Synthesis and characterization of some new pyrazolines and their inhibitory potencies against carbonic anhydrases

Article abstract of DOI:10.1002/ardp.201900292

The inhibition of the two human cytosolic carbonic anhydrase (hCA; EC 4.2.1.1) isozymes I and II with some new pyrazoline derivatives was investigated for the first time. The structures of the newly synthesized pyrazoline derivatives were characterized by

Full text of DOI:10.1002/ardp.201900292

Received: 5 October 2019
Revised: 18 December 2019
Accepted: 21 December 2019
|
|
DOI: 10.1002/ardp.201900292
F U L L P A P E R
Synthesis and characterization of some new pyrazolines and
their inhibitory potencies against carbonic anhydrases
Gonca Çelik1
|
Tayfun Arslan2
|
Murat Şentürk3
|
Deniz Ekinci4
1Department of Chemistry, Faculty of Science,
Karadeniz Technical University, Trabzon,
Turkey
Abstract
The inhibition of the two human cytosolic carbonic anhydrase (hCA; EC 4.2.1.1)
isozymes I and II with some new pyrazoline derivatives was investigated for the first
time. The structures of the newly synthesized pyrazoline derivatives were
characterized by Fourier transform‐infrared spectroscopy, H‐/13C‐nuclear magnetic
2Department of Chemistry, Faculty of Science,
Giresun University, Giresun, Turkey
3Department of Basic Sciences of Pharmacy,
Faculty of Pharmacy, Ibrahim Cecen
University, Agri, Turkey
1
resonance, and mass spectrometry, and elemental analysis. Compounds 1–6 showed
Ki values in the range of 16.4–205.9 nM for hCA I and of 6.08–93.21 nM against hCA
II. These hydroxyl and amino group‐containing compounds generally were compe-
titive inhibitors. The compounds investigated here showed effective hCA I and II
inhibitory effects, in the same range as the clinically used acetazolamide, and might be
used as leads for generating enzyme inhibitors, possibly targeting other CA isoforms
that have not yet been assayed for their interactions with such agents.
4Department of Agricultural Biotechnology,
Faculty of Agriculture, Ondokuz Mayıs
University, Samsun, Turkey
Correspondence
Tayfun Arslan, Department of Chemistry,
Faculty of Science, Giresun University, 28200
Giresun, Turkey.
Email: tayfun.arslan@giresun.edu.tr
K E Y W O R D S
carbonic anhydrase, chalcone, inhibitor, pyrazoline
|
1
INTRODUCTION
antioxidant activity. Moreover, compound II displays cytotoxicity toward
HeLa cancer cell line.[11,12] The aim of this study is to synthesize and
Pyrazolines, which are one of the most studied groups of the azole family,
consist of a five‐membered aromatic system.[1] The wide variety of
bioactivities of pyrazolines lead many researchers to synthesize new
pyrazoline derivatives. Pyrazoline substituents are important target
molecules for chemists because of their many potential applications,
such as pharmaceuticals and the like.[1,2] Some pyrazoline derivatives
have been shown to exhibit pharmacological effects such as antidepres-
sant,[3] antibacterial,[4] antitumor,[5] and anti‐inflammatory[6] activities.
Furthermore, substituted pyrazolines have been reported to display
multifarious pharmacological activities, including carbonic anhydrase (CA;
EC 4.2.1.1) inhibitory activity.[7,8] In addition, some 1,3,5‐trisubstituted‐
pyrazolines derivatives and polymethoxylated pyrazoline benzenesulfo-
namide derivatives have been used as CA inhibitors in some studies
previously conducted by different research groups.[9,10] There is a
considerable interest in the synthesis and characterization of pyrazoline
compounds 2‐[‐5‐(4‐chlorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl]pyridine
(I) and 1‐isobutyl‐N‐(4‐(5‐(4‐methoxyphenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐
yl)phenyl)‐1H‐imidazo[4,5‐c]quinolin‐4‐amine (II) were synthesized from
characterize some substituted pyrazoline molecules and to investigate
the effects of synthesized pyrazolines on human CA I and II isoenzymes.
CAs (EC 4.2.1.1), which are essential metalloenzymes, are common
to all organisms. These enzymes catalyze the reversible hydration of
carbon dioxide to form bicarbonates with generation of protons.[13] The
inhibitors of the two major cytosolic CA forms (hCA I and II) exhibit
60% sequence homology, several particular activities and several
immunologic specificities.[14] Whereas CA I, which is the most abundant
isozymes, has low enzyme activity, CA II (present in lower amounts) has
high activity.[15] Both isoforms are used as drugs for the treatment of
glaucoma and epilepsy for decades.[16] CA isozymes are involved in the
pH homeostasis, ion transport, water and electrolyte balance, bone
resorption, calcification, and tumorigenesis.[17] Over the last few years,
pyrazoline and its derivatives have gained much interest because of
their wide range of applications, especially in medicinal chemistry.
Current research focuses on the synthesis of pyrazoline analogues.
Thus, we have performed a facile synthesis of well‐defined novel
pyrazoline derivatives (1–6). We also investigated their inhibition
potential toward hCA I and II isoenzymes.
chalcones (Figure 1). Compound
I
shows high antimicrobial and
|
Arch Pharm Chem Life Sci. 2020;e1900292.
wileyonlinelibrary.com/journal/ardp
© 2020 Deutsche Pharmazeutische Gesellschaft
1 of 6
https://doi.org/10.1002/ardp.201900292

2 of 6
ÇELIK ET AL.
|
FIGURE 1 Examples of pyrazoline
compounds with biological activity
I
II
|
2
RESULTS AND DISCUSSION
Synthesis and characterization
ethanol leads to the formation of pyrazoline derivatives. At the end
of the synthesis, the crude product was purified by recrystallization
two times from EtOH/H2O. Compounds 1 and 3 were reported in a
previous study.[20] The synthesis of the compounds 2, 4–6 is being
reported for the first time in this study. The structures of synthesized
compounds were confirmed by spectral methods (1H‐NMR [nuclear
magnetic resonance],13C‐NMR, Fourier transform‐infrared spectro-
scopy, mass spectroscopy, and elemental analysis). Both analytical
and spectral data of all the synthesized compounds were in full
agreement with the proposed structures. The detailed synthetic
strategy is outlined in Scheme 1.
|
2.1
The synthesis of 4,5‐dihydro pyrazoline derivatives (1–6) followed
the general pathway outlined in Scheme 1. They are prepared in two
steps. First, the chalcones were obtained by direct Claisen–Schmidt
condensation between aromatic aldehydes and the substituted
acetophenone, using 20% potassium hydroxide/ethanol for 24 hr as
stated in previous works.[18,19] The chalcones are considered to be
useful intermediates in several cyclization reactions to produce
different types of heterocyclic compounds of diverse biological
importance. Second, for compounds 1–6, cyclization of different
chalcones with hydrazine hydrate under basic condition in refluxing
The formation of chalcones is observed in 1H‐NMR by the
disappearance of the aldehydic proton signal and the appearance
of AB spin systems due to the vinylic protons H‐α and H‐β. This
SCHEME 1 Synthetic route for the
preparation of the pyrazoline derivatives
1–6

ÇELIK ET AL.
3 of 6
|
anticipated spectral result was confirmed when compared to the
known structures referenced in Sci Finder.[16–19] The IR spectra of
the pyrazolines 1–6 revealed absorption bands in the regions
1,602–1,615 cm−1 corresponding to the C═N stretching bands
because of ring closure. In addition, the absorption bands at
1,446–1,495 cm−1 were attributed to the (N–N) stretch vibrations,
which also confirm the formation of the desired pyrazoline ring in
all the compounds. The 1H‐NMR spectrum of pyrazolines 1–6 did
not show the signals appearing as doublet for each of the alkenyl
protons of chalcones, confirming the (3 + 2) annulations between
chalcones and hydrazine hydrate to form the target compounds.
The synthesized pyrazolines possessed characteristic peaks in the
1H‐NMR spectrum at 2.95–3.17 and 3.30–3.70 ppm, recorded as
doublet of doublet (dd). These were assigned to the protons at the
4‐position. Protons at the 5‐position of pyrazoline rings are most
likely to interact with 4‐H protons, which was represented by a
doublet of doublet signal peak at 4.74–5.38 ppm. The aromatic ring
protons were observed at the expected chemical shifts and
integral values. In the 13C‐NMR spectrum, the carbons of newly
formed pyrazolines ring showed corresponding signals at δ 35.1,
77.2, and 147.3 ppm. The presence of carbon signals in this region
confirms the formation of the pyrazoline ring. Aromatic carbons
showed the signals in the region δ 112.2–164.2 ppm. All pyrazo-
lines of the synthesized series 1–6 showed similar and consistent
pattern signals in their respective spectra and showed satisfactory
elemental analyses compared with theoretical values, which
strongly favors the formation of the designed products. Additional
support for the formation of the pyrazolines (1–6) was obtained by
the appearance of molecular ion peak at corresponding m/z values,
confirming their molecular masses.
TABLE 1 Human carbonic anhydrases (hCA) I and II inhibition
data for pyrazolines 1–6
Ki (nM)a
Compound No.
hCA I
26.5
hCA II
6.08
1
2
20.0
33.42
93.21
49.51
44.59
35.57
370
3
16.4
4
66.4
5
205.9
81.5
6
Acetazolamide
36,200
aMean from at least three determinations. Errors in the range of 3–8% of
the reported value (data not shown).
hCA I isoenzyme inhibition properties with Ki values of 16.4 and
26.5 nM. In addition, the molecules that had affinity against CA
isoenzymes were known. The standard and clinically used drug
acetazolamide (AZA) demonstrated
a Ki value of 36,200 nM,
respectively (Table 1). Thus, the investigated compounds showed
better inhibitory profiles compared to AZA, a clinically used CA
inhibitor. In addition, CA II is often associated with several diseases
such as glaucoma, osteoporosis, and renal tubular acidosis. The hCA
II was also efficiently inhibited by the novel pyrazoline compound
(1–6) derivatives investigated here. These compounds appeared to
strongly inhibit hCA II, with Ki values ranging from 6.08 to 93.21 nM.
These values are better than those of the clinically used drug AZA
(Ki = 370 nM). All the investigated novel pyrazoline compound (1–6)
derivatives demonstrated marked inhibition against hCA II, but the
compound 1 showed excellent inhibitions profile against cytosolic
hCA II with a Ki value of 6.08 nM (Table 1). Considering the data of
Table 1, the amino or hydroxyl substituents on phenyl ring A and
nitrogen atoms of pyrazoline ring could easily be predicted to be
involved in making hydrogen bonds with the active site, as observed
in classical hCA I/II sulfonamide inhibitors (Scheme 1). It is clear from
the results that all molecules were found to act as low‐nanomolar
hCA I–II inhibitors. According to the experimental findings, new
pyrazoline compounds used in this study had better inhibition
constants than the clinically used inhibitor AZA.
|
2.2
Biological evaluation of the synthesized and
reference compounds for CA inhibitory activity
In this study, we obtained the effects of novel pyrazoline compound
(1–6) derivatives against hCA I and hCA II, which were purified from
human erythrocytes.[21] The inhibitory activity of the CA isoforms
has pharmacologic applications in several fields, such as antiglauco-
ma, diuretics, antiobesity, anticonvulsant, and anticancer agents/
diagnostic tools. Also, it can be used for designing anti‐infective, that
is, antibacterial, antifungal, and antiprotozoan agents with a new
process of action.[22,23] For a long time, it has been considered that
the pharmacologic effects of CA activation or inhibition are mostly
due to effects on pH regulation in tissues or cells where the enzymes
are present. We report the inhibition effects of these derivatives on
the activity of hCA I, hCA II under in vitro conditions. The following
results are presented in Table 1.
In a recent study, it was reported that different pyrazoline
derivatives, a simple compound lacking the sulfonamide, sulfamate,
or related functional groups that are typically found in all known CA
inhibitors, act as CA I and CA II inhibitors and could represent the
starting point for a new class of inhibitors that may have advantages
for patients with sulfonamide allergies.[13,14] However, it is critically
important to explore further classes of potent CAIs to detect
compounds with a different inhibition profile as compared to the
sulfonamides and their bioisosteres and to find novel applications for
the inhibitors of these widespread enzymes. CAIs possess an active
Zn2+ ion region, which is coordinated by three histidine residues (His
94, His 96, and His 119) and H2O molecule. The CAIs belong to four
main classes and two of them (a) phenols (such as the simple phenol
C6H5OH), which bind to the zinc‐coordinated water molecule/
Abnormal levels of CA I enzyme in the blood are used as a marker
for hemolytic anemia.[24] The slow cytosolic isoform hCA I was
inhibited by the investigated novel pyrazoline compound (1–6)
derivatives, with Ki values ranging between 16.4 and 205.9 nM.
Furthermore, compounds 1–3 demonstrated the most powerful

4 of 6
ÇELIK ET AL.
|
|
CONCLUSION
hydroxide ion from the active site, through a network of two
hydrogen bonds (Figure 2a), (b) the polyamines, such as spermine,
spermidine and congeners, which bind rather similarly but not
identically to phenols, that is, by anchoring to the water molecule/
hydroxide ion coordinated to Zn(II) (Figure 2b).[13,14] They are quite
similar in these small groups of pyrazoline, phenolic, and aniline rings
in new compounds, considering the structure of drugs used as
reference for CAs. These rings could easily be predicted to be
involved in making hydrogen bonds with the active site as observed
in classical hCA I and II inhibitors.[13] These data suggested that these
compounds showed hCA I and II inhibitory activity due to the
presence of the pyrazoline, phenolic and aniline groups in
compounds. The proposed mechanisms for enzymes inhibition are
given in Figure 2.
3
To summarize, design, synthesis, and characterization of some new
pyrazolines containing hydroxyl, amine and fluorine functional
groups were reported for the first time and their cytosolic CA forms
(hCA I and II) inhibitions were examined. Most of the synthesized
compounds showed against both hCA I and II inhibitory activity.
Though pyrazoline derivative 3 demonstrated the most powerful
hCA I isoenzyme inhibition properties with Ki values of 16.4 nM,
pyrazoline 1 showed excellent inhibitions profile against cytosolic
hCA II with Ki value of 6.08 nM. As a result of study, new pyrazoline
analogues showed inhibition at the nanomolar levels against these
enzymes. These results showed that newly synthesized pyrazolines
have the potential for hCA I and II inhibition.
(b)
(a)
(d)
(c)
FIGURE 2 CA (carbonic anhydrases) inhibition with phenol (a) and spermine (b) compounds. (c, d) Proposed hCA I inhibition mechanism by
pyrazolines 2 and 5

ÇELIK ET AL.
5 of 6
|
|
4
EXPERIMENTAL
Chemistry
J = 11.2 Hz), 119.4, 118.5, 116.9, 114.4 (d, J = 21 Hz), 112.2 (d,
J = 22 Hz), 77.2 (d, J = 2 Hz), and 35.1. Anal. calcd. for C15H13FN2O: C,
70.30; H, 5.11; N, 10.93. Found: C, 70.33; H, 5.10; N, 10.92. MS (ESI,
m/z) for C15H13FN2O [M+H2O]+: 274.2769.
|
4.1
|
4.1.1
General
2‐(5‐(2‐Fluorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)phenol (3)
Yield: 50%. m.p. 135–137°C. IR (ATR), ν cm−1: 3,370 (–OH), 1,602 (C═N),
1,446 (N–N), and 1,216 (C–N). 1H‐NMR (400 MHz, DMSO‐d6): δ 2.95
(1H, dd, J = 14.0–2.8 Hz), 3.28 (1H, m), 4.98 (1H, m), 6.80 (1H, m), 6.89
(1H, m), 7.02 (1H, m), 7.15 (1H, m), 7.24 (1H, m), and 7.40 (2H, m). 13C‐
NMR (100 MHz, DMSO‐d6): δ 163.5 (d, J = 244 Hz), 158.6, 154.4, 139.9
(d, J = 3.1 Hz), 129.8, 127.0 (d, J = 9 Hz), 126.1, 119.2, 118.5, 117.3, 115.6
(d, J = 21 Hz), 72.8 (d, J = 11 Hz), and 35.1. Anal. calcd. for C15H13FN2O: C,
70.30; H, 5.11; N, 10.93. Found: C, 70.33; H, 5.10; N, 10.89. MS (ESI, m/z)
for C15H13FN2O [M+H2O]+: 274.2761.
All reagents and solvents were of reagent grade quality and were
obtained from commercial suppliers. All solvents were dried and
purified as described by Armarego and Perrin.[25] Sulfanilamide,
Sepharose 4B, protein assay reagents, and 4‐nitrophenylacetate were
obtained from Sigma‐Aldrich Co. All other chemicals were analytical
grade and obtained from Merck. hCA I and II were purified from
human erythrocytes according to the literature.[21]
The InChI codes of the investigated compounds are provided as
Supporting Information.
2‐(5‐(2‐Fluorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)aniline (4)
Yield: 48%. Oil. IR (ATR), ν cm−1: 3,317 and 3,299 NH2, 1,607 (C═N),
1,486 (N–N), and 1,224 (C–N). 1H‐NMR (400 MHz, CDCl3): δ 3.17 (1H,
dd, J = 16,0–9.4 Hz), 3.70 (1H, dd, J = 16.0–10.6 Hz), 5.14 (1H, t,
J = 9.6 Hz), 5.90 (2H, –NH2), 6.0 (1H, –NH), 6.75–6.66 (2H, m),
7.29–7.03 (5H, m), 7.51 (1H, t, J = 7.6 Hz). 13C‐NMR (100 MHz, CDCl3):
δ 161.6 (d, J = 244 Hz), 154.0, 146.7, 129.4, 129.1 (d, J = 8.1 Hz), 128.9,
127.4 (d, J = 3.9 Hz), 124.5 (d, J = 3.4 Hz), 116.3, 115.6, 115.5 (d,
J = 21.6 Hz), 114.8, 55.7 (d, J = 2.7 Hz), and 41.2. Anal. calcd. for
C15H14FN3: C, 70.57; H, 5.53; N, 16.46. Found: C, 70.55; H, 5.51; N,
16.42. MS (ESI, m/z) for C15H13FN2O [M+H2O+H]+: 274.2726.
|
4.1.2
General methods for the synthesis of the
pyrazoline derivatives 1–6
To a stirred solution of chalcone (1 mmol) in ethanol, hydrazine
hydrate (80% aqueous solution, 10 mmol) was added. The mixture
was then refluxed for 18 hr, monitored by thin‐layer chromatogra-
phy. Upon completion, the solution was cooled to room temperature.
Water was added to the reaction mixture. The products were
extracted from the one‐third concentrated solution of reaction
mixture using chloroform. The organic layer was then evaporated to
yield the required crude 4,5‐dihydro pyrazoline derivatives. Residues
obtained were purified by column chromatography to afford pure
4,5‐dihydropyrazoline derivatives.
2‐(5‐(3‐Fluorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)aniline (5)
Yield: 55%. m.p. 73–75°C. IR (ATR), ν cm−1: 3,346 and 3,308 NH2,
1,607 (C═N), 1,449 (N–N), and 1,262 (C–N). 1H‐NMR (400 MHz,
2‐(5‐(2‐Fluorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)phenol (1)
Yield: 45%. m.p. 137–139°C. IR (ATR), ν cm−1: 3,370 (–OH), 1,615 (C═N),
1,485 (N–N), and 1,222 (C–N). 1H‐NMR (400 MHz, DMSO‐d6): δ 3.03
(1H, dd, J = 14–16 Hz), 3.30 (1H, dd, J = 11–14 Hz), 5.38 (1H, t, J = 9.6 Hz),
6.85 (1H, d, J = 7.6 Hz), 6.91 (1H, d, J = 8 Hz), 7.06 (1H, t, J = 9.6 Hz), 7.18
(2H, t, J = 6.8 Hz), 7.28 (1H, m), 7.45 (1H, d, J = 7.6 Hz), and 7.63 (1H, t,
J = 6.8 Hz). 13C‐NMR (100 MHz, DMSO‐d6): δ 160.5 (d, J = 210), 158.2,
154.8, 131.4 (d, J = 13.6 Hz), 129.7, 129.0 (d, J = 8.3 Hz), 126.8 (d,
J = 4.4 Hz), 126.4 (d, J = 2.3 Hz), 124.4 (d, J = 3.3 Hz), 119.4, 118.7, 117.0,
115.2 (d, J = 21.7 Hz), 67.0, and 34.1. Anal. calcd. for C15H13FN2O: C,
70.30; H, 5.11; N, 10.93. Found: C, 70.32; H, 5.10; N, 10.90. MS (ESI, m/z)
for C15H13FN2O [M+H2O+H]+: 275.1216.
CDCl3):
δ
3.14 (1H, dd, J = 16.0–9.4 Hz), 3.60 (1H, dd,
J = 16.0–10.6 Hz), 4.77 (1H, t, J = 10 Hz), 5.81 (2H, –NH2),
6.76–6.87 (2H, m), 6.97–7.17 (5H, m), and 7.30 (1H, t, J = 6.4). 13C‐
NMR (100 MHz, CDCl3): δ 165.1 (d, J = 244 Hz), 153.3, 146.4, 145.1
(d, J = 6 Hz), 130.1 (d, J = 8 Hz), 129.2, 128.6, 121.9 (d, J = 3 Hz),
116.1, 115.4, 114.4, 114.4 (d, J = 19 Hz), 113.4 (d, J = 21 Hz), 61.9,
and 42.5. Anal. calcd. for C15H14FN3: C, 70.57; H, 5.53; N, 16.46.
Found: C, 70.54; H, 5.51; N, 16.43. MS (ESI, m/z) for C15H13FN2O
[M+H2O+H]+: 274.2732.
2‐(5‐(4‐Fluorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)aniline (6)
Yield: 56%. m.p. 115–117°C. IR (ATR), ν cm−1: 3,345 and 3,309 NH2,
1,608 (C═N), 1,495 (N–N), and 1,228 (C–N). 1H‐NMR (400 MHz,
2‐(5‐(3‐Fluorophenyl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)phenol (2)
CDCl3):
δ
3.11 (1H, dd, J = 16,4–9.4 Hz), 3.56 (1H, dd,
Yield: 52%. m.p. 122–124°C. IR (ATR), ν cm−1: 3,369 (–OH), 1,615
(C═N), 1,449 (N–N), and 1,286 (C–N). 1H‐NMR (400 MHz, DMSO‐
d6): δ 3.01 (1H, dd, J = 14.4‐3.2 Hz), 3.31 (1H, dd, J = 14.4–9.6 Hz),
5.03 (1H, t, J = 3.2–3.2 Hz), 6.83 (1H, d, J = 7.2 Hz), 6.88 (1H, d,
J = 8 Hz), 6.97 (1H, m), 7.19 (1H, m), 7.23 (1H, m), and 7.29–7.36 (3H,
m). 13C‐NMR (100 MHz, DMSO‐d6): δ 164.2 (d, J = 244 Hz), 158.4,
154.1, 147.3 (d, J = 7 Hz), 130.1 (d, J = 8), 129.5, 126.2, 120.9 (d,
J = 16.0–10.6 Hz), 4.74 (1H, t, J = 9.8 Hz), 5.99 (2H, –NH2),
6.70–6.79 (2H, m), and 7.05–7.40 (6H, m). 13C‐NMR (100 MHz,
CDCl3): δ 164.1 (d, J = 243 Hz), 153.2, 146.3, 138.1 (d, J = 3.3 Hz),
129.0, 128.5, 128.1, 127.8 (d, J = 8 Hz), 115.9, 115.2 (d, J = 20 Hz),
114.3, 61.6, and 42.3. Anal. calcd. for C15H14FN3: C, 70.57; H, 5.53;
N, 16.46. Found: C, 70.55; H, 5.50; N, 16.43. MS (ESI, m/z) for
C15H13FN2O [M+H2O+H]+: 274.2730.

6 of 6
ÇELIK ET AL.
|
ACKNOWLEDGMENTS
[14] F. Turkan, A. Cetin, P. Taslimi, M. Karaman, İ. Gulçin, Bioorg. Chem.
2019, 86, 420.
We are grateful to Giresun University, Turkey, for financial support
for this study.
[15] M. Bozdag, S. Isik, S. Beyaztas, O. Arslan, C. T. Supuran, J. Enzyme
Inhib. Med. Chem. 2015, 30, 240.
[16] T. Arslan, E. A. Turkoglu, M. Senturk, C. T. Supuran, Bioorg. Med.
Chem. Lett. 2016, 26, 5867.
CONFLICT OF INTERESTS
[17] T. Arslan, G. Celik, H. Celik, M. Senturk, N. Yayli, D. Ekinci, Arch.
Pharm. 2016, 349, 741.
The authors declare that there are no conflicts of interests.
[18] T. Arslan, J. Chem. Res. 2018, 42, 267.
[19] T. Arslan, Erzincan Univ. J. Sci. Tech. 2018, 11, 321.
[20] D. S. Ghotekar, P. G. Mandhane, R. S. Joshi, S. S. Bhagat, C. Gill, Indian
J. Heterocycl. Chem. 2010, 19, 341.
ORCID
[21] E. A. Turkoglu, M. Senturk, C. T. Supuran, D. Ekinci, J. Enzyme Inhib.
Med. Chem. 2017, 32, 74.
Tayfun Arslan
http://orcid.org/0000-0002-1426-5857
[22] İ. Gulcin, P. Taslimi, Expert Opin. Ther. Pat. 2018, 28, 541.
[23] A. M. Marini, A. Maresca, M. Aggarwal, E. Orlandini, S. Nencetti, F.
Da Settimo, S. Salerno, F. Simorini, C. La Motta, S. Taliani, E. Nuti, A.
Scozzafava, R. McKenna, A. Rossello, C. T. Supuran, J. Med. Chem.
2012, 55, 9619.
REFERENCES
[1] V. K. Mishra, M. Mishra, V. Kashaw, S. K. Kashaw, Bioorg. Med. Chem.
2017, 25, 1949.
[24] B. Yiğit, M. Yiğit, D. Barut Celepci, Y. Gök, A. Aktaş, M. Aygün, P.
Taslimi, İ. Gulcin, ChemistrySelect 2018, 3, 7976.
[2] B. Sever, M. D. Altıntop, M. O. Radwan, A. Özdemir, M. Otsuka, M.
Fujita, H. I. Çiftci, Eur. J. Med. Chem. 2019, 182, 111648.
[3] Y. R. Prasad, A. L. Rao, L. Prasoona, K. Murali, P. R. Kumar, Bioorg.
Med. Chem. Lett. 2005, 15, 5030.
[25] W. L. F. Armarego, D. D. Perrin, Purification of Laboratory Chemicals, Reed
Educational and Professional Publishing Ltd., Woburn, MA 1996.
[4] P. L. Shubhalaxmi, K. Ananda, K. S. Bhat, Cogent Chem. 2016, 2,
1141388.
SUPPORTING INFORMATION
[5] M. A. Rahman, A. A. Siddiqui, Int. J. Pharm. Sci. Drug Res. 2010, 2, 165.
[6] N. M. Eid, R. F. George, Future Med. Chem. 2018, 10, 183.
[7] D. Moi, A. Nocentini, A. Deplano, G. Balbani, C. T. Supuran, V. Onnis,
Eur. J. Med. Chem. 2019, 182, 111638.
Additional supporting information may be found online in the
Supporting Information section.
[8] E. Mete, B. Comez, H. I. Gul, I. Gulcın, C. T. Supuran, J. Enzyme Inhib.
Med. Chem. 2016, 31, 1.
How to cite this article: Çelik G, Arslan T, Şentürk M, Ekinci
D. Synthesis and characterization of some new pyrazolines
and their inhibitory potencies against carbonic anhydrases.
Arch Pharm Chem Life Sci. 2020;e1900292.
[9] K. Kucukoglu, F. Oral, T. Aydin, C. Yamali, O. Algul, H. Sakagami, I. Gulcin,
C. T. Supuran, H. I. Gul, J. Enzyme Inhib. Med. Chem. 2016, 31, 20.
[10] H. I. Gul, E. Mete, P. Taslimi, I. Gulcin, C. T. Supuran, J. Enzyme Inhib.
Med. Chem. 2017, 32, 189.
[11] I. H. Lone, K. Z. Khan, B. I. Fozdar, Med. Chem. Res. 2014, 23, 363.
[12] D. S. Viveka, P. Naik, G. K. Nagaraja, Med. Chem. Res. 2014, 23, 4189.
[13] T. Arslan, Z. Biyiklioglu, M. Senturk, RSC Adv. 2018, 8, 10172.
https://doi.org/10.1002/ardp.201900292