, 111.6, 111.2; FTIR (cm ): 3294, 3134,
A mixture of phenacyl bromides (1 equiv) of various substituents and
DABCO (0.2 equiv), which is an efficient and recyclable catalyst, was
dissolved in dimethylformamide and stirred at 80°C for 10–15 min.
Then, 2‐aminothiadiazole (4a–c) (1 equiv) was added slowly to the re-
action mixture and stirred at the same temperature for 20–24 h. After
completion of the reaction confirmed by TLC, it was poured into ice
water with continuous stirring. The precipitate was then filtered and
dried. The obtained crude product was purified by using column
chromatography to get the pure product 5a–t with 50–85% yield.
1346, 1158, 1615, 1537, 1586, 1522, 1481; HRMS (ESI): m/z calc. for
+
+
16 4 2 2
C H12ClN O S [M+H] 91.0085 and found 391.0087.
3‐(6‐(4‐Fluorophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5e)
1
Light yellow solid, yield 62%, m.p. 247–249°C; H NMR (500 MHz,
6
DMSO‐d ) δ 8.81 (s, 1H), 8.39 (s, J = 1.7 Hz, 1H), 8.18 (d, J = 8.2 Hz,
1H), 8.05 (d, J = 8.1 Hz, 1H), 7.95 (d, 2H), 7.82 (t, J = 7.8 Hz, 1H), 7.62
13
(s, 2H), 7.29 (d, 2H); C NMR (125 MHz, DMSO‐d
6
) δ 160.4, 145.9,
1
45.4, 145.0, 131.1, 130.7, 130.7, 130.3, 129.1, 127.2, 127.1, 123.8,
−
1
3
‐(6‐Phenylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5a)
Pale yellow solid, yield 65%, m.p. 265–267°C; H NMR (500 MHz,
DMSO‐d ) δ 8.82 (s, 1H), 8.39 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.05 (d,
J = 7.9 Hz, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.82 (t, J = 7.8 Hz, 1H), 7.62 (s,
116.2, 116.0, 111.1; FTIR (cm ): 3296, 3134, 1615, 1346, 1158,
+
4 2 2
1514, 1483, 1088, 1003; HRMS (ESI): m/z calc. for C16H12FN O S
1
+
[M+H] 375.0386 and found 375.0382.
6
3‐(6‐(2,4‐Dihydroxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
1
3
2
H), 7.45 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H);
125 MHz, DMSO‐d ) δ 160.4, 146.3, 145.9, 144.9, 134.1, 131.0,
30.8, 130.3, 129.1, 129.0, 128.0, 125.2, 124.0, 123.8, 111.2; FTIR
C NMR
benzenesulfonamide (5f)
1
(
6
Yellow solid, yield 53%, m.p. 213–215°C; H NMR (500 MHz, DMSO‐
1
6
d ) δ 10.59 (s, 1H), 9.46 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.17 (d,
−
1
(
cm ): 3296, 3149, 2962, 1158, 1343, 1515, 1445, 1468, 1291,
J = 7.3 Hz, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.75 (d,
+
2
+
13
1
024; HRMS (ESI): m/z calc. for C16
H
13
N
4
O
2
S
[M+H] 357.0470
J = 8.2 Hz, 1H), 7.62 (s, 2H), 6.39 (s, 1H), 6.35 (d, J = 8.1 Hz, 1H);
NMR (125 MHz, DMSO‐d
43.2, 131.1, 130.8, 130.2, 128.9, 127.8, 123.7, 110.8, 110.6, 107.6,
C
and found 357.0480.
6
) δ 159.8, 158.4, 156.3, 145.8, 144.5,
1
−
1
3
‐(6‐(3,4‐Dimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5b)
Light orange solid, yield 72%, m.p. 257–258°C; H NMR (500 MHz,
DMSO‐d ) δ 8.73 (s, 1H), 8.38 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.04 (d,
J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.62 (s, 2H), 7.50 (s, 1H), 7.46
103.3; FTIR (cm ): 3134, 3304, 2989, 1604, 1452, 1331, 1150;
+
2
+
HRMS (ESI): m/z calc. for C16
H
13
N
4
O
4
S
[M+H] 389.0378 and
1
found 389.0386.
6
3‐(6‐(4‐Nitrophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5g)
13
(
s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H); C NMR
125 MHz, DMSO‐d ) δ 160.4, 159.0, 145.9, 144.7, 144.7, 134.2,
32.8, 132.6, 129.1, 127.8, 126.1, 125.1, 121.8, 114.8, 111.1, 57.2;
1
(
6
Brown solid, yield 82%, m.p. 246–248°C; H NMR (500 MHz, DMSO‐
1
6
d ) δ 9.11 (s, 1H), 8.41 (s, 1H), 8.32 (d, J = 8.9 Hz, 2H), 8.20 (d,
−
1
FTIR (cm ): 3305, 3140, 1599, 1345, 1169, 1682, 1590, 1551, 1490,
J = 4.4 Hz, 2H), 8.18 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.84 (t,
13
+
2
+
1
504, 1022; HRMS (ESI): m/z calc. for C18
H
17
N
4
O
4
S
[M+H]
6
J = 7.8 Hz, 1H), 7.63 (s, 2H); C NMR (125 MHz, DMSO‐d ) δ 160.4,
4
17.0691 and found 417.0699.
145.9, 145.4, 145.0, 131.1, 130.7, 130.7, 130.3, 129.1, 127.2, 127.1,
−1
1
23.8, 116.2, 116.0, 111.1; FTIR (cm ): 3304, 3102, 1598, 1509,
+
+
3
‐(6‐(4‐Bromophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
12 5 4 2
1156, 1330, 1499; HRMS (ESI): m/z calc. for C16H N O S [M+H]
benzenesulfonamide (5c)
402.0331 and found 402.0327.
1
Orange solid, yield 68%, m.p. 258–260°C; H NMR (500 MHz,
DMSO‐d
6
) δ 8.87 (s, 1H), 8.39 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.05 (d,
3‐(6‐(p‐Tolyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
J = 7.4 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.82 (t, J = 7.4 Hz, 1H), 7.64 (d,
benzenesulfonamide (5h)
1
3
1
J = 7.9 Hz, 2H), 7.61 (s, 2H); C NMR (125 MHz, DMSO‐d
6
) δ 160.7,
Yellow solid, yield 52%, m.p. 215–217°C; H NMR (500 MHz, DMSO‐
1
45.9, 145.2, 145.1, 133.4, 132.1, 131.9, 131.1, 130.7, 130.4, 129.1,
6
d ) δ 8.79 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.05 (dd, J = 7.9, 1.8 Hz, 1H),

8
of 10
SWAIN ET AL.
|
7
.91 (d, J = 7.2 Hz, 2H), 7.66 (s, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.44 (t,
2‐Methoxy‐5‐(6‐(4‐nitrophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5m)
13
J = 7.7 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 2.69 (s, 3H); C NMR
125 MHz, DMSO‐d ) δ 160.4, 146.1, 144.8, 143.7, 140.5, 140.5,
34.1, 134.1, 130.1, 129.1, 128.0, 127.9, 125.1, 111.2, 20.3; FTIR
1
(
6
Brown solid, yield 83%, m.p. 234–236°C; H NMR (500 MHz, DMSO‐
1
6
d ) δ 8.81 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 8.7, 2.4 Hz, 1H),
−
1
(
cm ): 3304, 3102, 2921, 1600, 1465, 1340, 1158, 1059, 1388;
7.85 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H),
13
+
2
+
HRMS (ESI): m/z calc. for C17
H
15
N
4
O
2
S
[M+H] 371.0636 and
6
7.37 (s, 2H), 4.02 (s, 3H); C NMR (125 MHz, DMSO‐d ) δ 160.4,
found 371.0635.
159.0, 145.0, 144.7, 132.7, 132.6, 130.7, 127.1, 127.0, 126.1, 121.7,
−
1
1
16.1, 115.9, 114.3, 111.0, 109.5, 57.2; FTIR (cm ): 3340, 3244,
2
‐Methoxy‐5‐(6‐phenylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
1699, 1334, 1159, 1508, 2984, 1033; HRMS (ESI): m/z calc. for
+
+
benzenesulfonamide (5i)
17 14 5 5 2
C H N O S [M+H] 431.0436 and found 431.0434.
1
Light orange solid, yield 85%, m.p. 207–209°C; H NMR (500 MHz,
DMSO‐d
6
) δ 8.75 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 8.7,
2‐Methoxy‐5‐(6‐(4‐methoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐
2‐yl)benzenesulfonamide (5n)
2
.4 Hz, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 3.6 Hz, 2H), 7.42 (d,
13
1
J = 3.1 Hz, 1H), 7.37 (s, 2H), 7.30 (t, J = 7.4 Hz, 1H), 4.02 (s, 3H);
NMR (125 MHz, DMSO‐d ) δ 160.4, 159.0, 145.9, 144.7, 144.7,
34.2, 132.8, 132.6, 129.1, 127.8, 126.1, 125.1, 121.8, 114.8, 111.1,
C
Light brown solid, yield 57%, m.p. 253–257°C; H NMR (500 MHz,
6
6
DMSO‐d ) δ 8.64 (s, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 8.7,
1
5
1
2.3 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (s,
13
−1
7.2; FTIR (cm ): 3320, 3128, 2982, 1600, 1461, 1338, 1156, 1518,
2H), 7.01 (d, J = 8.7 Hz, 2H), 4.03 (s, 3H), 3.80 (s, 3H); C NMR
+
2
+
256; HRMS (ESI): m/z calc. for C17
H
15
N
4
O
3
S
[M+H] 387.0586
6
(125 MHz, DMSO‐d ) δ 160.4, 159.0, 145.0, 144.7, 132.7, 132.6,
and found 387.0587.
130.7, 127.1, 127.0, 126.1, 121.7, 116.1, 115.9, 114.3, 111.2, 111.0,
−1
1
09.5, 57.2; FTIR (cm ): 3245, 2981, 1599, 1508, 1337, 1157, 1033;
+
+
5
‐(6‐(4‐Bromophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)−2‐
methoxybenzenesulfonamide (5j)
Light yellow solid, yield 57%, m.p. 220–222°C; H NMR (500 MHz,
DMSO‐d ) δ 8.81 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 8.7,
.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.43 (d,
HRMS (ESI): m/z calc. for C18
H
17
N
4
O
4
S
2
[M+H] 417.0691 and
found 417.0605.
1
6
2‐Methyl‐5‐(6‐phenylimidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5o)
2
1
3
1
J = 8.8 Hz, 1H), 7.37 (s, 2H), 4.02 (s, 3H); C NMR (125 MHz, DMSO‐
) δ 160.7, 159.1, 144.9, 144.7, 143.8, 133.5, 132.7, 132.7, 132.1,
Light orange solid, yield 82%, m.p. 265–267°C; H NMR (500 MHz,
d
6
DMSO‐d
6
) δ 8.79 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.05 (dd, J = 7.9,
−
1
1
3
C
27.1, 126.1, 121.6, 120.7, 114.4, 111.6, 57.2; FTIR (cm ): 3340,
1.8 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.66 (s, 2H), 7.63 (d, J = 8.0 Hz,
13
245, 1602, 1317, 1161, 1214, 1045; HRMS (ESI): m/z calc. for
2H), 7.44 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 2.69 (s, 3H);
NMR (125 MHz, DMSO‐d ) δ 160.4, 146.1, 144.8, 144.4, 143.7,
40.5, 134.1, 134.1, 130.1, 129.1, 128.0, 127.9, 125.1, 111.2, 20.3;
C
+
2
+
17
H
14BrN
4
O
3
S
[M+H] 464.9691 and found 464.9690.
6
1
−
1
5
‐(6‐(4‐Fluorophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)‐2‐
methoxybenzenesulfonamide (5k)
Pale yellow solid, yield 50%, m.p. 234–236°C; H NMR (500 MHz,
DMSO‐d ) δ 8.75 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 8.7,
.4 Hz, 1H), 7.93 (d, J = 3.2 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.37 (s,
FTIR (cm ): 3245, 2981, 1600, 1473, 1388, 1158, 1059, 1033;
+
2
+
HRMS (ESI): m/z calc. for C17
H
15
N
4
O
2
S
[M+H] 371.0636 and
1
found 371.0644.
6
2
2
5‐(6‐(3,4‐Dimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)‐2-
methylbenzenesulfonamide (5p)
1
3
H), 7.27 (t, J = 8.9 Hz, 1H), 4.03 (s, 3H); C NMR (125 MHz, DMSO‐
) δ 160.4, 159.0, 145.0, 144.7, 132.7, 132.6, 130.7, 127.1, 127.0,
1
d
6
Brown solid, yield 62%, m.p. 277–279°C; H NMR (500 MHz, DMSO‐
−
1
1
3
C
26.1, 121.7, 116.1, 115.9, 114.3, 111.0, 57.2; FTIR (cm ): 3340,
6
d ) δ 8.71 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.05 (dd, J = 7.9, 1.9 Hz, 1H),
245, 1599, 2923, 1469, 1334, 1156, 1230; HRMS (ESI): m/z calc. for
7.66 (s, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.45 (dd,
+
+
17 4 3 2
H14FN O S [M+H] 405.0491 and found 405.0488.
J = 8.3, 1.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H),
13
2
.69 (s, 3H); C NMR (125 MHz, DMSO‐d
6
) δ 160.0, 159.3, 146.1,
5
‐(6‐(2,4‐Dihydroxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)‐2‐
methoxybenzenesulfonamide (5l)
Light yellow solid, yield 79%, m.p. 202–204°C; H NMR (500 MHz,
DMSO‐d ) δ 10.61 (s, 1H), 9.43 (s, 1H), 8.45 (s, 1H), 8.28 (d, J = 2.0 Hz,
H), 8.14 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz,
143.8, 140.4, 134.1, 130.0, 128.0, 126.8, 126.5, 125.1, 114.6, 110.0,
−
1
55.6, 20.3; FTIR (cm ): 3245, 2937, 1596, 1466, 1335, 1166, 1020,
1
+
+
19 4 4 2
1033; HRMS (ESI): m/z calc. for C19H N O S [M+H] 431.0842
6
and found 431.0828.
1
1
13
H), 7.37 (s, 2H), 6.37 (s, 1H), 6.34 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H);
) δ 160.4, 159.0, 145.0, 144.7, 132.7,
32.6, 130.7, 127.1, 127.0, 126.1, 121.7, 116.1, 115.9, 114.3, 111.0,
C
5‐(6‐(4‐Chlorophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)‐2‐
NMR (125 MHz, DMSO‐d
6
methylbenzenesulfonamide (5q)
1
1
Yellowish‐brown solid, yield 82%, m.p. 277–279°C;
(500 MHz, DMSO‐d
1H), 7.93 (d, J = 7.7 Hz, 2H), 7.67 (s, 2H), 7.63 (d, J = 7.4 Hz, 1H), 7.50
H NMR
−
1
5
7.2; FTIR (cm ): 3340, 3245, 1599, 2923, 1469, 1334, 1156, 3304;
6
) δ 8.85 (s, 1H), 8.41 (s, 1H), 8.05 (d, J = 7.1 Hz,
+
2
+
HRMS (ESI): m/z calc. for C17
H
15
N
4
O
5
S
[M+H] 419.0484 and
13
found 419.0484.
6
(d, J = 7.6 Hz, 2H), 2.69 (s, 3H); C NMR (125 MHz, DMSO‐d ) δ

SWAIN ET AL.
9 of 10
|
1
1
1
60.7, 145.0, 144.9, 143.8, 140.5, 134.1, 133.1, 132.3, 130.1, 129.2,
enzyme solutions were preincubated together for 10 min at room
temperature before assay, to allow for the formation of the E–I complex.
Triplicate experiments were done for each inhibitor concentration, and
the values reported throughout the paper are the mean of such results.
The inhibition constants were obtained by nonlinear least‐squares
−
1
27.9, 126.8, 125.2, 111.6, 20.3; FTIR (cm ): 3245, 2923, 1513,
+
4 2 2
314, 1157, 1058; HRMS (ESI): m/z calc. for C17H14ClN O S
+
[
M+H] 405.0247 and found 405.0249.
[21,22]
5
‐(6‐(4‐Fluorophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)‐2‐
methods using the Cheng–Prusoff equation, as reported earlier,
methylbenzenesulfonamide (5r)
Brown solid, yield 51%, m.p. 277–279°C; H NMR (500 MHz, DMSO‐
) δ 8.78 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 8.04 (dd, J = 7.9, 1.9 Hz, 1H),
.94 (m, 2H), 7.66 (s, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 8.9 Hz,
and they represent the mean from at least three different determina-
tions. All CA isozymes used here were recombinant proteins obtained,
as reported earlier by our group, and their concentrations in the assay
1
d
6
[23–25]
7
2
1
1
1
3
system were in the range of 5–12 nM.
13
H), 2.69 (s, 3H); C NMR (125 MHz, DMSO‐d
6
) δ 160.7, 145.0,
44.9, 143.8, 140.5, 134.1, 133.1, 132.3, 130.1, 129.2, 127.9, 126.8,
−
1
25.2, 111.6, 20.3; FTIR (cm ): 3245, 3291, 1515, 1490, 1385, 1157,
4.3 Molecular docking
|
+
+
4 2 2
058, 1033,1228; HRMS (ESI): m/z calc. for C17H14FN O S [M+H]
89.0542 and found 389.0543.
Molecular docking studies were performed by using Schrödinger Suite
[26]
release 2019‐1.
complex with AAZ (PDB ID: 1AZM)
with 4‐(2‐hydroxyethyl)benzenesulfonamide (PDB ID: 4YYT)
The protein crystal structure of hCA I receptor in
[27]
2
‐Methyl‐5‐(6‐(4‐nitrophenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)-
benzenesulfonamide (5s)
Brown solid, yield 79%, m.p. 242–244°C; H NMR (500 MHz, DMSO‐
) δ 9.07 (s, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 8.9 Hz, 2H), 8.15
d, J = 8.8 Hz, 2H), 8.05 (dd, J = 7.9, 1.8 Hz, 1H), 7.67 (s, 2H), 7.62 (s,
and hCA II receptor in complex
[28]
was
1
retrieved from the RCSB Protein Data Bank. Next, proteins were pre-
pared by using Protein Preparation Wizard of Maestro. Hydrogen atoms
were added and appropriate protonation states were assigned to all the
residues using Epik. Missing amino acid residues were modeled using
d
6
(
1
3
1
1
1
1
H), 2.69 (s, 3H); C NMR (125 MHz, DMSO‐d
6
) δ 160.7, 145.0,
[29,30]
44.9, 143.8, 140.5, 134.1, 133.1, 132.3, 130.1, 129.2, 127.9, 126.8,
Prime.
The bound co‐crystallized ligands were used to define the
−
1
25.2, 111.6, 20.3; FTIR (cm ): 3245, 3291, 2923, 1598, 1510, 1387,
active site in hCA I and hCA II. All the ligands were built and optimized
using Maestro Molecule Builder and OPLS_2005 force field in LigPrep
modules of Schrödinger software, respectively. Furthermore, the pre-
pared ligands were docked at the active site of hCA I and hCA II using
the standard protocol implemented in Maestro.
+
14 5 4 2
339, 1167, 1033, 1058; HRMS (ESI): m/z calc. for C17H N O S
+
[
M+H] 416.0487 and found 416.0484.
5
‐(6‐(4‐Methoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐2‐yl)‐2‐
methylbenzenesulfonamide (5t)
Brown solid, yield 72%, m.p. 212–214°C; H NMR (500 MHz, DMSO‐
) δ 8.67 (s, 1H), 8.40 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.83 (d,
J = 8.5 Hz, 2H), 7.67 (s, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 8.5 Hz,
1
ACKNOWLEDGMENTS
d
6
Authors Baijayantimala Swain, Kamtam Aashritha, Priti Singh, and
Abhay Kothari are thankful to the Department of Pharmaceuticals,
Ministry of Chemicals and Fertilizers, Govt. of India, New Delhi, for
the award of a NIPER fellowship.
1
3
2
1
1
1
H), 3.80 (s, 3H), 2.69 (s, 3H); C NMR (125 MHz, DMSO‐d
6
) δ
60.0, 146.1, 143.8, 140.4, 134.1, 130.0, 128.0, 126.8, 126.5, 125.1,
−1
14.6, 110.0, 55.6, 20.3; FTIR (cm ): 3245, 3291, 2923, 1598, 1610,
+
332, 1157, 1033, 1060; HRMS (ESI): m/z calc. for C18
H
17
N
4
O
3
S
2
CONFLICTS OF INTERESTS
+
[
M+H] 401.0742 and found 401.0746.
The authors declare that there are no conflicts of interests.
ORCID
4.2
|
CA inhibition assay
Venkata M. Yaddanapudi
Mohammed Arifuddin
https://orcid.org/0000-0002-9813-8694
https://orcid.org/0000-0002-0158-5683
An SX.18MV‐R Applied Photophysics stopped‐flow instrument has been
[20]
used to assay the catalytic/inhibition of various CA isozymes.
Phenol
REFERENCES
Red (at a concentration of 0.2 mM) has been used as an indicator,
working at the absorbance maximum of 557 nm, with 10 mM HEPES
[1] C. T. Supuran, Expert Opin. Ther. Pat. 2013, 23, 677. https://doi.org/
0.1517/13543776.2013.778246
1
[
[
[
2] C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2013, 28, 229. https://
(
pH 7.4) as buffer, 10 mM NaClO
strength; this anion is not inhibitory in the used concentration), following
the CA‐catalyzed CO hydration reaction for a period of 5–10 s. Satu-
rated CO solutions in water at 25°C were used as a substrate. Stock
4
(for maintaining constant ionic
doi.org/10.3109/14756366.2013.761876
3] M. Nar, Y. Cetinkaya, I. Gulcin, A., Menzek, J. Enzyme Inhib. Med. Chem.
2013, 28, 402. https://doi.org/10.3109/14756366.2012.670807
4] N. Singasane, P. S. Kharkar, M. Ceruso, C. T. Supuran, M. P. Toraskar,
J. Enzyme Inhib. Med. Chem. 2015, 30, 901. https://doi.org/10.3109/
2
2
solutions of inhibitors were prepared at a concentration of 10 mM (in
DMSO–water 1:1, v/v), and dilutions up to 0.01 nM done with the assay
buffer mentioned above. At least seven different inhibitor concentra-
tions have been used for measuring the inhibition constant. Inhibitor and
14756366.2014.986118
[
5] D. Ekinci, I. Fidan, S. Durdagi, S. Kaban, C. T. Supuran, J. Enzyme Inhib.
Med. Chem. 2013, 28, 370. https://doi.org/10.3109/14756366.2012.
732071

10 of 10
SWAIN ET AL.
|
[
6] B. Swain, C. S. Digwal, A. Angeli, M. Alvala, P. Singh, C. T. Supuran,
M. Arifuddin, Bioorg. Med. Chem. 2019, 27, 115090. https://doi.org/
0.1016/j.bmc.2019.115090
7] C. T. Supuran, Future Med. Chem. 2011, 3, 1165. https://doi.org/10.
155/FMC.11.69
8] A. Scozzafava, C. T. Supuran, F. Carta, Expert Opin. Ther. Pat. 2013,
3, 725. https://doi.org/10.1517/13543776.2013.790957
[22] I. Nishimori, D. Vullo, A. Innocenti, A. Scozzafava, A. Mastrolorenzo,
C. T. Supuran, J. Med. Chem. 2005, 48, 7860. https://doi.org/10.
1021/jm050483n
1
[
[
[
[23] M. Ceruso, M. Bragagni, Z. AlOthman, S. M. Osman, C. T. Supuran,
J. Enzyme Inhib. Med. Chem. 2015, 30, 430. https://doi.org/10.3109/
14756366.2014.942659
4
2
[24] R. Z. Emameh, L. Syrjänen, H. Barker, C. T. Supuran, S. Parkkila,
J. Enzyme Inhib. Med. Chem. 2015, 30, 505. https://doi.org/10.3109/
14756366.2014.944178
9] C. Alp, A. Maresca, N. A. Alp, M. S. Gultekin, D. Ekinci,
A. Scozzafava, C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2013, 28,
2
94. https://doi.org/10.3109/14756366.2012.658788
10] E. Masini, F. Carta, A. Scozzafava, C. T. Supuran, Expert Opin. Ther. Pat.
013, 23, 705. https://doi.org/10.1517/13543776.2013.794788
[25] C. T. Supuran, M. Barboiu, C. Luca, E. Pop, M. E. Brewster,
A. Dinculescu, Eur. J. Med. Chem. 1996, 31, 597. https://doi.org/10.
1016/0223‐5234(96)89555‐9
[
[
[
2
11] C. T. Supuran, A. Scozzafava, A. Casini, Med. Res. Rev. 2003, 23, 146.
https://doi.org/10.1002/med.10025
[26] Schrödinger Release 2019‐1: Maestro, Schrödinger, LLC, New
York, NY 2019.
12] E. Mete, B. Comez, H. I. Gul, I. Gulcin, C. T. Supuran, J. Enzyme Inhib.
Med. Chem. 2016, 31, 1. https://doi.org/10.1080/14756366.2016.
[27] S. Chakravarty, K. K. Kannan, J. Mol. Biol. 1994, 243, 298.
[28] R. Gaspari, C. Rechlin, A. Heine, G. Bottegoni, W. Rocchia,
D. Schwarz, J. Bomke, H. D. Gerber, G. Klebe, A. Cavalli, J. Med.
Chem. 2016, 59, 4245.
1
181627
[
[
[
13] C. T. Supuran, A. Scozzafava, Exp. Opin. Ther. Pat. 2000, 10, 575.
14] K. K. Lata, A. Gupta, D. Meena, A. Verma, Heterocycl. Lett. 2015, 5, 489.
15] B. A. Bhongade, S. Talath, R. A. Gadad, A. K. Gadad, J. Saudi
Chem. Soc. 2016, 20, 463. https://doi.org/10.1016/j.jscs.2013.
[29] Schrödinger Release 2019‐1: Protein Preparation Wizard; Epik,
Schrödinger, LLC, New York, NY 2019; Impact, Schrödinger, LLC,
New York, NY 2019; Prime, Schrödinger, LLC, New York, NY 2019.
[30] G. M. Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, W. Sherman,
J. Comput.‐Aided Mol. Des. 2013, 27, 221.
0
1.010
[
[
[
[
16] A. Cristina, D. Leonte, L. Vlase, L. C. Bencze, S. Imre, G. Marc,
B. Apan, C. Mogoșan, V. Zaharia, Molecules 2018, 23, 2425. https://
doi.org/10.3390/molecules23102425
SUPPORTING INFORMATION
17] S. S. Karki, K. Panjamurthy, S. Kumar, M. Nambiar, S. A. Ramareddy,
K. K. Chiruvella, S. C. Raghavan, Eur. J. Med. Chem. 2011, 46, 2109.
https://doi.org/10.1016/j.ejmec.2011.02.064
Additional Supporting Information may be found online in the
supporting information tab for this article.
18] R. Kumar, S. Bua, S. Ram, S. D. Prete, C. Capasso, C. T. Supuran,
P. K. Sharma, Bioorg. Med. Chem. 2017, 25, 1286. https://doi.org/10.
1
016/j.bmc.2016.12.047
19] K. Tiwari, P. K. Verma, S. B. Singh, J. Singh, Synth. Commun. 2012,
2, 3021. https://doi.org/10.1080/00397911.2011.574329
How to cite this article: B. Swain, K. Aashritha, P. Singh, A.
Angeli, A. Kothari, D. K. Sigalapalli, V. M. Yaddanapudi, C. T.
Supuran, M. Arifuddin, Arch. Pharm. 2021, e2100028.
https://doi.org/10.1002/ardp.202100028
4
[
20] R. G. Khalifah, J. Biol. Chem. 1971, 246, 2561.
[
21] N. Korkmaz, O. A. Obaidi, M. Senturk, D. Astley, D. Ekinci,
C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2015, 30, 75. https://doi.
org/10.3109/14756366.2013.879656