Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization, biological evaluation, and molecular docking studies

Article abstract of DOI:10.1016/j.molstruc.2019.127297

Carvacrol, as a natural product used for many years in the treatment of various diseases, therefore it was chosen as the starting compound for this study. Novel carvacrol based new oxypropanolamine derivatives were synthesized and characterized by spectro

Full text of DOI:10.1016/j.molstruc.2019.127297

Journal of Molecular Structure xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Novel carvacrol based new oxypropanolamine derivatives: Design,
synthesis, characterization, biological evaluation, and molecular
docking studies
,
Arlinda Bytyqi-Damoni a, Ali Kestane b, Parham Taslimi c *, Burak Tuzun d,
b
b
e
_
Mustafa Zengin , Hayriye Genc Bilgicli , Ilhami Gulcin
a Faculty of Education, Department of Chemistry, Pristina University, 10000, Pristina, Kosovo
b Department of Chemistry, Faculty of Science and Arts, Sakarya University, 54187, Sakarya, Turkey
c Department of Biotechnology, Faculty of Science, Bartin University, 74100, Bartin, Turkey
d Department of Chemistry, Faculty of Science, Cumhuriyet University, 58140, Sivas, Turkey
e Department of Chemistry, Faculty of Sciences, Ataturk University, 25240, Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Carvacrol, as a natural product used for many years in the treatment of various diseases, therefore it was
chosen as the starting compound for this study. Novel carvacrol based new oxypropanolamine de-
rivatives were synthesized and characterized by spectroscopic methods. All new compounds were tested
as metabolic enzyme inhibitory agents. Their clinical usage of carvacrol has been established as diuretics,
antiepileptics, and anti-glaucoma factors, in the management of gastric, duodenal ulcers, mountain
sickness, osteoporosis, idiopathic intracranial hypertension, or neurological disorders. The in vitro anti-
hyperglycemic screening results showed that the compound 3d exhibits the maximum inhibitory effect
Received 15 September 2019
Received in revised form
23 October 2019
Accepted 24 October 2019
Available online xxx
Keywords:
against
a-glycosidase enzyme (IC50: 904.10 nM). In addition, the compounds 3d (IC50: 29.74 nM and
Oxypropanolamine
Acetylcholinesterase
Carbonic anhydrase
Enzyme inhibition
Molecular docking
23.64 nM) and 3e (IC50: 31.28 nM and 26.11 nM) were found to have a significant response to inhibit
carbonic anhydrase I, and II isoenzymes (hCA I and II), respectively. The novel carvacrol based oxy-
propanolamine compounds were effective inhibitors of the hCA I and II isozymes, and acetylcholines-
terase with Ki values in the range of 27.18e44.84 nM for hCA I, 25.62e38.71 nM for hCA II, and 99.83
e146.25 nM for AChE, respectively.
© 2019 Elsevier B.V. All rights reserved.
1. Introduction
has been used as an antimicrobial agent and furthermore it is the
most effective agent among other essential oils using for this pur-
Natural products are always the main inspiration for chemistry,
biology, and medicine [1,2]. Their complex treatment mechanisms
are not always completely understandable, thus their core struc-
tures attract the attention of scientists [3,4]. Carvacrol, a mono-
terpenic phenol produced by numerous aromatic plants, mainly
oregano and thyme is currently used as a preservative and food
flavoring and as a fragrance in cosmetic formulations. Recently,
important researches have been carried out in an effort to deter-
mine the biological effects of carvacrol for its potential use in
clinical applications as well [5]. In traditional medicine, carvacrol
pose [6]. Moreover, some results from in vivo and in vitro studies
show that carvacrol has a wide variety of pharmacological and
biological properties, including analgesic, antiallergic, antiarthritic,
antibiotic, anticarcinogenic, anticholesterol, antidiabetic, anti-
endotoxemic, antifungal, anti-inflammatory, antileishmanial, anti-
microbial, antioxidant, antitoxins, antiviral, cardioprotective,
gastroprotective, hepatoprotective, insecticidal, nematocidal, neu-
roprotective, and trypanocidal effects [7]. Although, the research on
the information on the toxicology of Carvacrol is limited, findings
from the study in the metabolism have showed that carvacrol was
discarded after 24 h in large quantities in urine as glucoronide and
sulfate conjugates [8].
* Corresponding author. Faculty of Science Department of Biotechnology Bartin
University 74100, Bartin, Turkey.
E-mail addresses: ptaslimi@bartin.edu.tr, parham_taslimi_un@yahoo.com
(P. Taslimi).
The 1,2-amino alcohol core is a common structure encountered
in a number of natural products like amino acids (serine, threonine,
and hydroxyproline), hormones (adrenaline and noradrenaline).
https://doi.org/10.1016/j.molstruc.2019.127297
0022-2860/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

2
A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
hold healthy functioning. In conflict, glucose molecule absorption
in patients with type-2 diabetes mellitus (T2DM) can cause clini-
cally important difficulties because the high activity of this enzyme
enhances plasma Mellitus glucose amounts [21e23]. The glucose
has been recorded to improve memory in humans and animals.
Studies that focused on animals have revealed that glucose can
improve memory through the facilitation of acetylcholine (ACh)
molecule synthesis and release in the brain cells. This glucose-
relevant memory progress has prompted research in elder age
[24]. These findings have recorded that the memory improving of
glucose depends on each single’s blood glucose regulation. Indeed,
some researchers have investigated the effect of glucose molecule
on memory in patients with Alzheimer’s disease (AD) [25]. The
acetylcholinesterase (AChE) enzyme catalyzes the hydrolysis of the
neurotransmitter ACh to choline and acetate in a synaptic cleft. So
far, AChE inhibition is one of the most successful methods for the
treatment of AD [26].
Referring to the previous studies [27e32] on the synthesis of
compounds having biological activity, in order that the structure of
the compound to be similarly synthesized is similar to the metab-
olites, natural products or present drugs, the higher the likelihood
of showing biological activity. In this regard, the study treats
carvacrol-derived oxypropanol amines as molecules which can
show high biological activity. In this study, synthesis, character-
ization, molecular docking, and metabolic enzymes inhibitory
properties of novel carvacrol based new oxypropanolamine de-
rivatives (3a-e) have been investigated.
Scheme 1. The procedure for the synthesis of 2 and 3a-e. (i) epichlorohydrin, NaOH/
water, 85 ꢀC, 0.5 h; (ii) Amine compound, saturated K2CO3 solution, room temperature,
8e12 h.
Furthermore, it can be encountered in the glycosidase inhibitor
nojirimycin, the antimalarial agent febrifugine, the anticancer
agent hapalosin, amino sugars such as antibiotic neomycin. Due to
the variety of biological activity that it offers, it has also taken place
in synthetic drug structures like Randolazine (antianginal), Zana-
mivir (influenza), Docetaxel (combat metastatic cancers) [9]. On the
other hand, the substructure of 1,2-amino alcohols oxypropanol-
amines have been known as
b-adrenoceptor antagonists [10]
particularly in cardiovascular disease since the 1960s, and also in
the treatment of many diseases such as thyrotoxicosis, angina
pectoris, hypertension, chronic pulmonary diseases [11], skin
inflammation [12] and diuretic [13].
2. Materials and methods
2.1. Chemistry
Carbonic anhydrases (CAs, E.C.4.2.1.1) are zinc-containing en-
zymes, which perform a very important reaction: the reversible
hydration of CO2 and water to proton and bicarbonate ions [14,15].
So far, twelve catalytically active CA isoenzymes have been iden-
tified that based on the several cellular distribution can be gathered
in four various groups: mitochondrial (CAs VA and VB), cytosolic
(CAs I, II, III, VII and XIII), membrane associated (CAs IV, IX, XII and
XIV), and secretory (CA VI) CAs [16,17]. These isoenzymes differ also
for tissue distribution and catalytic efficiency. Various CA iso-
enzymes play significant roles in diverse pathological mechanisms
related to epilepsy, cancer, glaucoma, obesity, etc. Thus, these iso-
enzymes have become relevant aims for the synthesis and design of
inhibitors with biological applications [18e20].
The oxyrane (2) derivative of carvacrol was prepared by the
treatment of carvacrol with epichlorohydrin and then the ring was
opened with various amine compounds. Primary or secondary
amines having different steric effects and bearing aliphatic, olefinic
or aromatic groups were selected. The synthetic route was given in
Scheme 1.
2.1.1. Synthesis of 2-((5-isopropyl-2-methylphenoxy)methyl)
oxirane (2)
Carvacrol (1 g, 6.6 mmol) and epichlorohydrin (10 mL) were
dissolved in methanol (10 mL) and sodium hydroxide (0.24 g,
6.6 mmol) in water (10 mL) was added dropwise over a period of
30 min to the solution under vigorous stirring at 85 ꢀC. The mixture
was further continued to be stirred for another 15 min at the same
temperature. The organic phase was mixed with ethyl acetate
(20 mL) and washed with brine (2 ꢁ 15 mL), dried over MgSO4, and
The a-glycosidase as a catabolic important enzyme hydrolyzes
carbohydrate molecules to crop energy sugars necessary for some
physiological functions. This enzyme provides energy sources to
Table 1
The enzyme inhibition results of Carvacrol based novel oxypropanolamine derivatives (3a-e) against human carbonic anhydrase isoenzymes I and II (hCA I and II), acetyl-
cholinesterase (AChE), and -glycosidase ( -Gly) enzymes.
a
a
Compounds
IC50 (nM)
Ki (nM)
hCA I
hCA I
r2
hCA II
r2
AChE
r2
a
-Gly
r2
hCA II
AChE
a-Gly
3a
3b
3c
3d
41.05
36.93
40.55
29.74
31.28
57.36
e
0.9817
0.9933
0.9427
0.9605
0.9872
0.9790
e
35.71
34.96
33.04
23.64
26.11
64.08
e
0.9748
0.9590
0.9681
0.9532
0.9831
0.9903
e
136.05
184.73
157.77
195.04
190.17
e
0.9682
0.9505
0.9835
0.9533
0.9073
e
984.62
1065.73
1013.63
904.10
1000.05
e
0.9382
0.9194
0.9724
0.9821
0.9120
e
44.84 10.53
34.12 8.58
42.65 6.08
27.18 6.86
30.57 8.60
51.83 7.83
e
38.71 5.17
31.74 9.33
36.30 7.18
25.62 6.11
27.93 4.13
60.77 14.07
e
99.83 14.75
125.06 25.82
119.85 34.81
146.25 17.22
138.60 26.02
e
1007.56 111.8
945.72 94.71
904.88 101.88
896.61 78.63
1026.80 147.3
e
3e
AZAa
TACb
ACRc
208.03
e
0.9628
e
e
e
177.15 39.05
e
e
e
e
e
e
22800
e
e
e
12600 78
a
Acetazolamide (AZA) was used as a control for hCA I and II isoenzymes.
Tacrine (TAC) was used as a control for AChE enzyme.
Acarbose (ACR) was used as a control for a-glycosidase enzyme which obtained from references [61] and [62].
b
c
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
3
filtered. The residue was vaporized under vacuum at 90e100 ꢀC to
remove excess epichlorohydrin. The oily residue was passed
through silica gel column chromatography with a mixture of hex-
ane: ethyl acetate (97:3) to provide pure oxirane 2 (1.22 g, 89%).
2.1.5. 1-(Tert-butylamino)-3-(5-isopropyl-2-methylphenoxy)
propan-2-ol (3c)
Colorless viscous liquid, Yield 1.45 g (88%); 1H NMR (300 MHz,
Chloroform-d)
d
7.10 (dd, J ¼ 7.6, 0.7 Hz, 1H), 6.85e6.54 (m, 2H),
4.17e4.04 (m, 3H), 4.03e3.90 (m,1H), 2.99e2.85 (m, 3H), 2.85e2.73
(m, 1H), 2.24 (s, 3H), 1.28 (d, J ¼ 6.9 Hz, 6H), 1.18 (d, J ¼ 1.2 Hz, 9H).
2.1.2. General synthesis of propan-2-ol amine derivatives (3a-e)
A mixture of the oxirane 2 (1 mmol), amine derivative (3 mmol)
and aqueous saturated solution of K2CO3 solution (2 mL) was
vigorously stirred at room temperature for 8e12 h. The reaction
was monitored with TLC. After the completed conversion, the re-
action mixture was extracted with ethyl acetate (10 mL) and water
(2 ꢁ 10 mL). The organic layer was separated and dried over
anhydrous MgSO4. The solvent was removed under reduced pres-
sure. The residue was purified by column chromatography with
hexane: ethyl acetate (97:3). The product was analyzed by 1H and
13C NMR.
13C NMR (75 MHz, CDCl3)
d 156.94, 148.30, 130.76, 124.21, 118.68,
109.79, 70.91, 68.88, 50.70, 45.25, 34.41, 29.24 (3C), 24.42, 24.36,
16.23.
2.1.6. 1-((2-(Cyclohex-1-en-1-yl)ethyl)amino)-3-(5-isopropyl-2-
methylphenoxy)propan-2-ol (3d)
Brown viscous liquid, Yield 1.57 g (80%); 1H NMR (300 MHz,
Chloroform-d)
d
7.05 (d, J ¼ 7.7 Hz, 1H), 6.74 (dd, J ¼ 7.6, 1.7 Hz, 1H),
6.70 (s, 1H), 5.46 (s, 1H), 4.22e3.84 (m, 3H), 3.07e2.61 (m, 4H), 2.18
(s, 3H), 2.05e1.86 (m, 7H), 1.70e1.50 (m, 6H),1.23 (d, J ¼ 6.7 Hz, 6H).
13C NMR (75 MHz, CDCl3)
d 156.83, 148.36, 135.40, 130.71, 124.22,
123.17, 118.67, 109.79, 70.69, 68.48, 52.14 (2C), 47.80, 34.34, 28.37,
25.46, 24.34 (2C), 23.14, 22.66, 16.11.
2.1.3. 1-(Allylamino)-3-(5-isopropyl-2-methylphenoxy)propan-2-ol
(3a)
Colorless viscous liquid, Yield 1.34 g (86%); 1H NMR (300 MHz,
2.1.7. 1-(5-Isopropyl-2-methylphenoxy)-3-((pyridin-3-ylmethyl)
amino)propan-2-ol (3e)
Chloroform-d)
d
7.06 (d, J ¼ 7.6 Hz, 1H), 6.76 (dd, J ¼ 7.6, 1.6 Hz, 1H),
Yellow viscous liquid, Yield 1.45 g, 78%; 1H NMR (300 MHz,
6.70 (d, J ¼ 1.6 Hz, 1H), 6.00e5.83 (m, 1H), 5.23 (dd, J ¼ 17.2, 1.6 Hz,
1H), 5.16 (dd, J ¼ 10.2, 1.6 Hz, 1H), 4.20e4.08 (m, 1H), 4.04 (dd,
J ¼ 9.2, 5.3 Hz, 1H), 3.97 (dd, J ¼ 9.2, 5.4 Hz, 1H), 3.44 (s, 2H), 3.34
(dd, J ¼ 6.2, 1.4 Hz, 2H), 2.94 (dt, J ¼ 12.2, 6.9 Hz, 1H), 2.89e2.79 (m,
2H), 2.19 (s, 3H), 1.24 (d, J ¼ 6.9 Hz, 4H). 13C NMR (75 MHz, CDCl3)
Chloroform-d)
d
8.57 (dd, J ¼ 1.6, 0.8 Hz, 1H), 8.50 (dd, J ¼ 4.9,
0.9 Hz,1H), 7.70 (ddd, J ¼ 7.8, 4.8,1.6 Hz,1H), 7.27 (dd, J ¼ 7.8, 4.9 Hz,
1H), 7.04 (dd, J ¼ 7.6, 1.6 Hz,1H), 6.75 (dd, J ¼ 7.6, 1.6 Hz,1H), 6.68 (d,
J ¼ 1.6 Hz, 1H), 4.27e4.06 (m, H), 4.06e3.96 (m, 2H), 3.86 (s, 2H),
3.06e2.70 (m, 3H), 2.23 (s, 1H), 2.15 (s, 3H), 2.04 (d, J ¼ 0.6 Hz, 1H),
d
156.78, 148.29, 135.85, 130.75, 124.18, 118.76, 117.28, 109.83, 70.67,
1.23 (d, J ¼ 7.0 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d 156.84, 149.54,
68.47, 52.30, 51.57, 34.35, 24.36 (2C), 16.12.
148.40, 148.28, 136.53, 135.80, 130.79, 124.16, 123.91, 118.77, 109.86,
70.79, 68.92, 52.01, 51.38, 34.36, 24.40, 24.35, 16.14.
2.1.4. 1-(Diethylamino)-3-(5-isopropyl-2-methylphenoxy)propan-
2-ol (3b)
Light yellow viscous liquid, Yield 1.22 g (74%); 1H NMR
2.2. Biological studies
(300 MHz, Chloroform-d)
d
7.06 (d, J ¼ 7.5 Hz, 1H), 6.75 (dd, J ¼ 7.5,
1.6 Hz,1H), 6.72 (d, J ¼ 1.5 Hz,1H), 4.20e3.91 (m, 3H), 2.80e2.93 (m,
J ¼ 6.9 Hz, 1H), 2.78e2.49 (m, 4H), 2.21 (s, 3H), 1.25 (d, J ¼ 6.9 Hz,
The purification of both cytosolic CA isoenzymes (CA I and II)
were performed with a simple one-step procedure by a Sepharose-
4B-L tyrosine-sulphanilamide affinity chromatoghraphy. The pro-
tein quantity in the column effluents were evaluated spectropho-
tometrically at 280 nm. For purity of both isoenzymes sodium
6H),1.07 (t, J ¼ 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d 157.01, 148.17,
130.65, 124.32, 118.55, 109.79, 70.62, 66.24, 56.36, 47.50 (2C), 34.36,
24.37 (2C), 16.07, 12.21 (2C).
Fig. 1. Demonstration of the interaction of 1OCE protein with the studied molecules.
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

4
A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
was applied. The CA inhibitory effects of new carvacrol based novel
oxypropanolamine derivatives (3a-e) were performed according to
Verpoorte et al. [33] as described in former studies [34e36] and
measured at 348 nm spectrophotometrically using the p-nitro-
phenylacetate as the main substrate [37]. For AChE, the inhibitory
effect of novel carvacrol based new oxypropanolamine derivatives
(3a-e) was calculated according to Ellman’s method [38]. Briefly,
computed in the Docking Server using the optimized structures
obtained. The interaction of each molecule against enzymes was
examined. The names of the protein molecules studied are AChE for
ID 1OCE, a-Glycosidase for ID 1XSI, hCA I for ID 2CAB, hCA II for ID
4R5B. The interactions of these proteins with the five studied was
compared by working in DockingServer.
3. Results and discussion
100
dissolved in deionized water at different concentrations, and 20
of AChE solution were mixed and incubated for 10 min at 25 ꢀC.
Then, 50 L of DTNB (0.5 mM) was added. Then reaction was
initiated by the addition of 50 L of AChI. The hydrolysis of these
mL of Tris/HCl buffer (1 M, pH 8.0), 780 mL of sample solution
mL
3.1. Chemistry
m
Carvacrol, as a natural product used for many years in the
treatment of various diseases, was chosen as the starting com-
pound for this study. After obtained oxirane derivative 2 from the
treatment of carvacrol with epichlorohydrin, the oxirane ring was
opened with various amines. Although having a steric effect, the
highest yield (88%) was obtained with the reaction of tert-butyl
amine (3c). The other highest yield was obtained from allylamine
with 86% (3a). In the presence of cyclohexylene ethylamine 80%
yield was observed (3d). The other primary amine containing a
pyridine group gave 78% yield (3e). As expected, the lowest yield
between of them was obtained from diethylamine with 74% (3b).
Biological activity studies of the oxypropanolamines derivatives
(3a-e) were subsequently performed.
m
substrates was monitored spectrophotometrically by formation of
the yellow 5-thio-2-nitrobenzoate anion as the result of the reac-
tion of DTNB with thiocholine, released by enzymatic hydrolysis of
AChI, with an absorption maximum at a wavelength of 412 nm
compatible to former studies [39,40] and measured at 412 nm
spectrophotometrically using acetylthiocholine iodide molecule as
a main substrate for the enzymatic reaction. 5,50-Dithio-bis(2-
nitro-benzoic) acid was utilized for the measurement of the AChE
activity [41,42]. For
compounds on -glycosidase enzyme activity was measured using
p-nitrophenyl-D-glycopyranoside (p-NPG) as molecule as the
substrate, according to the assay of Tao et al. [43]. Initially, 400 L of
phosphate buffer was mixed with 40 L of the homogenate solution
in phosphate buffer (0.15 U/mL, pH 7.4). Also, 100 L of p-NPG in
a-glycosidase, inhibitory effect of indicated
a
m
m
3.2. Biological results
m
phosphate buffer (5 mM, pH 7.4) after preincubation was added and
again incubated at 30 ꢀC. The absorbances were spectrophotomet-
rically measured at 405 nm, conforming to former studies [44e46].
Carvacrol based novel oxypropanolamine derivatives (3a-e)
were tested to evaluate their inhibitory effects towards the hCA I
and II isoenzymes, AChE, and
structure of these compounds is given in Scheme 1 and their AChE,
-glycosidase, and CA I, and II isoforms inhibition data are sum-
a-glycosidase enzymes. The chemical
2.3. Molecular docking
a
marized in Table 1.
The study compared the inhibition values of five molecules
against some enzymes performed and compared. In order to
compare the enzyme inhibition values of the molecules, the mol-
ecules were first optimized using the Gaussian package program in
HF/6-31þþg basis set [47e49]. Then, they molecules were
CA inhibitors (CAIs), such as acetazolamide (AZA), are used as
anti-glaucoma drugs to lower intraocular pressure, but it has been
found out that some of these drugs act as vasodilators of retinal
arteries [50]. The hCA I isoenzyme was inhibited by these com-
pounds; with Ki values which found between 27.18 6.86 and
Fig. 2. Demonstration of the interaction of 1XSI protein with the studied molecules.
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
5
Fig. 3. Demonstration of the interaction of 2CAB protein with the studied molecules.
44.84 10.53 nM. In addition, 1-((2-(cyclohex-1-en-1-yl)ethyl)
amino)-3-(5-isopropyl-2-methylphenoxy)propan-2-ol (3d), and 1-
(5-isopropyl-2-methylphenoxy)-3-((pyridin-3-ylmethyl)amino)
propan-2-ol (3e) were recorded the most powerful hCA I isoform
inhibition properties with Ki values of 27.18 6.86 and
30.57 8.60 nM, respectively. The control and clinically used drug
AZA demonstrated a Ki value of 51.83 7.83 nM. Hence, the inves-
tigated novel molecules showed better inhibition profiles when
compared to AZA (Table 1).
anthocyanidins, and stilbenes for a beneficial role in inhibiting
AChE enzyme. On the other hand, several plants extracts were
found rich in phytochemicals principally alkaloids having a po-
tential or capacity to inhibit AChE [54,55]. The inhibitory effects of
these compounds on AChE enzyme are shown in Table 1. The AChE
inhibition profiles of the molecules investigated here were really
interesting. Overall, these compounds had excellent inhibitory ac-
tivity with Ki values in ranging from 99.83 14.75 nM to
146.25 17.22 nM. Additionally, tacrine, utilized as a control AChEI
in this paper, demonstrated Ki value of 177.15 39.05 nM toward
AChE. The inhibition of AChE of Carvacrol based novel oxy-
propanolamine derivatives (3a-e) is much better than standard
drug. The compounds of 1-(allylamino)-3-(5-isopropyl-2-
methylphenoxy)propan-2-ol (3a), and 1-(tert-butylamino)-3-(5-
isopropyl-2-methylphenoxy)propan-2-ol (3c) showed excellent
inhibition profile against AChE with Ki values of 99.83 14.75 and
119.85 34.81 nM, respectively (Table 1). Various drugs utilized in
the therapy of AD are based on the appointed cholinergic hypoth-
esis, where the target is to enhance the concentration of ACh level
in the synaptic cleft by the inhibition of cholinesterase activity.
AChEIs prevent the breakdown of the cholinesterase enzyme,
augmenting the synaptic accessibility of ACh in the brain and
subsequently boosting cholinergic neurotransmission in forebrain
regions that result in compensating the loss of functioning of brain
cells. Owing to this, AChE inhibition has been documented as a
critical treatment route of AD [56,57].
CAIs have diverse therapeutic applications. For instance, hCA II,
and, IV and XII inhibitors are utilized as glaucoma and in diuretics.
The hCA II and VII inhibitors are utilized as anti-epileptic drugs,
whereas certain anti-inflammatory and antitumor CAIs are iso-
forms hCA IX and XII [51,52]. The results clearly showed that hCA II
was impressively inhibited by the carvacrol based novel oxy-
propanolamine derivatives (3a-e). These compounds had strong
hCA II inhibition with Ki values ranging from 25.62 6.11 to
38.71 5.17 nM. Ki values of novel molecules appear to be better
than those of the standard used drug AZA (Ki: 60.77 14.07 nM).
All the evaluated novel molecules showed potent inhibition against
hCA II, but the compounds of 1-((2-(cyclohex-1-en-1-yl)ethyl)
amino)-3-(5-isopropyl-2-methylphenoxy)propan-2-ol (3d), and 1-
(5-isopropyl-2-methylphenoxy)-3-((pyridin-3-ylmethyl)amino)
propan-2-ol (3e) showed significant inhibition profile against hCA
II with Ki values of 25.62 6.11 and 27.93 4.13 nM (Table 1).
There is much considerable concern in the mechanism of action
for different compounds against neurodegenerative diseases.
Principally in AD, some organic compounds have shown the
capability to address the etiology of neurological disturbances as
they deteriorate their molecule physiology by regulating thera-
peutic goals with decreased in the risk of AD with age [53]. Also, the
inhibitors of these enzymes can decrease inflammation by
behaving as anti-inflammatory factors and by reducing the risk of
oxidative stress. Indeed, there are some accessible reports in the
literature for diverse isoflavones, flavonols, flavones, curcuminoids,
One of the most beneficial therapeutics was proposed as
maintaining blood glucose at normal levels after a meal. This
approach may gradually help avoid chronic hyperglycemia, reduce
insulin resistance and consequently appear crucial in the hydrolysis
of polysaccharides to obtain glucose more suitable for absorption.
Hyperglycemia in patients with T2DM was attributed to starch
breakdown by pancreatic
tinal -glycosidase [58,59].
In fact, there are many available antidiabetic drugs such as
a-amylase and glucose uptake by intes-
a
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

6
A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
Fig. 4. Demonstration of the interaction of 4R5B protein with the studied molecules.
Table 2
Molecular energy data for studies molecule for hCA I, hCA II, AChE and
a
-glycosidase enzymes.
3a
Molecular energy data
3b
3c
3d
3e
hCA I
hCA I
AChE
Estimated Free energy of binding (kCal/mol)
Estimated Ki (mM)
vdW þ Hbond þ desolv energy (kCal/mol)
Electrostatic Energy (kCal/mol)
Total Intermolecular energy (kCal/mol)
Frequency
Interact. Surface
Estimated Free energy of binding (kCal/mol)
Estimated Ki (mM)
vdW þ Hbond þ desolv energy (kCal/mol)
Electrostatic Energy (kCal/mol)
Total Intermolecular energy (kCal/mol)
Frequency
Interact. Surface
Estimated Free energy of binding (kCal/mol)
Estimated Ki (mM)
ꢂ2.55
13.56
ꢂ4.84
ꢂ0.14
ꢂ4.98
%70
615.86
ꢂ4.68
368.87
ꢂ5.39
ꢂ0.42
ꢂ5.81
%10
590.22
ꢂ7.45
3.46
ꢂ7.22
ꢂ1.35
ꢂ8.57
%10
ꢂ2.41
17.14
ꢂ4.17
ꢂ0.06
ꢂ4.24
%80
629.83
ꢂ4.72
348.67
ꢂ6.28
ꢂ0.22
ꢂ6.50
510
601.41
ꢂ7.37
3.99
ꢂ7.94
ꢂ0.50
ꢂ8.44
%20
ꢂ1.45
86.49
ꢂ3.21
ꢂ0.19
ꢂ3.39
%40
644.61
ꢂ5.58
81.18
ꢂ5.89
ꢂ0.38
ꢂ6.27
%20
621.23
ꢂ8,19
986.22
ꢂ7.92
ꢂ0.82
ꢂ8.74
%10
9.58
e
1.89
e
4.58
ꢂ2.71
ꢂ0.28
ꢂ2.98
%20
632.59
ꢂ5.05
199.65
ꢂ5.61
ꢂ0.51
ꢂ6.12
%10
571.57
ꢂ8.38
714.61
ꢂ9.01
ꢂ1.36
ꢂ10.37
%20
ꢂ0.13
4.45
%20
645.43
ꢂ5.38
114.72
ꢂ5.99
0.04
ꢂ5.95
%20
544.87
ꢂ8.23
923.13
ꢂ8.16
ꢂ0.76
ꢂ8.93
%10
vdW þ Hbond þ desolv energy (kCal/mol)
Electrostatic Energy (kCal/mol)
Total Intermolecular energy (kCal/mol)
Frequency
Interact. Surface
Estimated Free energy of binding (kCal/mol)
Estimated Ki (mM)
vdW þ Hbond þ desolv energy (kCal/mol)
Electrostatic Energy (kCal/mol)
Total Intermolecular energy (kCal/mol)
Frequency
656.10
ꢂ6.31
23.79
ꢂ5.20
ꢂ2.31
ꢂ7.52
%20
920.95
ꢂ6.24
26.62
ꢂ6.21
ꢂ1.70
ꢂ7.91
%10
941.99
ꢂ6.75
11.31
ꢂ6.01
ꢂ1.98
ꢂ7.99
%10
989.56
ꢂ7.10
6.29
ꢂ7.83
ꢂ1.99
ꢂ9.82
%20
1037.67
ꢂ6.14
31.80
ꢂ5.97
ꢂ1.41
ꢂ7.38
%10
a
-Gly
Interact. Surface
657.57
671.27
640.28
744.47
680.09
biguanides, sulfonylureas, meglitinides, thiazolidinediones,
a
-
metabolic enzyme, the Carvacrol based novel oxypropanolamine
derivatives (3a-e) had IC50 values in the range of
904.10e1065.73 nM and Ki values in the range of
896.61 78.63e1026.80 147.3 nM (Table 1). The results clearly
glycosidase inhibitors, incretin mimetics, dipeptidyl peptidase-IV
inhibitors and insulin; however, the use of these pharmaceutical
drugs may cause undesired and severe side effects [60]. For this
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
7
Fig. 5. Showing of interactions between hCA I isoenzyme and novel oxypropanolamine derivative of 3a.
showed that all novel derivatives (3a-e) were recorded efficient
glycosidase inhibitory effects than that of acarbose (IC50
22800 nM) [61,62] as a control -glycosidase inhibitor. However,
the most effective Ki values were obtained by 1-((2-(cyclohex-1-
en-1-yl)ethyl)amino)-3-(5-isopropyl-2-methylphenoxy)propan-2-
ol (3d) and 1-(tert-butylamino)-3-(5-isopropyl-2-methylphenoxy)
propan-2-ol (3c), with Ki values of 896.61 78.63 and
904.88 101.88 nM, respectively. One remedial approach for
treating diabetes diseases involves regulating postprandial hyper-
a
-
:
inhibition of six
CA XIV, and two
a
-CAs, that are CA I, CA II, CA VA, CA IX, CA XII and
b-CAs from Candida glabrata and Mycobacterium
a
tuberculosis with these sulfamides was investigated. All CA iso-
zymes were inhibited in the low micromolar to nanomolar range by
the dopamine sulfamide analogues [17]. Zengin et al. (2018) a series
of thymol bearing oxypropanolamine compounds were synthe-
sized and characterized. Their in vitro antibacterial activity on
A. baumannii, P. aeruginosa, E. coli and S. aureus strains were
investigated with agar well diffusion method. These novel thymol
bearing oxypropanolamine derivatives were effective inhibitors of
glycemia by inhibiting the a-glycosidase enzyme in the digestive
tract, prolonging the overall digestion of carbohydrate. Also, car-
bohydrate digestion should decrease consequently to prevent
spikes and the rate of glucose absorption in the postprandial blood
glucose and insulin levels. Utilizing these enzyme inhibitors has
become a promising therapeutic mechanism for decreasing the
risks of carbohydrate-mediated diseases and diabetes, hyper-
lipoproteinemia, and obesity [63].
the
the range of 463.85e851.05
hCA I, 2.97e17.83 M for hCA II, and 13.58e31.45
respectively [22]. Also in the other study, Biçer et al. (2019) the
newly synthesized bis-thiomethylcyclohexanone compounds
showed Ki values of in range of 39.14e183.23 nM against hCA I,
46.03e194.02 nM against hCA II isoenzyme, 4.55e32.64 nM against
AChE and 12.77e37.38 nM against BChE. As a result, novel bis-
thiomethylcyclohexanone compounds can have promising anti
a
-glycosidase, hCA I and II isoforms, and AChE with Ki values in
M for -glycosidase, 1.11e17.34 M for
M for AChE,
m
a
m
m
m
In the previous studies, Aksu et al. (2013) A series of novel sul-
famides incorporating the dopamine scaffold were synthesized and
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

8
A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
Fig. 6. Showing of interactions between hCA II isoenzyme and novel oxypropanolamine derivative of 3c.
Alzheimer drug potential and record novel hCA I, and hCA II en-
zymes inhibitor [25]. When we compared these three studies, they
were obtained results similar to the inhibitor values in our study,
and our results were obtained at nM level.
II,
AChE, ꢂ6.31, ꢂ6.24, ꢂ6.75, ꢂ7.10, ꢂ6.14 for
that 3d is the most active molecule for -glycosidase. This result is
consistent with the experimental result. The next parameter is Est.
Inhibition constant (Ki) where the values for this parameter [65],
can be sorted as follows: 13.56,17.14, 86.49 for hCA I, 368.87, 348.67,
81.18, 114.72, 199.65 for hCA II, 3.46, 3.99, 986.22, 923.13, 714.61 for
ꢂ7.45,
ꢂ7.37,
ꢂ8,19,
ꢂ8.23,
ꢂ8.38
for
a
-Gly. The results show
a
3.3. Molecular docking
AChE, 23.79, 26.62, 11.31, 6.29, 31.80 for
a-glycosidase. This
Theoretical studies are the simplest and fastest method used to
determine the biological activities of molecules. The most impor-
tant of theoretical studies is molecular docking. In docking studies,
the interaction of enzymes formed by proteins and studied mole-
cules are examined. In this study, both the experimental and
theoretical approaches are studied. The theoretical study was
compared against the experimental findings. The enzymes formed
by the combination of proteins and ligands were studied. The in-
teractions of the studied with the enzymes are shown in Figs. 1e4.
In molecular docking, all calculations were made at pH 7.3. The
reason for making calculations at this pH is because of the pH value
at which these enzymes are most active in metabolisms. By
working at this pH, it was ensured that the experimental values and
theoretical values were compatible with each other [64].
parameter shows that both drug molecules can inhibit an enzyme
and drug molecules can interact with a substrate for the enzyme. If
the value of this parameter of one of the studied molecules is
greater than the other molecules, extra drug is needed to prevent
enzyme activity [66]. The lowest value for this parameter is the
AChE enzyme 3a molecule. This result is consistent with the
experimental
results.
The
next
parameter
is
vdW þ Hbond þ desolve Energy, whose numerical values are listed
as follows: 4.84, ꢂ4.17, ꢂ3.21, 4.58, ꢂ2.71 for hCA
I,
II,
ꢂ5.39,
ꢂ7.22,
ꢂ6.28,
ꢂ7.94,
ꢂ5.89,
ꢂ5.99,
ꢂ5.61
for
ꢂ9.01
hCA
for
ꢂ7.92,
ꢂ8.16,
AChE, ꢂ5.20, ꢂ6.21, ꢂ6.01, ꢂ7.83, ꢂ5.97 for
a-glycosidase. The
numerical values of this parameter are very important parameter
for molecular docking calculations. This parameter is an important
parameter used to determine the position of enzyme proteins
relative to the ligand studied. If this value has a negative value, it
shows good binding to the active site in the enzyme. The most
negative value for this parameter is the 3d molecule for the enzyme
Many parameters and data were obtained from the interaction
of molecules with studied enzymes. For this study, the first
parameter Est. Free Energy of Binding, where the numerical values
for this parameter can be sorted as follows: 2.55, ꢂ2.41, ꢂ1.45, 9.58,
1.89 for hCA I, ꢂ4.68, ꢂ4.72, ꢂ5.58, ꢂ5.38, ꢂ5.05 for hCA
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
9
Fig. 7. Showing of interactions between AChE enzyme and novel oxypropanolamine derivative of 3e.
a
-glycosidase. Final parameter for molecular docking calculations is
of 3a is 2.89 atomic units. However, the distance between the His-
119 protein and the H20 atom in molecule 3a is 3.52 atomic units.
The distance between the HIS-200 protein and the H21 atom in
novel oxypropanolamine derivative of 3a is 2.90 atomic units. On
the other hand, the interactions between the enzyme hCA II and the
novel oxypropanolamine derivative of 3c are shown in Fig. 6. The
hCA II is composed of several proteins, the names of which are Tyr-
7 and Asp-243. The distance between the Tyr-7 protein and the N1
atom in novel oxypropanolamine derivative of 3c is 2.73 atomic
units. The distance between the Asp-243 protein and the N1 atom
in molecule 3c is 3.03 atomic units. Moreover, the interactions
between the enzyme AChE and the molecule 3e are shown in Fig. 7.
The enzyme AChE is composed of several proteins, the names of
which are Ser-122, Tyr-334 and Asp-72. The distance between the
Ser-122 protein and the N2 atom in novel oxypropanolamine de-
rivative of 3e is 2.90 atomic units. The distance between the TYR-
334 protein and the H21 atom in novel oxypropanolamine deriv-
ative of 3e is 3.11 atomic units and the H20 atom in novel oxy-
propanolamine derivative of 3e is 3.11 atomic units. The distance
between the ASP122 protein and the N1 atom in molecule 3e is 2.78
atomic units and the H20 atom in molecule 3e is 2.38 atomic units
Electrostatic energies are ꢂ0.14, ꢂ0.06, ꢂ0.19, ꢂ0.13, ꢂ0.28 for hCA
I,
II,
ꢂ0.42,
ꢂ1.35,
ꢂ0.22,
ꢂ0.50,
ꢂ0.38,
ꢂ0.82,
0.04,
ꢂ0.51
for
ꢂ1.36
hCA
for
ꢂ0.76,
AChE, ꢂ2.31, ꢂ1.70, ꢂ1.98, ꢂ1.99, ꢂ1.41 for
a-glycosidase. If the
numerical value of this parameter has a negative value, it shows
that there is chemical interaction between molecules and proteins
that make up the enzyme [67]. The numerical value of this
parameter is obtained as a negative for all enzymes. This indicates
that all enzymes are in chemical interaction with proteins (Table 2).
There are many interactions between molecules and enzymes.
These interactions allow the molecule to bind to the protein. These
interactions increase the biological activity of the molecule. Thus,
the interactions between the hCA I isoenzyme, and the molecule 3a
are shown in Fig. 5. The hCA I is composed of several amino acid,
which named as His-94, His-119, and His-200. The distance be-
tween the His-94 protein and the N1 atom in novel oxypropanol-
amine derivative of 3a is 3.54 atomic units. The distance between
the His-94 protein and the H21 atom in novel oxypropanolamine
derivative of 3a is 3.58 atomic units. The distance between the His-
94 protein and the H20 atom in novel oxypropanolamine derivative
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

10
A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
Fig. 8. Showing of interactions between a-Gly enzyme and novel oxypropanolamine derivative of 3d.
and the H21 atom in molecule 3e is 2.96 atomic units. The in-
teractions between the -glycosidase and the molecule 3d are
shown in Fig. 8 whereby the enzyme -glycosidase is composed of
molecule 3d is 3.37 atomic units. The distance between the Phe-515
protein and the H20 atom in novel oxypropanolamine derivative of
3d is 3.23 atomic units.
a
a
several proteins, the names of which are Asp-482 and Phe-515. The
distance between the Asp-482 protein and the N1 atom in novel
oxypropanolamine derivative of 3d is 2.52 atomic units and the
H20 atom in molecule 3d is 2.75 atomic units and the H21 atom in
In the light of the above information, the obtained data indicate
that all interactions between the enzyme and the molecule are
mostly between heteroatoms. One of the most important factors
affecting the biological activity of the molecule is the interaction
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
11
and cardiac effectivity of a group of beta-receptor blockaders], Acta Biol. Med.
Ger. 37 (1978) 1081e1090.
[11] G. Bazylak, L.J. Nagels, A novel potentiometric approach for detection of beta-
adrenergics and beta-adrenolytics in high-performance liquid chromatog-
raphy, Farm, Soc. Chim. Ital. 58 (1989) 591e603, https://doi.org/10.1016/
S0014-827X(03)00096-X, 2003.
between molecules and proteins. As this interaction increases, the
biological activity of the molecule increases, too. Furthermore this
interaction increases, as the distance between the molecule and the
enzyme decreases.
[12] J.B. Wechsler, C.-L. Hsu, P.J. Bryce, IgE-mediated mast cell responses are
inhibited by thymol-mediated, activation-induced cell death in skin inflam-
mation, J. Allergy Clin. Immunol. 133 (2014) 1735e1743, https://doi.org/
10.1016/j.jaci.2013.12.024.
4. Conclusions
The results showed that experimental and theoretical results are
similar. The reason some of the differences is that the theoretical
studies are conducted in pure and isolated environment. There are
many experimental attempts to cause these differences in experi-
mental studies. As we explained above, novel molecules studied in
the work can be used in selective candidate drugs, the same as
hCAIs, for therapy of some diseases such as: glaucoma, epilepsy,
mountain sickness, osteoporosis, gastric and duodenal ulcers, or
neurological disturbances. All these molecules effectively inhibited
important enzymes such as hCA I, hCA II,
enzymes at the nanomolar levels. Inhibitors of
the break of starch in the little intestine and reduce the post-
prandial blood glucose deviation levels in diabetic patients.
Henceforth, the restraint of a-glycosidase conspicuous chemicals
[13] V. Cecchetti, A. Fravolini, F. Schiaffella, O. Tabarrini, G. Bruni, G. Segre, o-
Chlorobenzenesulfonamidic derivatives of (aryloxy)propanolamines as .beta.-
blocking/diuretic agents, J. Med. Chem. 36 (1993) 157e161, https://doi.org/
10.1021/jm00053a020.
€
_
[14] S.B. Oztürk Sarikaya, F. Topal, M. S¸ entürk, I. Gülçin, C.T. Supuran, In vitro in-
hibition of -carbonic anhydrase isozymes by some phenolic compounds,
a
Bioorg. Med. Chem. Lett 21 (2011) 4259e4262, https://doi.org/10.1016/
j.bmcl.2011.05.071.
_
[15] M. Nar, Y. Çetinkaya, I. Gülçin, A. Menzek, (3,4-Dihydroxyphenyl)(2,3,4-
trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase iso-
enzymes inhibitors, J. Enzyme. Inhib. Med. Chem. 28 (2013) 402e406, https://
doi.org/10.3109/14756366.2012.670807.
a
-glycosidase, and AChE
-glycosidase defer
[16] I. Gülçin, S¸ . Beydemir, Phenolic compounds as antioxidants: carbonic anhy-
a
drase isoenzymes inhibitors, Mini Rev. Med. Chem. 13 (2013) 408e430.
_
€
[17] K. Aksu, M. Nar, M. Tanc, D. Vullo, I. Gülçin, S. Goksu, F. Tümer, C.T. Supuran,
Synthesis and carbonic anhydrase inhibitory properties of sulfamides struc-
turally related to dopamine, Bioorg. Med. Chem. 21 (2013) 2925e2931,
https://doi.org/10.1016/j.bmc.2013.03.077.
_
has been set up as a practical and proficient methodology to
diminish the dimensions of postprandial hyperglycemia. Several
antidiabetic commercial drugs such as acarbose, voglibose, and
miglitol are currently available in the market in use for the treat-
[18] M. Güney, A. Cos¸ kun, F. Topal, A. Das¸ tan, I. Gülçin, C.T. Supuran, Oxidation of
cyanobenzocycloheptatrienes: synthesis, photooxygenation reaction and
carbonic anhydrase isoenzymes inhibition properties of some new benzo-
tropone derivatives, Bioorg. Med. Chem. 22 (2014) 3537e3543, https://
doi.org/10.1016/j.bmc.2014.04.007.
_
€
ꢀ
[19] S. Goksu, A. Naderi, Y. Akbaba, P. Kalın, A. Akıncıoglu, I. Gülçin, S. Durdagi,
R.E. Salmas, Carbonic anhydrase inhibitory properties of novel benzylsulfa-
mides using molecular modeling and experimental studies, Bioorg. Chem. 56
(2014) 75e82, https://doi.org/10.1016/j.bioorg.2014.07.009.
ment of a-amylase and a-glycosidase enzyme inhibition in diabetes
mellitus. Hence, findings indicate that these molecules can be
candidate drugs as potential inhibitors for some diseases. Their
clinical use has been established as diuretics, antiepileptics, and
anti-glaucoma factors, in the management of gastric, duodenal
ulcers, mountain sickness, osteoporosis, idiopathic intracranial
hypertension and neurological disorders.
[20] B. Arabaci, I. Gulcin, S. Alwasel, Capsaicin: a potent inhibitor of carbonic
anhydrase isoenzymes, Molecules 19 (2014) 10103e10114, https://doi.org/
10.3390/molecules190710103.
_
[21] Y. Demir, P. Taslimi, M.S. Ozaslan, N. Oztaskin, Y. Çetinkaya, I. Gulçin,
S¸ . Beydemir, S. Goksu, Antidiabetic potential: in vitro inhibition effects of
bromophenol and diarylmethanones derivatives on metabolic enzymes, Arch.
Pharm. (Weinheim) 351 (2018), e1800263, https://doi.org/10.1002/
ardp.201800263.
Declaration of competing interest
The authors declare no conflicts of interest.
Appendix A. Supplementary data
[22] M. Zengin, H. Genc, P. Taslimi, A. Kestane, E. Guclu, A. Ogutlu, O. Karabay,
_
I. Gulçin, Novel thymol bearing oxypropanolamine derivatives as potent some
metabolic enzyme inhibitors e their antidiabetic, anticholinergic and anti-
bacterial potentials, Bioorg. Chem. 81 (2018) 119e126, https://doi.org/
10.1016/j.bioorg.2018.08.003.
_
[23] P. Taslimi, H.E. Aslan, Y. Demir, N. Oztaskin, A. Maras¸ , I. Gulçin, S. Beydemir,
S. Goksu, Diarylmethanon, bromophenol and diarylmethane compounds:
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2019.127297.
discovery of potent aldose reductase,
as new therapeutic approach in diabetes and functional hyperglycemia, Int. J.
Biol. Macromol. 119 (2018) 857e863, https://doi.org/10.1016/
j.ijbiomac.2018.08.004.
[24] M. Huseynova, P. Taslimi, A. Medjidov, V. Farzaliyev, M. Aliyeva, G. Gondolova,
a-amylase and a-glycosidase inhibitors
References
€
_
O. S¸ ahin, B. Yalçın, A. Sujayev, E.B. Orman, A.R. Ozkaya, I. Gulçin, Synthesis,
characterization, crystal structure, electrochemical studies and biological
evaluation of metal complexes with thiosemicarbazone of glyoxylic acid,
Polyhedron 155 (2018) 25e33, https://doi.org/10.1016/j.poly.2018.08.026.
[25] A. Biçer, P. Taslimi, G. Yakalı, I. Gülçin, M. Serdar Gültekin, G. Turgut Cin,
[1] G. Li, H.-X. Lou, Strategies to diversify natural products for drug discovery,
Med. Res. Rev. 38 (2018) 1255e1294, https://doi.org/10.1002/med.21474.
[2] B. Shen, A new golden age of natural products drug discovery, Cell 163 (2015)
1297e1300, https://doi.org/10.1016/j.cell.2015.11.031.
[3] D.J. Newman, G.M. Cragg, Natural products as sources of new drugs from 1981
to 2014, J. Nat. Prod. 79 (2016) 629e661, https://doi.org/10.1021/
acs.jnatprod.5b01055.
[4] J. Clardy, C. Walsh, Lessons from natural molecules, Nature 432 (2004)
829e837, https://doi.org/10.1038/nature03194.
[5] Z.E. Suntres, J. Coccimiglio, M. Alipour, The bioactivity and toxicological ac-
tions of carvacrol, Crit. Rev. Food Sci. Nutr. 55 (2015) 304e318, https://doi.org/
10.1080/10408398.2011.653458.
Synthesis,
characterization,
crystal
structure
of
novel
bis-
thiomethylcyclohexanone derivatives and their inhibitory properties against
some metabolic enzymes, Bioorg. Chem. 82 (2019) 393e404, https://doi.org/
10.1016/j.bioorg.2018.11.001.
_
€
_
ꢀ
ꢀ
[26] B. Yigit, R. Kaya, P. Taslimi, Y. Is¸ ık, M. Karaman, M. Yigit, I. Ozdemir, I. Gulçin,
Imidazolinium chloride salts bearing wingtip groups: synthesis, molecular
docking and metabolic enzymes inhibition, J. Mol. Struct. 1179 (2019)
709e718, https://doi.org/10.1016/j.molstruc.2018.11.038.
[27] A. Bytyqi-Damoni, H. Genç, M. Zengin, S. Beyaztas, N. Gençer, O. Arslan,
[6] M. Sharifi-Rad, E.M. Varoni, M. Iriti, M. Martorell, W.N. Setzer, M. Del Mar
Contreras, B. Salehi, A. Soltani-Nejad, S. Rajabi, M. Tajbakhsh, J. Sharifi-Rad,
Carvacrol and human health: a comprehensive review, Phytother. Res. PTR. 32
(2018) 1675e1687, https://doi.org/10.1002/ptr.6103.
In vitro effect of novel
b-lactam compounds on xanthine oxidase enzyme
activity, Artif. Cells Blood Substit, Biotechnology 40 (2012) 369e377, https://
doi.org/10.3109/10731199.2012.678943.
[28] D. Demir, N. Gençer, O. Arslan, H. Genç, M. Zengin, In vitro inhibition of
polyphenol oxidase by some new diarylureas, J. Enzyme. Inhib. Med. Chem. 27
(2012) 125e131, https://doi.org/10.3109/14756366.2011.580743.
[29] H. Genç, M. Zengin, E. Yavuz, N. Gençer, O. Arslan, Synthesis and tyrosinase
inhibitory properties of novel isoquinoline urea/thiourea derivatives, Artif,
Cells Nanomed. Biotechnol. 42 (2014) 178e185, https://doi.org/10.3109/
10731199.2013.785953.
[30] A. Akıncıoglu, H. Akıncıoglu, I. Gülçin, S. Durdagi, C.T. Supuran, S. Goksu,
Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors:
novel sulfamoylcarbamates and sulfamides derived from acetophenones,
Bioorg. Med. Chem. 23 (2015) 3592e3602, https://doi.org/10.1016/
[7] M. Friedman, Chemistry and multibeneficial bioactivities of carvacrol (4-
isopropyl-2-methylphenol), a component of essential oils produced by aro-
matic plants and spices, J. Agric. Food Chem. 62 (2014) 7652e7670, https://
doi.org/10.1021/jf5023862.
[8] M. De Vincenzi, A. Stammati, A. De Vincenzi, M. Silano, Constituents of aro-
matic plants: carvacrol, Fitoterapia 75 (2004) 801e804, https://doi.org/
10.1016/j.fitote.2004.05.002.
[9] O. Karjalainen, Substrate Controlled Synthesis of 1,2-Amino Alcohols, Aalto
University, 2013. https://aaltodoc.aalto.fi:443/handle/123456789/11280.
(Accessed 12 July 2019).
_
ꢀ
ꢀ
€
[10] H. Bercher, W. Siegmund, A. Grisk, [Correlations between chemical structure
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297

12
A. Bytyqi-Damoni et al. / Journal of Molecular Structure xxx (xxxx) xxx
j.bmc.2015.04.019.
spectral, structural, computational and anticancer studies, RSC Adv. 7 (2017)
56296e56305, https://doi.org/10.1039/C7RA10517G.
[49] S. Kaya, B. Tüzün, C. Kaya, Conceptual density functional theoretical investi-
gation of the corrosion inhibition efficiencies of some molecules containing
[31] H. Genc, B. Ceken, C. Bilen, Z. Sackes, N. Gencer, O. Arslan, Synthesis and
biological evaluation of new 4-thiazolidinone derivatives as carbonic anhy-
drase inhibitors, Lett. Org. Chem. 14 (2017) 80e85, https://doi.org/10.2174/
1570178614666161230121658, 2017.
mercapto (-SH), Group
7
(2017) 147e153, doi:info:, doi/10.2174/
[32] A. Atahan, N. Gencer, C. Bilen, E. Yavuz, H. Genc, F. Sonmez, M. Zengin,
M. Ceylan, M. Kucukislamoglu, Synthesis, biological activity and structure-
activity relationship of novel diphenylurea derivatives containing tetrahy-
droquinoline as carbonic anhydrase I and II inhibitors, ChemistrySelect 3
(2018) 529e534, https://doi.org/10.1002/slct.201702562.
1877946806666160622075604.
_
€
[50] K. Oktay, L.P. Kose, K. S¸ endil, M.S. Gültekin, I. Gülçin, C.T. Supuran, The syn-
thesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acids derivatives and determi-
nation of their inhibition properties against human carbonic anhydrase I and
II isoenzymes, J. Enzyme. Inhib. Med. Chem. 31 (2016) 939e945, https://
doi.org/10.3109/14756366.2015.1071808.
[33] J.A. Verpoorte, S. Mehta, J.T. Edsall, Esterase activities of human carbonic
anhydrases B and C, J. Biol. Chem. 242 (1967) 4221e4229.
_
€
[51] H. Genç, R. Kalin, Z. Koksal, N. Sadeghian, U.M. Kocyigit, M. Zengin, I. Gülçin,
_
€
[34] M. Boztas¸ , Y. Çetinkaya, M. Topal, I. Gülçin, A. Menzek, E. S¸ ahin, M. Tanc,
H. Ozdemir, Discovery of potent carbonic anhydrase and acetylcholinesterase
C.T. Supuran, Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII
inhibitory effects of dimethoxybromophenol derivatives incorporating
cyclopropane moieties, J. Med. Chem. 58 (2015) 640e650, https://doi.org/
10.1021/jm501573b.
inhibitors: 2-aminoindan b-lactam derivatives, Int. J. Mol. Sci. 17 (2016) 1736,
https://doi.org/10.3390/ijms17101736.
[52] F. Topal, I. Gulcin, A. Dastan, M. Guney, Novel eugenol derivatives: potent
acetylcholinesterase and carbonic anhydrase inhibitors, Int. J. Biol. Macromol.
94 (2017) 845e851, https://doi.org/10.1016/j.ijbiomac.2016.10.096.
_
[35] H. Gocer, A. Aslan, I. Gülçin, C.T. Supuran, Spirobisnaphthalenes effectively
ꢀ
€
inhibit carbonic anhydrase, J. Enzyme. Inhib. Med. Chem. 31 (2016) 503e507,
[53] A. Behçet, T. Çaglılar, D. Barut Celepci, A. Aktas¸ , P. Taslimi, Y. Gok, M. Aygün,
_
https://doi.org/10.3109/14756366.2015.1043298.
R. Kaya, I. Gülçin, Synthesis, characterization and crystal structure of 2-(4-
_
[36] M. Kucuk, I. Gulcin, Purification and characterization of the carbonic anhy-
hydroxyphenyl)ethyl and 2-(4-nitrophenyl)ethyl Substituted Benzimidazole
Bromide Salts: their inhibitory properties against carbonic anhydrase and
acetylcholinesterase, J. Mol. Struct. 1170 (2018) 160e169, https://doi.org/
10.1016/j.molstruc.2018.05.077.
drase enzyme from Black Sea trout (Salmo trutta Labrax Coruhensis) kidney
and inhibition effects of some metal ions on enzyme activity, Environ. Toxicol.
Pharmacol. 44 (2016) 134e139, https://doi.org/10.1016/j.etap.2016.04.011.
€
_
_
€
€
[37] B. Ozgeris¸ , S. Goksu, L. Polat Kose, I. Gülçin, R.E. Salmas, S. Durdagi, F. Tümer,
C.T. Supuran, Acetylcholinesterase and carbonic anhydrase inhibitory prop-
erties of novel urea and sulfamide derivatives incorporating dopaminergic 2-
aminotetralin scaffolds, Bioorg. Med. Chem. 24 (2016) 2318e2329, https://
doi.org/10.1016/j.bmc.2016.04.002.
[54] P. Taslimi, I. Gulçin, Antioxidant and anticholinergic properties of olivetol,
J. Food Biochem. 42 (2018), e12516, https://doi.org/10.1111/jfbc.12516.
_
[55] I. Gulçin, P. Taslimi, Sulfonamide inhibitors: a patent review 2013-present,
Expert Opin. Ther. Pat. 28 (2018) 541e549, https://doi.org/10.1080/
13543776.2018.1487400.
ꢀ
ꢀ
€
[38] G.L. Ellman, K.D. Courtney, V. Andres, R.M. Featherstone, A new and rapid
colorimetric determination of acetylcholinesterase activity, Biochem. Phar-
macol. 7 (1961) 88e95, https://doi.org/10.1016/0006-2952(61)90145-9.
[56] B. Yigit, M. Yigit, D. Barut Celepci, Y. Gok, A. Aktas¸ , M. Aygün, P. Taslimi,
_
I. Gülçin, Novel benzylic substituted imidazolinium, tetrahydropyrimidinium
and tetrahydrodiazepinium salts: potent carbonic anhydrase and acetylcho-
linesterase inhibitors, ChemistrySelect 3 (2018) 7976e7982, https://doi.org/
10.1002/slct.201801019.
€
ꢀ
[39] M. Ekiz, A. Tutar, S. Okten, B. Bütün, Ü.M. Koçyigit, P. Taslimi, G. Topçu, Syn-
thesis, characterization, and SAR of arylated indenoquinoline-based cholin-
esterase and carbonic anhydrase inhibitors, Arch. Pharm. (Weinheim) 351
(2018) 1800167, https://doi.org/10.1002/ardp.201800167.
_
€
[57] F. Erdemir, D. Barut Celepci, A. Aktas¸ , P. Taslimi, Y. Gok, H. Karabıyık, I. Gülçin,
2-Hydroxyethyl substituted NHC precursors: synthesis, characterization,
crystal structure and carbonic anhydrase, a-glycosidase, butyrylcholinester-
_
[40] U. Atmaca, A. Yıldırım, P. Taslimi, S.T. Çelik, I. Gülçin, C.T. Supuran, M. Çelik,
Intermolecular amination of allylic and benzylic alcohols leads to effective
inhibitions of acetylcholinesterase enzyme and carbonic anhydrase I and II
isoenzymes, J. Biochem. Mol. Toxicol. 32 (2018), e22173, https://doi.org/
10.1002/jbt.22173.
ase, and acetylcholinesterase inhibitory properties, J. Mol. Struct. 1155 (2018)
797e806, https://doi.org/10.1016/j.molstruc.2017.11.079.
_
[58] P. Taslimi, C. Caglayan, I. Gulcin, The impact of some natural phenolic com-
pounds on carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase,
€
_
ꢀ
€
[41] S. Okten, M. Ekiz, Ü.M. Koçyigit, A. Tutar, I. Çelik, M. Akkurt, F. Gokalp,
and
a-glycosidase enzymes: an antidiabetic, anticholinergic, and antiepileptic
_
P. Taslimi, I. Gülçin, Synthesis, characterization, crystal structures, theoretical
study, J. Biochem. Mol. Toxicol. 31 (2017), https://doi.org/10.1002/jbt.21995.
_
calculations and biological evaluations of novel substituted tacrine derivatives
as cholinesterase and carbonic anhydrase enzymes inhibitors, J. Mol. Struct.
1175 (2019) 906e915, https://doi.org/10.1016/j.molstruc.2018.08.063.
[59] P. Taslimi, H. Akıncıoglu, I. Gülçin, Synephrine and phenylephrine act as
a-
amylase, -glycosidase, acetylcholinesterase, butyrylcholinesterase, and car-
a
bonic anhydrase enzymes inhibitors, J. Biochem. Mol. Toxicol. 31 (2017),
e21973, https://doi.org/10.1002/jbt.21973.
_
ꢀ
ꢀ
€
[42] B. Yigit, M. Yigit, P. Taslimi, Y. Gok, I. Gülçin, Schiff bases and their amines:
synthesis and discovery of carbonic anhydrase and acetylcholinesterase en-
zymes inhibitors, Arch. Pharm. (Weinheim) 351 (2018) 1800146, https://
doi.org/10.1002/ardp.201800146.
_
[60] P. Taslimi, I. Gulçin, Antidiabetic potential: in vitro inhibition effects of some
natural phenolic compounds on
a-glycosidase and a-amylase enzymes,
J. Biochem. Mol. Toxicol. 31 (2017), e21956, https://doi.org/10.1002/jbt.21956.
ꢁ
[43] Y. Tao, Y. Zhang, Y. Cheng, Y. Wang, Rapid screening and identification of
a
-
[61] M. Torres-Naranjo, A. Suarez, G. Gilardoni, L. Cartuche, P. Flores, V. Morocho,
glucosidase inhibitors from mulberry leaves using enzyme-immobilized
magnetic beads coupled with HPLC/MS and NMR, Biomed. Chromatogr.
BMC. 27 (2013) 148e155, https://doi.org/10.1002/bmc.2761.
Chemical constituents of muehlenbeckia tamnifolia (kunth) meisn (polygo-
naceae) and its in vitro
Molecules 21 (2016) 1461, https://doi.org/10.3390/molecules21111461.
[62] H. Teng, L. Chen, T. Fang, B. Yuan, Q. Lin, Rb2 inhibits -glucosidase and
a-amilase and a-glucosidase inhibitory activities,
_
[44] I. Gulçin, P. Taslimi, A. Aygün, N. Sadeghian, E. Bastem, O.I. Kufrevioglu,
a
F. Turkan, F. S¸ en, Antidiabetic and antiparasitic potentials: inhibition effects of
regulates glucose metabolism by activating AMPK pathways in HepG2 cells,
some natural antioxidant compounds on
glutathione S-transferase enzymes, Int. J. Biol. Macromol. 119 (2018)
741e746, https://doi.org/10.1016/j.ijbiomac.2018.08.001.
a
-glycosidase,
a
-amylase and human
J. Funct. Foods 28 (2017) 306e313, https://doi.org/10.1016/j.jff.2016.10.033.
€
_
€
[63] N. Oztas¸ kın, R. Kaya, A. Maras¸ , E. S¸ ahin, I. Gülcin, S. Goksu, Synthesis and
characterization of novel bromophenols: determination of their anticholin-
ergic, antidiabetic and antioxidant activities, Bioorg. Chem. 87 (2019) 91e102,
https://doi.org/10.1016/j.bioorg.2019.03.010.
[45] P. Taslimi, C. Caglayan, V. Farzaliyev, O. Nabiyev, A. Sujayev, F. Turkan, R. Kaya,
_
I. Gulçin, Synthesis and discovery of potent carbonic anhydrase, acetylcho-
linesterase, butyrylcholinesterase, and
a
-glycosidase enzymes inhibitors: the
[64] B. Tüzün, C. Kaya, Investigation of DNAeRNA molecules for the efficiency and
activity of corrosion inhibition by DFT and molecular docking, J. Bio Tribo
Corros. 4 (2018) 69, https://doi.org/10.1007/s40735-018-0185-5.
[65] E. Hazai, S. Kovacs, L. Demko, Z. Bikadi, [DockingServer: molecular docking
calculations online], Acta Pharm. Hung. 79 (2009) 17e21.
novel N,N0-bis-cyanomethylamine and alkoxymethylamine derivatives,
J. Biochem. Mol. Toxicol. 32 (2018), e22042, https://doi.org/10.1002/jbt.22042.
[46] S. Burmaoglu, A.O. Yilmaz, P. Taslimi, O. Algul, D. Kilic, I. Gulcin, Synthesis and
ꢁ
ꢁ
ꢁ
biological evaluation of phloroglucinol derivatives possessing a-glycosidase,
acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase inhibitory
activity, Arch. Pharm. (Weinheim) 351 (2018) 1700314, https://doi.org/
10.1002/ardp.201700314.
[66] J.B. Billones, Reverse docking study unravels the potential Mycobacterium
tuberculosis enzyme targets of Agelasine F, Orient, J. Chem. 32 (2016)
851e858.
[47] S. Kaya, B. Tüzün, C. Kaya, I.B. Obot, Determination of corrosion inhibition
effects of amino acids: quantum chemical and molecular dynamic simulation
study, J. Taiwan Inst. Chem. Eng. 58 (2016) 528e535, https://doi.org/10.1016/
j.jtice.2015.06.009.
[67] T. Tantimongcolwat, S. Prachayasittikul, V. Prachayasittikul, Unravelling the
interaction mechanism between clioquinol and bovine serum albumin by
multi-spectroscopic and molecular docking approaches, Spectrochim. Acta. A.
Mol. Biomol. Spectrosc. 216 (2019) 25e34, https://doi.org/10.1016/
j.saa.2019.03.004.
[48] C. Hepokur, A. Günsel, M. Nilüfer Yarasir, A.T. Bilgiçli, B. Tüzün, G. Tüzün,
_
I. Yaylim, Novel type ketone-substituted metallophthalocyanines: synthesis,
Please cite this article as: A. Bytyqi-Damoni et al., Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization,
biological evaluation, and molecular docking studies, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2019.127297