Synthesis, characterization and biological activity evaluation of novel naphthalenylmethylen hydrazine derivatives as carbonic anhydrase inhibitors

Article abstract of DOI:10.1016/j.molstruc.2020.128657

In the current study some derivatives of naphthalenylmethylen hydrazine were synthesized and possible in vitro hCA I and II enzymes inhibition effects were investigated. The designed compounds were synthesized by condensation of phenylhydrazine with 1-naphthaldehyde or 6-methoxy-2-naphthaldehyde and eight compounds (1a-h) were obtained. The novel Schiff bases derivatives (compounds 1a-1h) were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) with Ki values in the range of 80.60 ± 17.90 to 492.53 ± 95.23 nM for hCA I, 102.88 ± 18.44 to 461.09 ± 102.50 nM for hCA II. 1f compound shows a remarkable inhibitory effect of hCA I and hCA II isoenzymes among the new synthesized compounds. The new derivatives of naphthalenylmethylen hydrazine can be a potent inhibitor of both cytosolic CA isoenzymes which are commonly used in the pharmaceutical industries and medical areas.

Full text of DOI:10.1016/j.molstruc.2020.128657

Journal of Molecular Structure 1220 (2020) 128657
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis, characterization and biological activity evaluation of novel
naphthalenylmethylen hydrazine derivatives as carbonic anhydrase
inhibitors
Hanif Shirinzadeh , Esra Dilek b
a, *
a
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erzincan Binali Yildirim University, Yalnizbag, Erzincan, Turkey
Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yildirim University, Yalnizbag, Erzincan, Turkey
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2020
Received in revised form
In the current study some derivatives of naphthalenylmethylen hydrazine were synthesized and possible
in vitro hCA I and II enzymes inhibition effects were investigated. The designed compounds were syn-
thesized by condensation of phenylhydrazine with 1-naphthaldehyde or 6-methoxy-2-naphthaldehyde
and eight compounds (1a-h) were obtained. The novel Schiff bases derivatives (compounds 1a-1h)
were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) with Ki values
in the range of 80.60 ± 17.90 to 492.53 ± 95.23 nM for hCA I, 102.88 ± 18.44 to 461.09 ± 102.50 nM for
hCA II. 1f compound shows a remarkable inhibitory effect of hCA I and hCA II isoenzymes among the new
synthesized compounds. The new derivatives of naphthalenylmethylen hydrazine can be a potent in-
hibitor of both cytosolic CA isoenzymes which are commonly used in the pharmaceutical industries and
medical areas.
8
June 2020
Accepted 8 June 2020
Available online 15 June 2020
Keywords:
Carbonic anhydrase
Enzyme inhibition
Naphthalenylmethylen hydrazine
Synthesis
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
contain sixteen isoenzymes in mammals (CAI-CAXVI). Since most
carbonic anhydrase enzymes contain zinc ions, they are classified
Metalloenzymes are a combination of a metal ion or several
metal ions in which the metal ion is strongly held in a protein.
Using the enzyme as a scaffold for transition metal complexes, it
becomes possible to carry out chemical transformations with
selectivity. It should be well known which metal ions bind strongly
to proteins. Knowing which metal ions are bound to proteins will
contribute greatly to enzymatic analysis [1,2]. Metalloenzymes are
central to a wide range of essential biological activities, including
detoxification, nucleic acid modification, protein degradation, and
many others [2,3]. The role of metalloenzymes in these processes
also makes them central for the progression of many diseases and,
as such, makes metalloenzymes attractive targets for therapeutic
intervention [3].
as metalloenzymes. Human carbonic anhydrase enzymes are
catalyzed the reversible hydration of carbon dioxide (CO2), which
generates a proton (Hþ) and bicarbonate anion (HCO3ꢀ) lead to
expressed as pH regulating enzyme in most tissues, especially in
erythrocytes [4e9]. Many such CA isozymes which make these
functions are important therapeutic targets with the potential to be
inhibited/activated for the treatment of diseases such as glaucoma,
edema, obesity, osteoporosis, epilepsy and cancer [5e11]. CA in-
hibitors (CAIs) such as acetazolamide (AZA), zonisamide (ZNS),
methazolamide (MZA) and topiramate (TPM) are utilized in clinic
as diuretics and factors for glaucoma-relevant intraocular hyper-
tension [12,13].
Inhibitory effects of different phenols [14], anions [15], metal
ions [16], sulfonamides [17], schiff bases and their amines [18], 1H-
indazole molecules [19], amides [20], some chalcones [21],
pyrimidine-thiones [22], some aminomethyl derivatives [23] which
are specific inhibitors have been investigated against many CAs up
to now. CA II inhibitors are used for various objectives like treat-
ment of epilepsy, glucoma, antitumor agents/diagnostic tools or
diuretics [8,24e26].
Human carbonic anhydrase enzyme (hCA; Carbonate hydroly-
ses, EC 4.2.1.1) is a member of metalloenzyme family which are
*
Corresponding author. Department of Pharmaceutical Chemistry, Faculty of
Pharmacy, Erzincan Binali Yildirim University, 24100, Yalnizbag, Erzincan, Turkey.
Tel.: þ00990(446)2245344-40201, fax: 0090(446)2245343.
E-mail addresses: hshirinzade@erzincan.edu.tr (H. Shirinzadeh), edilek@
erzincan.edu.tr (E. Dilek).
Nowadays, scientists are interested in discovery of novel CA
https://doi.org/10.1016/j.molstruc.2020.128657
0
022-2860/© 2020 Elsevier B.V. All rights reserved.

2
H. Shirinzadeh, E. Dilek / Journal of Molecular Structure 1220 (2020) 128657
inhibitors [8,14,24e27]. Recent studies are demonstrated that
various derivatives of phenols [8,14], salicylic acid derivatives [28],
different benzenes and bisphenols which have antioxidant prop-
erties and their various derivatives [29,30] are potential inhibitor of
CA I and II isozymes.
measured with a Varian 400 MHz spectrometer device (Palo Alto,
CA) using TMS as an internal standard and DMSO‑d as solvent. ESI
6
mass spectra were determined by a Waters Micromass ZQ device.
Elemental analyses were performed using a CHNS-932 instrument
(Leco Corporation, St. Joseph, MI). All spectral analyses were per-
formed at the Central Laboratory of the Faculty of Pharmacy at
Ankara University. Chromatography was carried out using Merck
silica gel 60 (230e400 mesh ASTM). Sepharose-4B, indozole mol-
ecules, and chemical substances used for electrophoresis were
In the current study, naphthalene ring which substituted with
formation of imine were synthesized. All synthesized schiff bases
compounds except 1e [31] were new compounds. Furthermore, the
compounds 1c and 1d have CAS registry numbers, but no infor-
mation exist in the literature related to the biological activity of 1c
and 1d. The synthesized compounds were characterized on the
obtained from Sigma-Aldrich. L-tyrosine was obtained E. Merck.
The chemical reagents that were used in synthesis and other
chemical substances were purchased from Sigma (Germany) and
Aldrich (USA).
1
13
basis of H and C NMR, mass spectra and elemental analyses. The
CA inhibitory effect of the new synthesized compounds on CA I and
II isoenzymes which isolated from human erythrocytes was per-
formed by two different values, IC50 and Ki. IC50 values were
calculated by determining percent activity at various inhibitor
concentrations, with substrate concentrations kept constant, and
then determining the concentration of inhibitor causing 50% inhi-
bition graphically. The results were compared with acetazolamide
2.2. General procedure for synthesis of compounds 1a-h
1 mmol of 1-naphthaldehyde or 6-Methoxy-2-naphthaldehyde
and 1.2 mmol of phenyl hydrazine hydrochloride or its de-
rivatives were dissolved in absolute ethanol (20 mL) and heated for
(
AZA).
3
60 min on a hot water bath in the presence of CH COONa (0.4 g).
After completion of the reaction, the reaction mixture was cooled to
room temperature. The precipitate was collected, washed with cold
EtOH and recrystallized from EtOH to achieve 1a-1h (except 1e)
with 70.79%e94% yield. For synthesis of 1e compound, the solution
of 1-naphthaldehyde (2 mmol) and hydrazine hydrate (1 mmol) in
EtOH (25 mL) was heated for 4 h on a hot water bath. After cooling,
the precipitate was collected then washed with cold EtOH to give
2
. Material and methods
This study was designed to synthesize, characterize and inves-
tigate the possible in vitro CA I and II enzyme inhibitory effect of
new naphthalenylmethylen hydrazine derivatives. The designed
compound was synthesized by condensation of phenylhydrazine
with 1-naphthaldehyde or 6-methoxy-2-naphthaldehyde. All new
imines were obtained by using a methodology similar to that in a
previous study [32] (Fig. 1). Two series of new compounds were
synthesized (Table 1). First group are 1-substituted phenyl-2-
1,2-bis(naphthalen-1-ylmethylene)hydrazine (1e) in 40.90% yield.
2
(
.2.1. 1-(2-bromophenyl)-2-(naphthalen-1-ylmethylene)hydrazine
1a)
Yield 84.76%, m.p. 154e155 C; 1H NMR:
ꢁ
d
6.75e8.67 (m, 11H
(
naphthalen-1-yl methylene)hydrazine and second group are 1-
1
3
ArH); 9.12 (s, 1H, HC]N); 9.80 (s, 1H, NH); C NMR:
14.34, 120.38, 123.60, 124.91, 125.67, 125.67, 126.01, 126.79, 128.71,
28.88,130.09,130.67,132.63,133.56,139.85,142.30 (C]N): MSI MS
d 106.02,
substituted phenyl-2-(6-methoxynaphthalen-1-yl methylene)hy-
drazine. Substituted naphthalene ring in second group help us to
evaluate the effect of substituents in the naphthalene rings.
1
1
þ
m/z 325 (M , 100%). Anal. calcd. for C17H13BrN2: C, 62.79%; H,
4.03%; N, 8.61%. Found: C,62.48%; H, 4.11%; N, 8.72%.
2.1. Chemistry e experimental and instruments
2.2.2. 1-(3-bromophenyl)-2-(naphthalen-1-ylmethylene)
Uncorrected melting points were determined with a Stuart
melting point SMP30 apparatus. The H and C NMR spectra were
hydrazine(1b)
Yield 70.79%, m.p. 101e102 C; 1H NMR:
ArH); 8.55 (s, 1H, HC]N); 10.65 (s, 1H, NH); C NMR:
14.15, 121.16, 122.48, 122.48, 123.75, 125.55, 125.65, 126.01, 126.83,
1
13
ꢁ
d
6.90e8.68 (m, 11H
13
d
111.08,
1
1
28.72, 129.76, 130.54, 131.16, 133.59, 137.48, 146.77 (C]N): MSI MS
þ
m/z 325 (M , 100%), 327 (Mþ2, 97%). Anal. calcd. for C17H13BrN2:
C, 62.79%; H, 4.03%; N, 8.61%. Found: C,62.42%; H, 3.96%; N, 8.61%.
2
.2.3. 1-(4-bromophenyl)-2-(naphthalen-1-ylmethylene)
hydrazine(1c)
Yield 86.79%, m.p. 138e139 C; 1H NMR:
ꢁ
d
7.05e8.71 (m, 11H
13
ArH); 8.53 (s, 1H, HC]N); 10.60 (s, 1H, NH); C NMR:
13.04, 123.87, 125.51, 125.62, 126.00, 126.83, 128.56, 128.70,128.38,
d 109.65,
1
1
29.70,130.67,131.83,133.61,137.04,144.50 (C]N): MSI MS m/z 325
þ
(M , 100%), 327 (Mþ2, 80%). Anal. calcd. for C17H13BrN2: C,
62.79%; H, 4.03%; N, 8.61%. Found: C,62.74%; H, 3.96%; N, 8.67%.
2.2.4. 1-(2-chlorophenyl)-2-(naphthalen-1-ylmethylene)hydrazine
(
1d)
Yield 89.14%, m.p. 132e133 C; 1H NMR:
AreH), 9.06 (s, 1H, HC]N), 9.99 (s, 1H, NH); C NMR:
16.16, 119.69, 123.59, 124.99, 125.67, 126.02, 126.82, 128.17, 128.72,
ꢁ
d
6.78e8.65 (m, 11H,
13
d
113.88,
1
1
28.87, 129.41, 130.05, 130.66, 133.57, 139.74, 141.28 (C]N); MSI MS
þ
m/z 281 (M þ H, 100%), 283 (M þ2, 35%). Anal. calcd. for
C17H13ClN2: C, 72.73%; H, 4.67%; N, 9.98%. Found: C,72.94%; H,
4.84%; N, 9.99%.
Fig. 1. Synthetic route to obtain new naphthalenylmethylen hydrazine derivatives.

H. Shirinzadeh, E. Dilek / Journal of Molecular Structure 1220 (2020) 128657
3
Table 1
Chemical structures of newly synthesized compounds.
2
.2.5. 1,2-bis(naphthalen-1-ylmethylene)hydrazine (1e)
2.2.8. 1-((6-Methoxynaphthalen-2-yl)methylene)-2-
phenylhydrazine(1h)
ꢁ
1
Yield 40.90%, m.p. 153e154 C; H NMR:
d
7.61e9.18 (m, 14H
13
ꢁ
1
ArH); 9.42 (s, 2H, HC]N); C NMR:
d
125.06, 125.54, 126.44,
Yield 90.68%, m.p. 229e230 C; H NMR:
6.72e7.93 (m, 11H ArH); 7.97 (s, 1H, HC]N); 10.29 (s, 1H, NH);
NMR: 55.20 (OCH ), 106.31, 111.94, 118.60, 118.82, 123.03, 125.69,
127.15, 128.46, 129.10, 129.40, 131.38, 134.16, 136.79, 145.40 (C]N),
57.47(OeC): MSI MS m/z 277 (M þ H, 100%). Anal. calcd. for
C18H16N2O: C, 78.24%; H, 4.5.84%; N, 10.14%. Found: C,60.78%; H,
.37%; N, 8.04%.
d
3.86 (s, 3H, OCH
3
);
C
1
3
127.60, 128.77, 129.19, 130.36, 131.93, 133.55, 161.98 (C]N): MSI MS
þ
m/z 309 (M þ H, 100%), 308 (M , 55%). Anal. calcd. for C22H16N2: C,
d
3
8
5.69%; H, 5.23%; N, 9.08%. Found: C,85.10%; H, 5.27%; N, 9.02%.
1
2.2.6. 1-(4-fluorophenyl)-2-((6-methoxynaphthalen-2-yl)
4
methylene)hydrazine (1f)
Yield 85.03%, m.p. 206e207 C; H NMR:
.03e7.92 (m, 10H, Ar- H), 7.96 (s, 1H, HC]N), 10.32 (s, 1H, NH);
NMR: 55.20 (OCH
25.72, 127.15, 128.46, 129.39, 131.31, 134.17, 136.88, 142.08 (C]N),
ꢁ
1
d
3.85 (s, 3H, O CH
3
),
C
1
3
3. Experimental e biochemical activity
7
d
3
), 106.31, 112.85, 115.48, 115.70, 118.83, 123.01,
3.1. Purification of carbonic anhydrase isoenzymes and inhibition
1
studies
1
54.65, 156.97, 157.49 (OeC); MSI MS m/z 295 (M þ H, 100%), 296
þ
(
M þ1, 28%). Anal. calcd. for C18H15FN2O: C, 73.45%; H, 5.14%; N,
The whole purification procedure was performed according to
our previous studies [28e30]. Briefly, red blood cells which were
9
.52%. Found: C,73.63%; H, 5.32%; N, 9.61%.
isolated from fresh blood were hemolyzed and the pH of the ob-
ꢁ
2.2.7. 1-(4-chlorophenyl)-2-((6-methoxynaphthalen-2-yl)
tained hemolysate was adjusted to 8.7 with solid Tris at 4 C. Hu-
methylene)hydrazine(1g)
Yield 83.87%, m.p. 220e221 C; 1H NMR:
.07e7.92 (m, 10H ArH); 7.97 (s, 1H, HC]N); 10.46 (s, 1H, NH);
NMR: 55.21 (OCH ), 106.32, 113.34, 118.86, 121.79, 123.01, 126.00,
27.17, 128.42, 128.88, 129.44, 131.09, 134.28, 137.67, 144.28 (C]N),
man erythrocyte hemolysate was applied to the Sepharose 4BL-
tyrosine-sulfanilamide affinity column. The human carbonic
anhydrase isozymes (hCA-I and hCA-II) were eluted with 1.0 M
NaCl/25mMNa2HPO4 (pH 6.3) and 0.1M NaCH3COO/0.5M NaClO4
(pH 5.6), respectively. For purity of both isoenzymes sodium
dodecyl sulfateepolyacrylamide gel electrophoresis (SDSePAGE)
was applied and obtained single band (Fig. 2). The protein deter-
mination in the effluents showing activity were evaluated
ꢁ
d
3
3.86 (s, 3H, OCH );
13
7
C
d
3
1
157.57 (OeC): MSI MS m/z 311 (M þ H, 100%), 312 (Mþ1, 32%). Anal.
calcd. for C18H15ClN2O: C, 69.56%; H, 4.86%; N, 9.01%. Found:
C,69.61%; H, 5.08%; N, 9.13%.

4
H. Shirinzadeh, E. Dilek / Journal of Molecular Structure 1220 (2020) 128657
[37] antiproliferative [38], anticancer [39], cytotoxic [40] antifungal
and other activities [41]. In this study we investigated, whether the
inhibition effect of some naphthalenylmethylen hydrazine de-
rivatives on CA I and II isoenzymes isolated from human erythro-
cytes. As part of our ongoing research, we were synthesized eight
new compounds of naphthalenylmethylene hydrazine derivatives
to investigate their possible in vitro CA I and II enzymes inhibitory
effects.
In our study, the inhibitory effect of naphthalenylmethylen hy-
drazine derivatives was determined by two different values of IC50
and Ki. IC50 were calculated by determining percent activity at
various inhibitor concentrations, with substrate concentrations
kept constant, and then determining the concentration of inhibitor
causing 50% inhibition graphically. For hCA-I, the obtained IC50
values are respectively 106.30,116.60,129.70, 160.27, 172.55, 201.57,
207.05, 248.71, 424.33 nM for 1f, 1g, 1h, 1c, 1b, 1a, 1d, 1e and AZA
compounds. Also, the obtained IC50 values for hCA-II enzyme are
respectively 79.50, 93.20, 113.37, 141.50, 142.05, 162.32, 167.53,
202.67, 232.48 nM for 1f, 1g, 1c, 1h, 1b, 1a, 1d, 1e and AZA com-
pounds. Among the synthesized compounds, 1f demonstrated a
potent inhibitory effect for both hCA I and hCAII (Table 2).
To determine the Ki constant, LineweavereBurk graphs were
drawn, and Ki constants and inhibition types were determined
from these graphs. The Ki constant is a value which indicates the
binding affinity of the inhibitor to the enzyme. The cytosolic
enzyme hCA I was inhibited by the novel naphthalenylmethylen
hydrazine derivatives (1f, 1g, 1h, 1c, 1b, 1a, 1d, 1e), with Ki values
ranging between 80.60 ± 17.90 and 492.5330 ± 95.23 nM. Ki values
of newly molecules except 1e are better than those of the standard
used drug AZA (Ki 446.83 ± 149.27 nM) (Table 2 and Fig. 3).
Accordingly, 1f (Ki: 80.60 ± 17.90 nM) had a high binding affinity for
hCA I.
Fig. 2. PAGE of the purified CA isozymes. Lane 1: Standard proteins (24.5e116 kDa),
lane 2: CA I, lane 3: CA II.
spectrophotometrically at 595 nm using the Bradford method [33].
CA isoenzymes activities were obtained in conforming to the pro-
cedure of Verpoorte et al. [34]. The increase in absorbance of the
reaction medium was spectrophotometrically obtained at 348 nm.
The esterase activity procedure was utilized for ascertaining the
inhibition agents by the LineweavereBurk procedure [35] CA ac-
tivity (%) versus inhibitory concentration and 1/V versus 1/[S]
graphs were drawn.
The cytosolic enzyme hCA II was inhibited by the novel naph-
thalenylmethylen hydrazine derivatives (1f,1g,1h,1c,1b,1a,1d, 1e),
Bovine serum albumin was used as standard protein as given
previously in details [28e30]. For the designation of the inhibition
efficacy of each novel naphthalenylmethylen hydrazine derivatives
with Ki values ranging between 126.70
61.09 ± 102.50 nM. Accordingly, 1g (Ki: 126.70 ± 33.20 nM) had a
high binding affinity for hCAII. The clinically and standard used
drug acetazolamide (AZA) calculated Ki value of
32.18 78.44 nM. Thus, the evaluated novel naph-
±
33.20 and
4
(
(
la-h) on both hCA isoenzymes, a percent activity versus inhibitor
naphthalenylmethylen hydrazine) concentration graph was
a
drawn. The IC50 values were obtained from these graphs. For the
calculation of Ki values, three different novel naph-
thalenylmethylen hydrazine concentrations were used. In this
study, they were given graphs which are drawn for the compound
showing the most effective inhibition (Fig. 3).
3
±
thalenylmethylen hydrazine derivatives except 1e showed consid-
erable inhibitory profiles when compared to the AZA molecule
(Table 2 and Fig. 3).
5. Conclusion
4
. Results and discussion
The investigated compounds exhibited more effective inhibitory
As a result of inhibition studies on CA enzyme activity, it can be
profiles compared to AZA used as standard drug. Therefore new
compounds inhibited the hCA I and hCA II activities at more low
concentrations. When the most effective compounds (1f and 1g)
are assessed, two important properties of these compounds stand
out. The first one is that naphthalene ring have methoxy group in
sixth position and second one is the phenyl group on hydrazine
molecule are para-halogenated. It is believed that, the oxygen in the
methoxy group and the halogen in the para position of the phenyl
ring may made hydrogen bond with CAs enzymes.
In the study of heterocyclic series of aromatic sulfonamides
binding to CA, the halogenated benzene ring significantly enhanced
the observed affinities as it increased the fraction of deprotonated
ligand [42,43]. In this study, the derivatives with a halogenated
benzene ring, particularly on the para-position demonstrated more
activity. In addition, one of the sulfonamide oxygens which is
making ionic interaction with existing zinc ion in the active site of
the enzyme was reported in other studies [43,44]. In the present
study, when the compound of 1f and 1g, whose activity is very high,
was examined, it was observed that a naphthalene ring has a
used in the treatment of glaucoma. In these inhibition studies, the
catalytic mechanisms of CA enzyme have been tried to be eluci-
dated. The distribution of the enzyme in tissues and their vital
functions in these tissues has been revealed as a result of these
studies. As a result of all these developments, studies of synthe-
sizing inhibitors and activators of the enzyme have increased
rapidly. Therefore, many types of enzyme inhibitors have been
synthesized and used as primarily medicines for the treatment of
glaucoma. As well as glaucoma, it is also currently used in clinics as
antitumor, analgesic, epilepsy, antiulcer, diuretics, antibiotics and
neurological disease drugs [36].
The new compounds based on Schiff bases were synthesized
and the inhibition effect on CA enzyme was observed. Compounds
with the structure of eC]N- (azomethine group) which are usually
synthesized from the condensation of primary amines and active
carbonyl groups are known as Schiff bases. Schiff bases and their
derivatives were investigated in many studies and established to be
associated with a variety of biological activities like anticonvulsant

H. Shirinzadeh, E. Dilek / Journal of Molecular Structure 1220 (2020) 128657
5
Fig. 3. Determination of % Activity/[1f] curve and LineweavereBurk graphs for excellent inhibitors of hCA I and hCA II isoenzymes.
Table 2
IC50 and K
i
values of hCA I and hCA II with compounds and AZA, by an esterase assay.
Compounds
IC50 (nM)
hCA I
i
K (nM)
r2
hCA II
r2
hCA I
hCA II
1
1
1
1
1
1
1
1
a
b
c
d
e
f
201,57
172,55
160,27
207,05
248,71
106,30
116,60
129,70
424,33
0.977
0.992
0.990
0.988
0.972
0.996
0.982
0.990
0.981
162,32
142,05
113,37
167,53
202,67
79,50
93,20
141,50
232,48
0.984
0.995
0.979
0.994
0.981
0.987
0.993
0.986
0.972
194.18 ± 51.30
201.29 ± 42.44
149.43 ± 30.03
232.18 ± 23.45
259.07 ± 28.01
80.60 ± 17.90
116.20 ± 22.50
148.80 ± 9.97
446.83 ± 149.27
136.17 ± 36.22
152.83 ± 51.22
102.88 ± 18.44
147.81 ± 23.48
217.45 ± 48.51
129.70 ± 29.10
126.70 ± 33.20
135.30 ± 7.16
332.18 ± 78.44
g
h
Acetazolamide (AZA)
Mean from at least three determinations. Errors in the range of 3e5% of the reported value (data not shown).
methoxy group at the 6th position. Presumably, the oxygen’s ionic
bonding with zinc in the active site of the enzyme played an
important role in making the compound much more effective than
AZA.
administration, Resources, Supervision. Esra Dilek: Writing - re-
view editing, Methodology, Investigation, Validation,
Visualization.
&
Although our results are promising, in order to obtain a perfect
and reliable hCA I and II enzyme inhibitor, we intend to undertake
advanced studies to explain the cytotoxicity and action mechanism
of these compounds. Thus, we believe that these novel naph-
thalenyl methylene hydrazine derivatives compounds are hopeful
as leading compounds to improve as CA inhibitors.
Acknowledgements
The authors appreciate the Scientific Research Council of
Erzincan Binali Yildirim University for their support of the Project
(Project No: SAG-A-240215-0120).
Appendix. Supplementary data
Declaration of competing interest
Supplementary data associated with this article can be found in
the online version, at https://doi.org/10.1016/j.molstruc.2020.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
128657. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References
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