Novel hypervalent iodine catalyzed synthesis of α-sulfonoxy ketones: Biological activity and molecular docking studies

Article abstract of DOI:10.1016/j.molstruc.2021.130492

The novel di((camphorsulfonyl)oxy)iodo]benzene (DCIB) was synthesized from [Bis(trifluoroacetoxy)iodo]benzene in the mild conditions. The α-sulfonoxylation of various ketones with novel hypervalent iodine was reported in excellent yield. α-Hydroxyketones

Full text of DOI:10.1016/j.molstruc.2021.130492

Journal of Molecular Structure 1239 (2021) 130492
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Novel hypervalent iodine catalyzed synthesis of α-sulfonoxy ketones:
Biological activity and molecular docking studies
Ufuk Atmacaa,b, Cemalettin Alpc, Hulya Akincioglud, Halide Sedef Karamana,
a
a,∗
˙
Ilhami Gülçin , Murat Çelik
a Department of Chemistry, Faculty of Sciences, Atatürk University, 25240, Erzurum, Turkey
b Oltu Vocational School, Ataturk University, Erzurum, Turkey
c Cayirli Vocational School, Erzincan University, Erzincan, Turkey
d Department of Chemistry, Faculty of Sciences and Arts, Ag˘rı Ibrahim Cecen University, Ag˘rı, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The
novel
di((camphorsulfonyl)oxy)iodo]benzene
(DCIB)
was
synthesized
from
Received 1 January 2021
Revised 2 April 2021
Accepted 14 April 2021
Available online 21 April 2021
[Bis(trifluoroacetoxy)iodo]benzene in the mild conditions. The α-sulfonoxylation of various ketones
with novel hypervalent iodine was reported in excellent yield. α-Hydroxyketones were synthesized
from α-sulfonoxy compounds (caphorsulfonoxy ketones) with Li/NH3(g) at -20 °C in THF. Then, some
biochemical studies including several enzyme inhibition linked some global diseases were carried
out. For this purpose, the inhibitory potentials of synthesized novel camphorsulfonoxy ketones were
investigated against hCA I, and hCA II isoenzymes, AChE, and BChE enzymes. When the results were
evaluated, novel α-sulfonoxy ketones were found to have strong inhibition effects on these metabolic
enzymes. IC50 values and Ki values were determined for each compounds and compared with putative
and positive controls. The synthesized α-sulfonoxy ketone compounds showed Ki values of in range
of 73.2–406.0 μM against hCA I, and 57.12–526.05 μM against hCA II closely associated with various
physiological and pathological processes in living organisms. On the other hand, Ki values were found in
range of 28.80–140.3 μM against AChE, and 7.186–40.0 μM against BChE enzymes. Within the scope of
the study, the inhibition types of the α-sulfonoxy ketones with novel hypervalent iodine were evaluated.
Camphorsulfonoxy moiety caused to inhibition of the enzymes through hydrophobic interaction and
hydrogen bond.
Keywords:
Hypervalent iodine
Carbonic anhydrase
A-sulfonoxyketones
A-hydroxyketones
Acetylcholinesterase
Butyrylcholinesterase
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
ing HMBI (hydroxy (mesyloxy) iodo benzene) in yields ranging of
50–96% as seen Scheme 1.
α-Sulfonoxy ketones are key structure in many bioactive, natu-
ral and pharmacological targets [1,2] and used in the synthesis of
valuable cyclic compounds [3]. The synthetic routes to these com-
pounds include α-substitute sulfoxylation of α-position of ketones
[4,5], which key structure in many bioactive compounds. They have
been prepared by using hypervalent iodine reagents [6-8]. They
have non-metallic character and highly selective oxidants. Espe-
cially, Koser reagent’s (hyroxy(tosyloxy)iodo benzene) (HTIB) and
hydroxy(mesyloxy)iodo benzene (HMBI) are advantageous reagents
of α-mesylation and α-tosylation of ketones. α-Keto sulfonates
have been prepared according to method of Lodoya and cowork-
ers [9]. They have reported the synthesis of mesyloxy ester by us-
Also, Yusubou and coworkers have been studied the recy-
clable hypervalent iodine reagents. For preparation of the α-
tosylation and α-mesylation compounds with m-iodobenzoic acid
is a preferably labeled hypervalent iodine (III) reagent that gives
effortless purifications [10]. Herein, we present an effective, di-
rect and simple method for the synthesis of novel DCIB (3) from
PIFA ([Bis(trifluoroacetoxy)iodo]benzene) (1) and synthesis of α-
sulfonxyketones with DCIB from various cyclic and acyclic ketones.
Carbonic anhydrases (CAs, E.C.4.2.1.1) were firstly discovered in
the 1930s. They catalyze the hydrolysis of carbon dioxide (CO2) to
bicarbonate (HCO3–) and protons (H+) [11-13]. CAs exist in many
–
organisms due to respiratory, CO2/HCO3 conversion, pH regula-
tion, CO2 homeostasis, electrolyte release in various organs and tis-
sues, bone resorption, calcification, tumor formation and biosyn-
thesis reactions including gluconeogenesis, lipogenesis, ureagene-
sis and other physiological or pathological processes [14-16]. Vari-
∗
Corresponding author.
E-mail address: mcelik@atauni.edu.tr (M. Çelik).
https://doi.org/10.1016/j.molstruc.2021.130492
0022-2860/© 2021 Elsevier B.V. All rights reserved.

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
Scheme 1. Synthesis of α-sulfonxyketones with hypervalent iodine reagents.
ous CA inhibitors (CAIs) are used as antiglaucoma, anticonvulsant,
antiepileptic, antiurolitic and anticancer agents. Also, some of these
inhibitors are considered medicines for treatment of cancer in the
development phase. Some of CAIs are continue their clinical tri-
als [17,18]. Besides metabolism and cancer formation, CA has to do
with cell growth and apoptosis [19-21]. Up to now, eight different
CA family including α-, β-, γ -, δ-, ζ-, η-, ɵ- and ι-CAs have been
discovered in various species [22,23]. Humans have only α-CA fam-
ily and sixteen variants or α-CA isoenzymes were sorted depend-
ing on their subcellular localizations. The CA I, and II isoenzymes
are the most reputed and studied ones and cytosolic proteins. Like
other isoenzymes, CA I, and CA II isoenzymes implicated in differ-
ent important physiological process [24-26]. However, recently, the
inhibition of CA isoenzymes has been extensively studied as their
dysfunction, which often associated with their diverse pathologies
like mental disorders (CAs II, VII, VIII and XIV), obesity (CAs VA and
VB), edema (CAs I and II), glaucoma (CAs II, IV and XII) and cancer
(CAs IX and XII) [27]. The hCAs I, and II isoforms is found to be re-
sponsible for a great part of side effects of the clinically used CAIs.
Both isoenzymes are abundantly found in many tissues and organs
with well-determined physiological functions [28-30]. They inter-
enzyme, also called non-specific pseudo cholinesterase, is found in
the liver, pancreas, blood serum and central nervous system (CNS)
[44-46]. In case the AChE enzyme is not fully functional, some
problems may occur. CNS, parasympathetic and sympathetic mo-
tor nerves fail when they encounter an obstacle in AChE’s work
[47,48]. Alzheimer’s disease (AD) is observed with a decrease in
the neurotransmitter in the brain. Among the neurotransmitters,
the most decreasing was observed in ACh [49-53]. AD is a very
common dementia disease and characterized as a dysfunction of
memory [54-56]. The reduction of ACh level in the brain is the
biggest change in AD in biochemical sense [57-59]. However, it
has been reported that these drugs cause side effects such as gas-
trointestinal disorders and hepatotoxicity. So, they are not effective
and safe drugs [60]. Therefore, the growing researches on safer in-
hibitors for both cholinergic enzymes have been going on expo-
nentially recently.
In this study, we aimed the synthesis of novel α-camphor sul-
fonyloxyketones (5a-g) and noted theirs inhibition profiles against
hCA I, and hCA II isoenzymes, AChE, and BChE enzymes. Also,
molecular docking was studied for the most active compound
against each enzyme.
act in their deprotonated forms directly with the zinc ions (Zn2+
)
2. Results and discussion
of the active site CAs. However, there is a growing researches re-
lated to novel inhibitors including alternative chemical structures
with significant CA isoform selectivity profiles [31-33].
Practically, 1.1 equiv. of PIFA (1) dissolved in anhydrous ace-
tonitrile and 2.2 eq. of 10-camphor sulfonic acid (2) was added to
the solution and stirred for 3 h at room temperature. The corre-
sponding DCIB was successfully obtained quickly in 98% yield. But
the trifluoroacetic acid was removed in high vacuum evaporation.
Because of DCIB is very hydroscopic and it is not thermal stable.
Therefore, the DCIB dissolved methylene chloride, and stored up in
0 °C. In addition it should be freshly synthesized before use.
The DCIB was identified on the basis of their NMR spectra in-
cluding 1H NMR and HR-ESI-MS studies. Two peaks present at 3.04
(d, A part of AB system, J = 14.6 Hz, 2H) and 2.50 (d, B part of AB
Cholinesterases are responsible for responding to stress, cell dif-
ferentiation and regeneration [34-36]. To regulate cholinergic neu-
ron, they hydrolyze acetylcholine (ACh) to choline and acetate ions
[37,38]. The strong pharmacological effect of ACh as a neurotrans-
mitter and as a neuromodulator was found in 1906 and plays
an important role in neural transmission [39,40]. However, recent
studies have shown that this is not the only task of ACh. In ad-
dition, it has been found that ACh is involved in the formation of
bioelectric current in nerve cells and muscle fibers [41-43]. BChE
2

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
Scheme 2. Synthesis of [di((camphorsulfonyl)oxy)iodo]benzene (3).
system, J = 14.6 Hz, 2H) in 1H NMR. These peaks are belonging to
camphor CH2-SO2. In addition to, proton of benzene ring‘s ortho-
is present at 7.87 ppm (d, 2H, J = 8.05 Hz), in 1H NMR spectra of
compound 3 DCIB (Scheme 2), DCIB (3) was found with HR-ESI-
MS: m/z Calcd for [M + H+]: 667.0891; found: 667.0888.
suggested the inhibition type of enzyme inhibition of hCA I and
II isoenzymes, AChE and BChE enzymes. Both cytosolic hCA isoen-
zymes inhibition results are summarized in Table 3.
The IC50 values of the α-camphorsulfonyloxy ketones (5a-g) for
hCA-I isoenzyme are between 149.39 and 641.07 μM. Also, for the
hCA II isoenzyme, IC50 values are between 310.76–529.41 μM. Ki
values for both hCA isoenzymes were determined at the μM level.
Ki values of α-camphorsulfonyloxyl ketones (5a-g) for hCA I isoen-
zyme are in the range of 73.18 2.42 – 406.0 166.7 μM. In addi-
tion, Ki values of α-camphorsulfonyloxy ketones (5a-g) for hCA II
isoenzyme are in the range 57.12 3.01–526.05 211.52 μM. When
the results are compared to AZA, the positive control molecule,
they have been shown to have strong inhibition potential (Table 3),
As it is known, AD has been associated with cholinergic loss
since 1970s. For this reason, it was thought that strengthening
the cholinergic system could treat AD. In the treatment of AD,
reducing ACh destruction increased cholinergic effect. ACh is the
key molecule of signal transduction in the brain’s attention and
memory-related areas [77,78]. Drugs that increase ACh prevent
some of the loss of neuronal function, but this is short-lived. These
drugs not prevent the progressive loss of neurons AChE inhibitors.
They are used to support the cholinergic effect in the treatment of
dementia diseases. However, since these inhibitors cause side ef-
fects in terms of live metabolism, the trend towards new natural
and effective inhibitors increases day by day [79,80]. In the first
step of our biochemical studies, newly synthesized ketones (5a-g)
were screened for their inhibitory potency against both choliner-
gic AChE and BChE enzymes, which present in the central nervous
system and tissue, muscle and red cells. With the completion of
the inhibition studies, the inhibition parameters like IC50 and Ki
values were calculated for each α-camphorsulfonoxy ketone (5a-
g) molecule. The results were given in the table together with the
results of Tacrine, the positive control molecule [81,82].
In addition, significant advances made in the synthesis of
α–hydroxy ketones, the improving mild and eco-friendly (green
chemistry) reaction with excellent functional groups compatibly
are highly attractive [61,62]. Hypervalent iodine reagents have
arisen as important oxidants in the organic synthesis due to their
varied reactivities, easily handling, and low toxicities [63-65]. We
initially discovered method for the α-sulfonxylation of ketones
using [di((camphorsulfonyl)oxy)iodo]benzene (3) in DCM at room
temperature.
The camphorsulfonoxy ketones (5a-d, and g) from cyclic and
acyclic ketones were synthesized in dichloromethane at room tem-
perature in good yields with DCIB, which is novel hypervalent io-
dine compound (Table 1), The aromatic group substitute camphor-
sulfonoxy ketones (5e-f) was also synthesis in excellent yields. The
products (5a-g) were supported by 1H NMR, 13C NMR spectra, ele-
mental analysis, and HR-MS.
α-Sulfonoxyl ketones have received much attention. However,
sulfonoxyl groups are much better reducing group than other es-
ters. They show chemistry that is greatly facilitating over that
found for analogues esters [66]. We synthesized α–hydroxy ke-
tones (6a-g) from α-sulfonoxyketones (5a-g) with lithium and NH3
gas in THF, in good yield at −20 °C [67] (Table 2),
Reduction reaction of sulfonoxyl compounds whose α-position
of ketone bear heteroatoms such as SO2 and O− groups are im-
portant under mild conditions. Therefore reduction of sulfonoxyl
groups was performed at −20 °C with gaseous NH3 and lithium, in
mild condition and good yield.
In the first step of this studies, we investigated the inhibi-
tion effect of newly synthesized ketones on hCA I, and hCA II
isoenzymes. Newly synthesized ketones were screened for their in-
hibitory potency against two CA isoenzymes, namely the widely
distributed off-target cytosolic hCA I, and hCA II. CA isoenzymes
have been the target enzymes for medicinal products used in
animals and especially humans [68-70]. Drugs with sulfonamide
derivatives such as acetazolamide, dorzolamide and brinzolamide
are potent CAIs. Also, CAIs are also widely used in humans for
the treatment of glaucoma, edema and epilepsy [71-73]. How-
ever, many chemicals can significantly reduce the CA activity and
even stop it completely. In drug design studies conducted in re-
cent years, to minimize side effects is one of the main goals. The
inhibition studies data for both hCA I and hCA II isoenzymes were
evaluated and the IC50 and Ki values of each molecule were de-
termined [74-76]. The substrate-dependent enzyme kinetics eval-
uated the mode of enzyme inhibition for each novel compound
using the Lineweaver-Burk reciprocal 1/Vmax Vs. 1/S plot, which
When the inhibition results for AChE enzyme are evaluated,
IC50 values were found in the range of 55.35–377.24 μM. On
the other hand, Ki values of these molecules have been found
in the range of 28.8
8.00–364.01 55.2 μM. Looking at the
results, the newly synthesized ketone with the best inhibition
potential for the AChE enzyme is found as 2-oxocyclohexyl(7,7-
dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methane sulfonate (5b),
Also, the inhibition type of this molecule (5b) has been de-
termined as competitive. Considering Table 4, the results for
BChE enzyme are as follows; while IC50 values were between
8.915–73.201 μM, Ki values have found between 7.186 2.782-
40.0
2.01 μM. For BChE enzyme, the best IC50 value
belongs to the 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl
(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (5f)
and the best Ki value belongs to the 2-oxocyclopentyl(7,7-
dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl) methane-sulfonate (5a),
For AChE and BChE enzymes of Tacrine used as positive control,
3

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
Table 1
α-Sulfonoxylation of ketones with DCIB.
aReaction conditions: 1.0 mmol of ketones (4a-g), 1.1 mmol of DCIB, 15 mL DCM, reaction was stirred for 4h
.bIsolated yield and literature.
Table 2
Hydrolysis of α-camphorsulfonyloxy ketones (6a-g).
aReaction conditions: 1.0 mmol of α-camphorsulfonyloxy ketones (5a-g), 1.1 mmol Li,
10 mL THF, reaction was stirred for 2 h.
bIsolated yield and literature.
4

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
Table 3
Inhibition results of hCA I and hCA II isoenzymes.
hCA I
hCA II
hCA I and II
Compounds
Inhibition types
IC50 (μM)
R2
Ki (μM)
IC50 (μM)
R2
Ki (μM)
5a
207.49
336.74
239.54
334.62
149.39
519.10
641.07
0.413
0.8569
0.8644
0.9522
0.9472
0.9704
0.8363
0.9057
0.9918
80.6
6.6
347.37
378.03
310.76
411.03
435.58
311.73
529.41
0.388
0.8913
0.8598
0.9129
0.8695
0.8905
0.9275
0.9985
0.9395
57.12 3.00
Competitive
Competitive
Competitive
Competitive
Competitive
5b
5c
73.2
2.4
93.78 32.20
222.39 51.40
206.90 6.20
149.74 21.00
91.2
1.9
5d
5e
93.4
16,7
124.1
259.5
406.0
53.4
5f
77,2
526.05 211.52
393.031 86.50
0.059 0.004
Noncompetitive
Noncompetitive
Competitive
5 g
AZA
166.7
0.116 0.019
Table 4
Inhibition parameters of IC50 and Ki belongs to newly synthesized ketones (5a-g) for acetylcholinesterase (AChE) and
butyrylcholinesterase (BChE) enzymes.
AChE
BChE
Compounds
Inhibition Types
IC50 (μM)
R2
Ki (μM)
IC50(μM)
R2
Ki (μM)
5a
295.02
55.35
0.9811
0.9675
0.9646
0.9409
0.9114
0.9181
0.8743
0.9665∗
198.6
28.8
6.5
8.0
73.20
33.77
38.37
24.75
12.32
8.915
36.76
34.36∗
0.9952
0.9268
0.9263
0.9603
0.9581
0.9627
0.9442
0.9609
7.18 2.78
Competitive
5b
14.61 2.12
11.79 4.88
40.00 2.00
10.77 2.25
21.20 9.92
20.10 6.31
20.00 7.33∗
Competitive
5c
63.69
140.3
364.0
74.5
23.4
55.2
Noncompetitive
Noncompetitive
Noncompetitive
Noncompetitive
Competitive
5d
137.15
67.29
5e
16.0
5f
377.25
205.39
166.10∗
138.9
198.1
90.9
46.3
6.58
11.2∗
5 g
Tacrine
Competitive
∗nM: Nanomolar.
Table 5
Table 6
Inhibition constant (Ki, μM) and enzyme selectivity of acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE) enzymes for the novel synthesized
ketones (5a-g).
Binding energy (kcal/mol) of α-sulfonoxy ketones in
the catalytic sites of acetylcholinesterase (AChE), butyryl-
cholinesterase (BChE), human carbonic anhydrase
isoenzymes (hCA I, and hCA II).
I and II
Compounds
BChE
AChE
BChE/AChE Selectivity
Docking Score
Compounds
5a
7.186 2.782
14.606 2.12
11.79 4.88
198.6
28.8
6.5
8.0
23.4
0.036183
0.507153
0.084034
0.10989
5b
AChE
BChE
hCA I
hCA II
5c
140.3
5b (R, S, R)
5a (S, S, R)
5b (S, S, R)
5a (R, R, S)
−8.571
–
–
–
5d
40.0
2.00
364.03 55.2
–
–
–
−7.718
–
–
5e
10.77 2.25
74.5
16.02
46.3
0.144564
0.152628
0.101464
0.220022
–
–
−6.214
–
5f
21.2
20.1
9.92
6.31
138.9
198.1
90.9
–
−6.731
5 g
Tacrine
6.58
11.20∗
20.01∗ 7.33
IC50 values were determined as 166.10 and 34.359 nM respec-
tively. For AChE and BChE enzymes of Tacrine molecule, Ki values
reported scores by former study [85]. The binding energies also
confirmed results of in vitro studies.
were determined as 90.9
11.2–20.03 7.30 nM. When evaluated
The possible inhibition mechanisms of the inhibitors were de-
termined by analyzing their poses with best-binding energies. Ac-
cording to the poses, the inhibitors well fitted into the catalytic
active sites. Especially, locations of the inhibitors in AChE and
BChE enzymes were better than that of the inhibitors in hCA
I, and hCA II isoenzymes due to active sites’ volume of ChEs
has bigger than the active site of CAs. This has caused to some
parts of inhibitors stays out the active site of CAs as seen in
Fig. 1. The poses were also analyzed with 2D and 3D modes
based on interactions between inhibitor and residues of the active
site. 2D interaction mode helped us recognize which stereoisomer
poses with best-binding energies is. 2D interaction mode was il-
lustrated in Supplementary Figure 1. According to Supplementary
Figure 1a, (R, S, R) stereoisomer of 2-oxocyclohexyl(7,7-dimethyl-
2-oxobicyclo[2.2.1]heptan-1-yl)methane sulfonate (5b) has best-
binding energies against AChE enzyme. It formed two hydrogen
bonds (direct) with Phe295 and Arg296 through the oxygen of
camphor sulfonyl moiety. Phe295 of these residues provides sub-
strate specificity for AChE enzyme by preventing the entrance of
molecules on the catalytic site [86]. The interaction between in-
hibitor and Phe295 can extinguish its substrate specificity and
therefore can cause inhibition of the enzyme.
in terms of selectivity, the molecules appear to be selective for the
BChE enzyme. Especially other molecules except molecule 5b are
more selective than Tacrine and the most selectivity belongs to the
molecules 5a and 5c. This comparison is given in Table 5.
In recent years, molecular docking and modeling studies gain
great importance for understanding the possible inhibition mech-
anism of inhibitors. For this reason, the possible inhibition mech-
anisms of compounds, which displayed the most active inhibitory
effect in vitro studies, were determined using the induced-fit dock-
ing method. The docking method had been validated with the re-
docking process using co-crystallized ligand. The validations have
exhibited the same root-mean-square deviation (RMSD) values in
˚
previous studies were obtained. The values were 0.106 A and
˚
˚
˚
2.706 A for AChE and BChE enzymes [83] and 0.446 A and 0.452 A
for hCA I and hCA II isoenzymes [84], respectively. Following dock-
ing studies, the best docking scores were detected and were pre-
sented in Table 6. According to Table 6, novel synthesized ketones
5a and 5b displayed better binding energy against BChE and AChE
enzymes, respectively than hCA I and hCA II isoenzymes. However,
the binding energy of the compounds against hCA I, and hCA II
isoenzymes were enough good, as well. They are compatible with
5

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
Fig. 1. The predicted catalytic active site of the enzymes and the poses of 5a and 5b in the active sites: a) 5b-AChE, b) 5a-BChE, c) 5b-hCA I, and d) 5a-hCA II. The catalytic
active site is represented as a gray mesh surface, the hydrophobic site is represented as a yellow bubble, the hydrophilic site is represented as a green bubble and metallic
site is represented as purple bubble.
The inhibitor also formed a water-mediated hydrogen bond
with Ser293 (Supplementary Figure 1a), Along with His447 and
Glu334, Ser203 constitutes catalytic triad and the triad called es-
teratic site. The residues in esteratic site provide the transfer of
the acetyl group to the catalytic serine from acetylcholine [87].
The water-mediated hydrogen bond between inhibitor and Ser293
most probably reduces enzyme activity. The interactions are quite
similar to dihydrotanshinone I, which is a potent AChE inhibitor.
In addition to these interactions, it formed an aromatic hydrogen
bond with Tyr 341 (Fig. 2a), The residue is coordinated by a water
molecule in the catalytic site and is a part of a large water network
[88]. (S, S, R) stereoisomer of compound 5a has best-binding ener-
gies against BChE enzyme. The stereoisomer of 5a formed a hy-
drogen bond (direct) with Thr120 through the oxygen of cyclopen-
tanone moiety (Supplementary Figure 1b), The camphor sulphonyl
moiety of compound 5a constituted hydrophobic interactions with
hydrophobic residues as the same moiety of 5b did (Figs. 1a and
1b), This stereoisomer of compound 5a possibly provides more hy-
drophobic interactions. Among these hydrophobic residues, Tyr82
and Tyr 332 closely interacted with the inhibitor (Supplementary
Figure 1b), It was reported that Tyr82 and Tyr 332 are quite im-
portant for the stabilization of non-covalent inhibitor in the active
site of BChE [89]. As seen in Fig. 2b, the inhibitor couldn’t form an-
other interaction with residues of the active site of BChE enzyme.
The hydrophobic interactions have provided that the compound 5a
become a potent BChE inhibitor even it has not more hydrogen
bonds.
It was observed that the activity of hCA I enzyme was inhib-
ited by compound 5bin vitro studies. However, (S, S, R) stereoiso-
mer of 5b had better binding energy that its other stereoisomers.
Thereby, it can be highly effective that the other stereoisomers. Ac-
cording to its binding modes, an oxygen atom of sulfonyl group
constituted metal coordination with Zn atom, which is responsible
for the catalytic activity of CAs (Supplementary Figure 1c), The in-
teraction interrupts coordination between Zn atom and three his-
tidine residues and a water molecule [90] and this can be cause
losing catalytic activity of the enzyme. This interaction is a typical
effect mechanism for sulphonyl containing compounds and it has
reported that many potent inhibitors with same effect mechanism
have been reported in various publications [91,92]. The inhibitor
was also formed aromatic a hydrogen bond with Phe191 through
the oxygen of camphor sulphonyl moiety as seen in Fig. 2c. The in-
teraction has provided to the enzyme inhibition. Lastly, it has been
detected that (R, R, and S) stereoisomer of 5a had better bind-
ing energy that other 5a stereoisomers. The stereoisomer didn’t
form typical interaction between sulphonyl containing compounds
and CAs. However, it farmed critical hydrogen bonds with Gln92,
Thr199, and Thr200 residue (Supplementary Figure 1d), Because
the residues occupy hydrophilic cleft of the catalytic active site and
Gln92 is responsible for ligand binding. In addition to this, Thr199
contributes protecting of tetrahedral geometry of coordination be-
tween Zn atom and three histidine residues [90]. The critical hy-
drogen bond interactions make inevitable the enzyme inhibition.
We detected similar interactions between potent CA II inhibitor in
our previous studies [93,94]. Distances of interactions between in-
6

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
Fig. 2. 3D interaction mode of 5a and 5b in the active sites: a) 5b-AChE, b) 5a-BChE, c) 5b-hCA I, and d) 5a-hCA II. The hydrogen bond is represented with black dashed
line, the aromatic hydrogen bond is represented with turquoise dashed line and coordination is represented with red-gray dashed line.
Table 7
Drug-likeness properties of the most active α-sulfonoxy ketones.
Compounds
rtvGa
MWb
DHBc
AHBd
logPo/wf
logHERGf
logBBg
CaCoh
PMDCKi
% Hum. Oral Abs.j
5a (R,R,S)
5a (S,S,R)
5b (R,S,R)
5b (S,S,R)
2
2
2
2
314.396
328.423
342.449
316.412
0
0
0
0
8
8
8
8
1.011
0.972
1.331
1.136
−3.529
−3.667
−3.687
−3.675
−0.706
−0.771
−0.686
−0.862
744.068
666.589
828.593
533.797
359.400
319.126
403.726
251.001
84.264
83.181
86.970
82.414
a
b
c
d
e
f
Reactive group (tox).
Molecular weight.
Number of hydrogen bond donors.
Number of hydrogen bond acceptors.
Octanol/water partition coefficient.
IC50 value for the blockage of HERG K+ channels.
g
h
i
Brain/blood partition coefficient.
Caco-2 cell membrane permeability.
MDCK Cell permeability in nm/sec.
Qualitative human oral absorption.
j
hibitors and residues of the receptors were presented in Supple-
and 5b were nontoxic compound due to their two reactive groups.
They also were not a blocker for the Human Ether-a-go-go-related
Gene (hERG) Potassium Channel due to high values from −5. The
inhibitors can orally absorb and across to blood/brain barrier with
moderate brain/blood partition coefficient. In addition to this, they
easily absorb from Caco-2 and MDCK cells membrane due to great
cell permeability values. According to Lipinski’s rule of five, the
˚
mentary Figure 2. All distances were less than 3 A. The results have
indicated that the interactions can accept important interaction re-
sponsible for inhibition.
After the detection of the possible inhibition mechanisms of the
inhibitors, their drug-likeness properties were calculated and pre-
sented in Table 7. According to these results, stereoisomers of 5a
7

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
yield. 1H NMR (200 MHz, CDCl3, ppm): δ= 0.88 (s, 3H), 1.13 (s,
3H), 1.24–2.59 (m, 13H), 3.32 (dd, B part of AB system, J = 15.1,
3.4 Hz, 1H), 3.78 (dd, A part of AB system, J = 15.1, 4.9 Hz, 1H),
4.98 (dd, J = 10.01, 2.03 Hz, 1H), 13C NMR (50 MHz, CDCl3, ppm):
δ= 19.0, 21.7, 21.8, 27.3, 28.9, 31.6, 36.4, 44.5, 45.0, 49.9, 51.2, 60.2,
82.2, 211.8, 215.5, IR:(KBr) νmax = 2961, 2932, 1747, 1455, 1365,
1168, 1009, 947, 840, 748. Anal. Calcd. for C15H22O5S: C, 57.31; H,
7.05; S, 10.20. Found: C, 57.42; H, 7.18; S, 10.43, HR-ESI-MS: m/z
Calcd for [M + H+]: 315.1261; found: 315.1268.
inhibitors have good drug properties compared those of 95% of
known drugs.
Conclusions
In summary, we have first synthesized the novel hyperva-
lent iodine compound (III) [di((camphorsulfonyl)oxy)iodo]benzene
3 (DCIB) by our group. Further, we have described an easy and
useful method for conversion of α-camphorsulfonyloxy ketones to
the corresponding α–hydroxy ketones in good yields using Lithium
and NH3 in THF. The studies have been conducted recently that
novel synthesized compounds are very remarkable, as enzyme in-
hibitors exhibit a wide spectrum of activities [95,96]. Also, in this
study, inhibition potentials of α-camphorsulfonyloxy ketones (5a-
g) against AChE, BChE, hCA I, and hCA II enzymes were evaluated.
Studies have shown that these molecules have strong inhibitory ef-
fects [97,98]. IC50 values determined as a result of inhibition stud-
ies on CA enzymes are close to each other and are at the μM level
due to there is a functional sulphonyl group in the structure of
the molecules. In order to solve the target problem in the treat-
ment of some diseases, enzyme selectivity is important in addi-
tion to the inhibitory effects of inhibitors. In our study, molecules
showed selective properties for BChE enzyme. This finding is quite
interesting. Their inhibitory properties against AChE and BChE en-
zymes result from hydrophobic character of camphor sulfonyl moi-
ety and hydrophilic character of ketone groups. As a result, as we
discussed above, novel α-sulfonyloxy ketones can be good candi-
date drugs, as hCA I and hCA II inhibitors, for treatment of some
diseases including glaucoma, epilepsy, mountain sickness, gastric
and duodenal ulcers, neurological disorders, or osteoporosis. Also,
these molecules have potency drugs as AChE and BChE inhibitors
to treat dementia, myasthenia gravis and Alzheimer’s disease.
2-Oxocyclohexyl(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl)methane sulfonate (5b), Obtained as colorless oil. 98% yield.
1H NMR (400 MHz, CDCl3, ppm): δ=0.87 (s, 3H), 1.10 (s, 3H),
1.40–2.15 (m, 10H), 2.26–2.58 (m, 5H), 3.34 (dd, B part of AB
system, J = 15.1, 4.2 Hz, 1H), 3.74 (dd, A part of AB system,
J = 15.1, 4.2 Hz, 1H), 5.12 (m, 1H), 13C NMR (100 MHz, CDCl3,
ppm): δ=19.9, 20.0, 20.1, 23.8, 25.1 25.2, 27.0, 27.2, 34.9, 41.1, 42.7,
43.0, 49.1, 82.4, 204.1, 214.5, IR:(KBr) νmax = 2956, 2924, 1746,
1454, 1358, 1173, 1021, 922. Anal. Calcd. for C16 H24O5S: C, 58.51;
H, 7.37; S, 7.96. found: C, 58.25; H, 7.23; S, 7.84, HR-ESI-MS: m/z
Calcd for [M + H+]: 329.1417; found: 329.1419.
2-Oxocycloheptyl(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl) methane sulfonate (5c), Obtained as colorless oil. 93% yield.
1H NMR (400 MHz, CDCl3, ppm): δ= 0.82 (s, 3H), 1.04 (s, 3H),
1.35–1.42 (m, 2H), 1.73–2.13 (m, 11H), 2.26–2.58 (m, 4H), 3.20
(dd, B part of AB system, J = 15.1, 4.2 Hz, 1H), 3.64 (dd, A part
of AB system, J = 15.1, 4.2 Hz, 1H), 5.17–5.22 (m, 1H), 13C NMR
(100 MHz, CDCl3, ppm): δ=19.7, 23.1, 23.8, 24.9, 25.5, 26.9, 28.2,
61.6, 40.4, 42.5, 42.7, 47.9, 48.6, 58.0, 84.4, 206.6, 214.3, IR:(KBr)
νmax = 2938, 2864, 1746, 1455, 1359, 1171, 987, 863, 736, 575.
Anal. Calcd. for C17 H26O5S: C, 59.63; H, 7.65; S, 9.36. found:
C, 59.42; H, 7.36; S, 9.74, HR-ESI-MS: m/z Calcd for [M + H+]:
343.1574; found: 343.1571.
2-Oxocyclooctyl(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl)methane sulfonate (5d), Obtained as colorless oil. 94% yield.
1H NMR (400 MHz, CDCl3, ppm): δ=0.87 (s, 3H), 1.10 (s, 3H),
1.24–2.56 (m, 19H), 3.20 (dd, B part of AB system, J = 15.1, 8.9 Hz,
1H), 3.70 (dd, A part of AB system, J = 15.1, 8.9 Hz, 1H), 5.18 (dd,
J = 7.41, 4.03 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm): δ= 21.7,
23.5, 26.5, 27.1, 27.5, 28.9, 33.7, 41.6, 44.5, 44.8, 49.9, 50.0, 50.5,
60.0, 84.7, 212.1, 215.9, IR:(KBr) νmax = 2932, 2856, 1746, 1466,
1361, 1172, 947, 828. Anal. Calcd. for C18 H28O5S: C, 60.65; H, 7.92;
S, 8.99. found: C, 60.43; H, 7.76; S, 8.73, HR-ESI-MS: m/z Calcd for
[M + H+]: 357.1730; found: 357.1736.
Experimental section
General. All chemical compounds are conventional available.
1H- and 13C NMR spectras were recorded on a 400 and 100 Varian
spectrometers, respectively. Chemical shifts were calibrated with
CDCl3. All chemical shifts are reported in ppm and J values are
quoted in Hz. FT-IR spectras were recorded on a FT-IR spectrome-
ter Mattson 1000 with KBr pellet. Elemental analyses: LECO CHNS-
932 apparatus. Mass spectras were recorded on Agilent Technolo-
gies 6530 Accurate-Mass Q-TOF LC/MS.
Synthesis of [di((camphorsulfonyl)oxy)iodo]benzene (DCIB)
(3), PIFA (1) (5.0 g, 11.63 mmol, 1 eq.) was dissolved in 50 mL
dry acetonitrile at room temperature. DL-Camphor sulfonic acid (2)
(5.7 g, 24.4 mmol, 2.1 eq) was added and reaction mixture was
stirred for 3 hour in the N2 atmosphere. The solvent was evap-
orated, yellow product 7.6 gr (98%): 1H NMR (400 MHz, CDCl3:
DMSO/4:1): δ 7.87 (d, J = 8.05 Hz, 2H), 7.20–7.29 (m, 3H), 3.04 (d,
A part of AB system, J = 14.6 Hz, 2H), 2.50 (d, B part of AB system,
J = 14.6 Hz, 2H), 2.20–2.28 (m, 2H), 1.99–2.05 (m, 2H), 1.65–1.78
(m, 6H), 1.27–1.34 (m, 2H), 1.07–1.11 (m, 2H), 0.77 (s, 6H), 0.53 (s,
6H) ppm. 13C NMR (100 MHz, CDCl3): δ 215.8, 133.6, 131.9, 130.9,
123.7, 58.2, 47.8, 47.6, 42.7, 42.5, 26.9, 24.5, 19.9, 19.7 ppm. HR-ESI-
MS: m/z Calcd for [M + H+]: 667.0891; found: 667.0888.
1-Oxo-2,3-dihydro-1H-inden-2-yl(7,7-dimethyl-2-
oxobicyclo[2.2.1]heptan-1-yl) methanesulfonate (5e) [6]. Ob-
tained as colorless oil. 92% yield. 1H NMR (400 MHz, CDCl3, ppm):
δ=0.94 (s, 3H), 1.16 (s, 3H), 1.43–2.57 (m, 7H), 3.33 (dt, B part of
AB system, J = 17.2, 4.8 Hz, 1H), 3.40 (dd, B part of AB system,
J = 15.1, 20.1 Hz, 1H), 3.73 (ddd, A part of AB system, J = 8.1, 7.0,
3.2 Hz, 1H), 3.40 (dd, A part of AB system, J = 15.1, 34.7 Hz, 1H),
5.41 (m, 1H), 7.42–7.48 (m, 2H), 7.68 (t, J = 15.1, 7.4 Hz, 1H), 7.79
(d, J = 7.4 Hz, 1H), 13C NMR (100 MHz, CDCl3, ppm): δ= 19.9,
24.9, 25.3, 26.9, 33.9, 42.5, 42.8, 48.1, 49.2, 58.2, 124.7, 126.7, 128.5,
133.6, 136.5, 150.1, 198.7, 214.1, IR:(KBr) νmax = 2961, 2927, 1733,
1610, 1368, 1174, 1055, 996, 922. Anal. Calcd. for C19 H22O5S: C,
62.96; H, 6.12; S, 8.85. found: C, 60.43; H, 7.76; S, 8.73, HR-ESI-MS:
m/z Calcd for [M + H+]: 363.1261; found: 363.1265.
General Synthesis of α-((Camphorsulfonyl)oxy) Ketones (5a-
g), The ketones (4a-g) (1 eq) were dissolved in 25 mL
dichloromethane. DCIB (3) (1.1 eq) was added at room tempera-
ture and resulting solution was stirred for 4 h. The reaction mix-
ture was extracted with DCM (3 × 25 mL) and the organic sol-
vents dried over Na2SO4. The solvent was removed in vacuo and
the crude residue purified by column chromatography on silica gel
(hexane/EtOAc 8:2),
5-Oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl(7,7-
dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)
methanesulfonate
(5f), Obtained as colorless oil. 91% yield. 1H NMR (400 MHz,
CDCl3, ppm): δ=0.93 (s, 3H), 1.11 (s, 3H), 1.40–1.98 (m, 3H), 2.01–
2.26 (m, 4H), 2.33–2.48 (m, 4H), 3.02 (m, 2H), 3.24 (dd, B part of
AB system, J = 11.1, 15.1 Hz, 1H), 3.73 (dd, A part of AB system,
J = 11.1, 6.0 Hz, 1H), 5.46 (m, 1H), 7.12–7.17 (m, 1H), 7.33–7.36
(m, 1H), 7.42–7.46 (m, 1H), 7.73–7.78 (m, 1H), 13C NMR (100 MHz,
2-Oxocyclopentyl(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl) methane-sulfonate (5a) [6]. Obtained as colorless oil. 92%
8

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
CDCl3, ppm): δ= 19.7, 23.1, 24.9, 26.9, 30.5, 33.8, 42.6, 42.8, 48.1,
48.7, 48.9, 58.1, 83.1, 126.9, 129.4, 130.1, 132.5, 136.2, 141.5, 198.6,
214.2, IR:(KBr) νmax = 2960, 2912, 1743, 1644, 1359, 1163, 1050,
952. Anal. Calcd. for C21H26O5S: C, 64.59; H, 6.71; S, 8.21. found:
C, 64.68; H, 6.82; S, 8.42, HR-ESI-MS: m/z Calcd for [M + H+]:
391.1574; found: 391.1577.
CDCl3, ppm): δ= 1.50–2.40 (m, 4H), 2.88–3.05 (m, 2H), 4.53 (dd,
J = 5.5, 11.4 Hz, 1H), 7.07–7.49 (m, 3H), 7.91–7.93 (m, 1H), 13C NMR
(100 MHz, CDCl3, ppm): δ= 23.8, 32.4, 34.8, 76.1, 127.1, 130.0, 130.7,
133.2, 140.2, 143.2, 204.9, IR:(KBr) νmax = 3420, 2925, 1718, 1615,
1473.
2-Hydroxypentan-3-one (6 g) [105]. Obtained as colorless oil.
92% yield. 1H NMR (200 MHz, CDCl3, ppm): δ= 1.09 (t, J = 7.3 Hz,
3H), 1.35 (d, J = 7.1 Hz, 3H), 2.34–2.56 (m, 2H), 4.24 (q, J = 7.1 Hz,
1H), 13C NMR (50 MHz, CDCl3, ppm): δ= 9.5, 21.9, 32.7, 74.4, 215.0,
IR:(KBr) νmax = 3415, 2963, 2928, 1717, 1561, 1459, 1376, 1272,
1174, 1105.
3-Oxopentan-2-yl(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl)methane sulfonate (5 g), Obtained as colorless oil. 95% yield.
1H NMR (200 MHz, CDCl3, ppm): δ=0.86 (s, 3H), 1.10 (s, 3H),
1.22–2.64 (m, 15H), 3.14 (dd, B part of AB system, J = 6.3, 15.1 Hz,
1H), 3.63 (d, A part of AB system, J = 11.1, 6.0 Hz, 1H), 5.06 (q,
J = 7.0 Hz, 1H), 13C NMR (50 MHz, CDCl3, ppm): δ= 9.1, 19.8,
21.6, 21.9, 27.0, 28.9, 33.4, 44.5, 44.8, 50.1, 50.5, 60.1, 82.2, 208.2,
216.1, IR:(KBr) νmax = 2971, 2925, 1746, 1637, 1361, 1174, 1023,
911. Anal. Calcd. for C15H24O5S: C, 56.94; H, 7.65; S, 10.13. found:
C, 56.73; H, 7.48; S, 9.87, HR-ESI-MS: m/z Calcd for [M + H+]:
317.1417; found: 317.1422.
Biochemical methods
Determination of AChE and BChE inhibition studies
Inhibition studies of AChE and BChE enzymes were done using
Ellman’s colorimetric assay [106]. The basis of this method can be
explained as follows; as mentioned above, cholinesterases catalyze
the breakdown reaction of ACh or BCh to thiocholine and acetate
or butyrate. As a result of reaction of DTNB with thiocholine, 5-
thio-2-nitrobenzoic acid, which gives yellow color, is formed. The
intensity of the resulting color gives absorbance at 412 nm. The
only difference in the method used when studying the BChE en-
zyme is the use of butyrylcholine iodide instead of acetylthio-
choline iodide. Briefly, 100 μL of Tris/HCl buffer (pH 8.0, 1.0 M) and
diverse concentration of sample solutions (50–200 μL) dissolved in
deionized water were transferred to 50 μL of AChE/BChE solutions
(5.32×10−3 EU), Then the mixture was incubated for 10 min at
20 °C. Finally, 50 μL of DTNB (0.5 mM) was added to incubated
mixture. Also, the reaction was initiated by the addition of 50 mL
of acetylthiocholine iodide/butrylcholine iodide (AChI/BChI), Activi-
ties of both cholinergic enzymes were evaluated spectrophotomet-
rically at a wavelength of 412 nm [107]. On the other hand, one
BChE/AChE enzyme unit is the amount of enzyme that hydrolyzes
1.0 μmol of ACh/BCh to choline and acetate/butyrate per minute at
pH 8.0 at 37 °C. For determination of half maximal inhibitory con-
centration (IC50) of novel synthesized α-camphor sulfonyloxylated
ketones (5a-g) on AChE/BChE activity, (%)-[α-Camphor sulfonyloxy-
lated ketones] graph was drowned. The IC50 values were obtained
from activity (%) versus compounds plots. On the other hand,
for determination of the inhibition constant (Ki) for each novel
synthesized camphorsulfonoxy (5a-g) ketones against AChE/BChE,
Lineweaver-Burk graphs were used to. Also, Ki values were cal-
culated from these graphs for both enzymes. For the calculation
of Ki values, three different novel synthesized α-camphor sul-
fonyloxylated ketones (5a-g) concentrations were used. Finally, the
Lineweaver-Burk curves were drawn as given in details.
General Synthesis of α-Hydroxy Ketones (6a-g), α-
((Camphorsulfonyl)oxy) ketones (5a-g) (1 eq) were dissolved
in 25 mL fresh distilled dry THF. The flask was attached to gas
ammonia (NH3) and it was stirred. Then, the reaction mixture
was cooled in ice bath and then freshly cuttting lithium (2 eq)
was added slowly over 3–5 min. The temperature of the bath was
allowed to rise gradually to room temperature. The reaction mix-
ture was stirred for 2 h. The mixture was cooled in an ice-water
bath again. Cold water was added slowly and carefully to the flask
until all the lithium was consumed. The reaction mixture was
poured into mixture of water and filtered. The reaction mixture
was extracted with EtOAc (3 × 25 mL) and the combined organic
solvent dried over Na2SO4. The solvent was removed in vacuo and
the crude residue purified by column chromatography on silica gel
(hexane/EtOAc 8:2),
2-Hydroxycyclopentan-1-one (6a) [99]. Obtained as colorless
oil. 75% yield. 1H NMR (400 MHz, CDCl3, ppm): δ= 4.05 (m,
1H), 2.96 (bs, 1H), 2.51–1.92 (m, 3H), 1.88–1.56 (m, 3H), 13C NMR
(100 MHz, CDCl3, ppm): δ= 16.5, 30.9, 34.2, 76.1, 218.5, IR:(KBr)
νmax = 3465, 2926, 2857, 2683, 1699, 1454, 1404, 1265, 1195,
1105, 1079, 1043, 931, 893, 803.
2-Hydroxycyclohexan-1-one (6b) [100]. Obtained as colorless
oil.82% yield. 1H NMR (400 MHz, CDCl3, ppm): δ= 1.39–1.92 (m,
4H), 2.07–2.11 (m, 1H), 2.28–2.56 (m, 3H), 3.90 (bs, 1H), 4.07–4.12
(m, 1H), 13C NMR (100 MHz, CDCl3, ppm): δ=23.6, 27.8, 36.9, 39.7,
75.5, 211.5, IR:(KBr) νmax = 3411, 2924, 2851, 2313, 1717, 1672,
1446, 1336, 1166, 1096, 920.
2-Hydroxycycloheptan-1-one (6c) [101]. Obtained as colorless
oil. 76% yield. 1H NMR (400 MHz, CDCl3, ppm): δ= 0.83–2.04 (m,
8H), 2.39–2.47 (m, 1H), 2.62–2.69 (m, 1H), 4.24–4.27 (m, 1H), 13C
NMR (100 MHz, CDCl3, ppm): δ= 23.7, 26.8, 29.7, 34.0, 40.3, 77.3,
213.9. IR:(KBr) νmax = 3465, 2926, 2857, 2683, 1699, 1454, 1404,
1265, 1195, 1105, 1079, 1043, 931, 893, 803.
Purification and inhibition studies of hCA I and II isoenzymes
2-Hydroxycyclooctan-1-one (6d) [102]. Obtained as colorless
oil. 78% yield. 1H NMR (400 MHz, CDCl3, ppm): δ= 0.80–0.91 (m,
2H), 1.12–2.01 (m, 6H), 2.23–2.70 (m, 4H), 4.15–4.17 (m, 1H), 5.26
(bs, 1H), 13C NMR (100 MHz, CDCl3, ppm): δ= 22.2, 24.7, 25.7, 28.9,
29.3, 37.5, 76.4 217.6. IR:(KBr) νmax = 3415, 2963, 2928, 1717, 1561,
1459, 1376, 1272, 1174, 1105.
Purification of both cytosolic hCA I, and II isoenzymes was
performed by a simple one-step method with Sepharose-4B-l-
Tyrosine-sulfanilamide affinity chromatography [108]. The protein
amount of the enzyme taken from the colon was determined
spectrophotometrically at 280 nm [109]. Sodium dodecyl sulfate-
polyacrylamide gel electrophoresis (SDS-PAGE) was applied to
check the purity of both isoenzymes [110]. The activities of CA
isoenzymes have been described in Verpoorte et al. [111] deter-
mined according to the method [112]. Inhibition studies were per-
formed according to the esterase method. Esterase method is based
on the fact that CA has esterase activity [113]. The principle of the
method is briefly as follows; the carbonic anhydrase enzyme hy-
drolyzes p-nitrophenylacetate, used as substrate, to p-nitrophenol
or p-nitrophenolate. p-Nitrophenol and p-nitrophenolate give high
absorbance at 348 nm [114]. CA activity was assayed by following
2-Hydroxy-2,3-dihydro-1H-inden-1-one (6e) [103]. Obtained
as colorless oil. 81% yield. 1H NMR (400 MHz, CDCl3, ppm): δ=
2.98–3.04 (dd, B part of AB system, J = 7.5, 16.2 Hz, 1H), 3.57 (dd,
A part of AB system, J = 7.7, 16.5 Hz, 1H), 4.16 (bs, 1H), 4.56 (dd,
J = 5.1 Hz, 1H), 7.36–7.45 (m, 2H), 7.60–7.63 (m, 1H), 7.70–7.74 (m,
1H), 13C NMR (100 MHz, CDCl3, ppm): δ= 35.4, 74.4, 124.7, 127.0,
128.2, 134.3, 136.1, 151.2, 207.1, IR:(KBr) νmax = 3422, 2923, 1720,
1609, 1467.
6-Hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (6f)
[104]. Obtained as colorless oil. 76% yield. 1H NMR (400 MHz,
9

U. Atmaca, C. Alp, H. Akincioglu et al.
Journal of Molecular Structure 1239 (2021) 130492
the change in absorbance at 348 nm of 4-nitrophenylacetate (NPA)
to 4-nitrophenylate ion over a period of 3 min at 25 °C using a
spectrophotometer. The enzymatic reaction, in a total volume of
3.0 mL, contained 1.4 mL Tris-SO4 buffer (pH 7.4, 50 mM), 1 mL
4-nitrophenylacetate (3 mM), 0.5 mL deionized water, and 0.1 mL
enzyme solution. The increase in the absorbance of the reaction
medium was recorded spectrophotometrically at 348 nm [115].
One CA activity unit was defined as the amount of CA enzyme,
which had absorbance change at 348 nm of 4-nitrophenylacetate
to 4-nitrophenylate ions over a period of 3 min at 25 °C [116,117].
Different novel synthesized α-camphor sulfonyloxylated ketones
(5a-g) concentrations were employed. Control cuvette activity in
the absence of inhibitor was accepted as 100%.
Acknowledgements
˙
Financial support from the TUBITAK (107T390) is gratefully ac-
knowledged. The authors are grateful to Dr. Muhammet Kara-
man for providing his technical guidance while processing docking
study of this article and for supporting small drug discovery suite
software.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130492.
For the determination of the inhibition effect of each novel syn-
thesized camphorsulfonyloxy (5a-g) ketones on AChE, BChE and
both hCA isoenzymes and activity (%)-[α-Camphor sulfonyloxy-
lated ketones] graph was drawn. The IC50 values were obtained
from activity (%) versus compounds plots [118]. For the calcula-
tion of Ki values, three different novel synthesized α-Camphor sul-
fonyloxylated ketones (5a-g) concentrations were used. Finally, the
Lineweaver-Burk curves were drawn [119] as given in details [120].
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