Synthesis, dielectric properties, molecular docking and ADME studies of pyrrole-3-ones

Article abstract of DOI:10.1080/07391102.2021.1914174

A novel series of pyrrole-3-one derivatives were synthesized using furan-3-one derivatives and various aromatic amines. The synthesized compounds were identified by spectral studies such as IR, NMR and HRMS. Dielectric properties of the target compounds w

Full text of DOI:10.1080/07391102.2021.1914174

Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
Synthesis, dielectric properties, molecular docking
and ADME studies of pyrrole-3-ones
İrfan Çapan, Mehmet Gümüş, Halil Gökce, Hidayet Çetin, Yusuf Sert & İrfan
Koca
To cite this article: İrfan Çapan, Mehmet Gümüş, Halil Gökce, Hidayet Çetin, Yusuf Sert & İrfan
Koca (2021): Synthesis, dielectric properties, molecular docking and ADME studies of pyrrole-3-
ones, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2021.1914174
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2021.1914174
Synthesis, dielectric properties, molecular docking and ADME studies
of pyrrole-3-ones
a
b,c
d
c
, Halil Gokce
, Hidayet C¸etine , Yusuf Serte,f
and Irfan Koca
_
Irfan C¸apan
_
€ €
, Mehmet Gumus¸
€
aDepartment of Material and Material Processing Technologies, Technical Sciences Vocational College, Gazi University, Ankara, Turkey;
b
c
ꢀ
Akdagmadeni Health College, Yozgat Bozok University, Yozgat, Turkey; Department of Chemistry, Faculty of Art & Sciences, Yozgat Bozok
d
e
University, Yozgat, Turkey; Vocational School of Health Services, Giresun University, Giresun, Turkey; Department of Physics, Faculty of Art
& Sciences, Yozgat Bozok University, Yozgat, Turkey; Sorgun Vocational School, Yozgat Bozok University, Yozgat, Turkey
f
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
Received 8 February 2021
Accepted 3 April 2021
A novel series of pyrrole-3-one derivatives were synthesized using furan-3-one derivatives and various
aromatic amines. The synthesized compounds were identified by spectral studies such as IR, NMR and
HRMS. Dielectric properties of the target compounds were experimentally determined by dielectric
spectroscopy in the frequency range of 20 Hz ꢀ 1 MHz. The real part of the dielectric constant, dielec-
tric loss tangent and conductivity of the samples were investigated as a function of applied frequency.
Dielectric measurements showed Ata7 has the maximum dielectric constant at 1 kHz, while Ata1 has
a negative dielectric constant value. When the result is evaluated with theoretical calculations, grain
boundaries play an effective role in the experimental observed dielectric constant. Additionally, in this
research the pyrrole-3-one derivatives (Ata1-9) were theoretically optimized and over these structures,
NMR with GIAO (gauge-independent atomic orbital), UV with TD (time dependent), frontier orbitals
(HOMO and LUMO), NLO (nonlinear optical properties) and MEP (molecular electrostatic potential) ana-
lysis were carried out. Quantum chemical computations were performed by Density Functional Theory
(DFT) using B3LYP functional and 6-311þþG (d,p) basis set. Later, the molecular docking analysis
between Ata1-9 and two different receptors such as 3RZE and 3TDA was performed using AutoDock
Vina program. Lastly, drug-likeness, physicochemical and ADME/T properties of the designed com-
pounds were computed with the help of SwissADME online tool.
KEYWORDS
Pyrrole-3-one; dielectric
spectroscopy; quantum
chemical computations;
molecular docking; ADME/T
1. Introduction
are likely to be more effective. Considering the recent results,
especially in drug design and in the prediction of reaction
mechanisms, it can be said that molecular modeling is an
essential guide for the experimental chemistry (Frisch, 2009).
Pyrrole is one of the most important simple five mem-
bered heterocyclic compounds found in the structure of a
wide variety of natural products and pharmaceutical mole-
cules, and is becoming more and more important in materi-
als science (Bhardwaj et al., 2015; Gholap, 2016). Pyrrole
derivatives have been displayed a wide spectrum of activities
such as antibacterial, antifungal, anti-inflammatory or antitu-
mor. Due to its mentioned properties, pyrrole synthesis is
important for scientists (Aksu et al., 2019; Koca & Yildirim,
2012; Qin et al., 2020; Vengatesh et al., 2020). Synthesis and
characterization studies of various pyrrol-3-one compounds
that were generated from furan-3-ones with amino nucleo-
philes such as amines, amino acids and antranilic acid deriva-
tives have been reported previously by us and our close
Computational chemistry/physics is a branch of chemistry/
physics that utilizes computer simulation to help solve chem-
istry problems with different approach quantum methods.
Since molecules are more complicated than atoms, computer
programs have been developed to study molecular structure.
With these programs, many properties of molecules or reac-
tions can be calculated theoretically. Computer-aided drug
design aims to produce a better quality drug in a short time
with low cost, with the contributions it makes at the begin-
ning of the classical drug production process. Although
molecular docking is a new subject, studies in this area
attract a lot of attention. Molecular docking studies play a
major role in determining whether or not millions of com-
pounds synthesized are effective. It is impossible to study
each of the millions of chemicals individually in vitro and
molecular docking studies play a crucial role in selecting of
most effective substances. In addition, it prepares the ground
for the modification of the molecule with the correct estima-
tion of the binding modes of the relevant molecule and cre-
colleagues (Koca et al., 2014; Sac¸macı et al., 2006; Sac¸macı
€
€
et al., 2005; Ungoren et al., 2004). Literature research reveals
that compounds close in structure to target compounds
ates a strategic infrastructure for synthesis of molecules that have been synthesized so far, but there are no detailed
_
CONTACT Irfan Koca
i_koca@yahoo.com
Faculty of Arts and Sciences, Department of Chemistry, Yozgat Bozok University, Yozgat, Turkey; Yusuf Sert
yusuf.sert@bozok.edu.tr
Sorgun Vocational School Yozgat, Yozgat Bozok University, Turkey
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2021.1914174.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
İ. ÇAPAN ET AL.
theoretical and molecular docking studies about them. In pale yellow color. The crude product was purified by recrys-
this study, a number of pyrrole-3-one derivatives were syn- tallization from proper solvents.
thesized within the scope of synthesis studies. Aromatic
amines with electron-donating and electron-withdrawing
groups were used to determine the effect of N-substituted
groups on the experimental and physical properties of pyr-
role-3-one compounds. The structures of the synthesized
compounds have been proved by molecular spectro-
scopic methods.
2.1.1. Ethyl 2-(1-(4-(dimethylamino)phenyl)-2-hydroxy-4-
(4-methoxybenzoyl)-5-(4-methoxyphenyl)-3-oxo-
2,3-dihydro-1H-pyrrol-2-yl)acetate (Ata1)
Recrystallized from methanol, Yield 0.382 g, 70%, mp 204 ꢁC.
1H-NMR (400 MHz; DMSO-d6, ppm): d 7.83–6.59 (m, 12H,
Ar–H), 7.41 (s, 1H, OH), 4.07(q, 2H, J ¼ 6.9 Hz, OCH2), 3.84,
3.70 (2 s, 6H, 2 MeO), 2.98 (d, 1H, J ¼ 16.3 Hz, CH2COOMe,
2. Experimental section
Part A of AB system), 2.87 (s,6H, N(CH3)2), 2.49 (d, 1H,
J ¼ 16.4 Hz, CH2COOMe, Part B of AB system), 1.15 (t, 3H,
J ¼ 7.1 Hz, CH3). 13C-NMR (100 MHz; DMSO-d6, ppm): d 194.5
(CO, ketone), 188.1 (CO, aroyl), 177.5 (CO, ester), 168.7 (N-
C ¼ C), 163.0, 161.0, 149.6, 132.4, 132.1, 131.2, 129.4, 124.9,
122.6, 114.0, 113.6, 112.3, 110.7 (C@C), 89.6 (N–C–OH), 60.9
(OCH2), 55.9, 55.6 (2 ꢂ OCH3), 40.3 (N(CH3)2), 14.5 (CH3). FTIR
(ATR, cmꢀ1): ꢀ 3300 (OH), 3055-2845 (aromatic and aliphatic
CH), 1723, 1650, 1623 (C ¼ O), 1607–1463 (C ¼ C, C ¼ N),
1245, 1228 (C-O-C). HRMS: m/z (M þ H) calcd. for
C31H32N2O7: 545.224; found: 545.191.
All chemicals and solvents used were obtained from com-
mercial sources and were used as received without further
purification. All reactions were viewed by TLC performed on
precoated 60 F254 plates (Merck, Whitehouse Station, NJ).
Visualization was affected with UV using Camag Thin-Layer
Chromatogram Lamp (254/366 nm). Melting points were
uncorrected and recorded on Electrothermal 9200 digital
melting point apparatus (Yozgat Bozok Unıversıty). IR spectra
were measured with Perkin Elmer Spectrum Two Model FT-IR
Spectrophotometer (Yozgat Bozok Unı versı ty) using ATR
method with a resolution of 4 cmꢀ1 at room temperature
and its scan number is 100 and its form is solid phase and
region 4000–400 cmꢀ1. The 1H-NMR spectra were recorded
on Bruker 400-MHz spectrometer (Ercıyes Unıversıty) and are
reported in ppm (d) relative to tetramethylsilane (TMS) as the
internal standard and 13C-NMR (100 MHz) is referenced to
DMSO-d6. Chemical shifts were reported in ppm (parts per
million) values. The data were presented as follows: chemical
shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet, br ¼ broad), and coupling con-
stants (J) in Hertz (Hz), integration. High-resolution mass
spectra data (HRMS) were collected in-house using a Waters
LCT Premier XE Mass Spectrometer (high-sensitivity orthog-
onal acceleration time-of-flight instrument) operating in ESI
(þ) method, also coupled to an AQUITY Ultra Performance
Liquid Chromatography system (Waters Corporation, Milford,
MA) (Gazı Unı versı ty). Electrical properties of the samples
were investigated by Agılent 4284a, an LCR meter equipped
with the software (Yozgat Bozok Unıversıty). Before electrical
measurement, open and short calibration of the LCR meter
2.1.2. Methyl 2-(1-(4-(dimethylamino)phenyl)-2-hydroxy-4-
(4-methoxybenzoyl)-5-(4-methoxyphenyl)-3-oxo-2,3-
dihydro-1H-pyrrol-2-yl)acetate (Ata2)
Recrystallized from methanol, Yield 0.402 g, 76%, mp 210 ꢁC.
1H-NMR (400 MHz; DMSO-d6, ppm): d 7.82–6.59 (m, 12H,
Ar–H), 7.42 (s, 1H, OH), 3.84, 3.71, 3.60 (3 ꢂ s, 9H, 3 ꢂ MeO),
2.99 (d, 1H, J ¼ 16.4 Hz, CH2COOMe, Part A of AB system),
2.87 (s,6H, N(CH3)2), 2.50 (d, 1H, J ¼ 16.4 Hz, CH2COOMe, Part
B of AB system). 13C-NMR (100 MHz; DMSO-d6, ppm): d 194.5
(CO, ketone), 188.2 (CO, aroyl), 177.5 (CO, ester), 169.2 (N-
C ¼ C), 163.0, 16.1, 149.6, 132.4, 132.1, 131.2, 129.4, 124.8,
122.6, 114.0, 113.6, 112.3, 110.6 (C@C), 89.6 (N–C–OH), 55.9,
55.6, 52.2 (3 x OCH3), 40.3 (N(CH3)2), 40.1 (CH2). FTIR (ATR,
cmꢀ1): ꢀ 3400 (OH), 3075–2840 (aromatic and aliphatic CH),
1735, 1728, 1695, 1646, 1620 (C ¼ O), 1600-1476 (C ¼ C,
C ¼ N), 1250 (C-O-C). HRMS: m/z (M þ H) calcd. for
C30H30N2O7: 531.209; found: 531.179.
was performed. The samples were prepared as pellets under 2.1.3. Ethyl 1-(4-(dimethylamino)phenyl)-5-hydroxy-5-(2-
the pressure of 10 tons. 16451 B test fixtures were used dur-
ing the measurement with contact dielectric measurement
mode. All the measurements were performed under the
atmosphere at room temperature. During the measurement,
0.010 A oscillator current with 1.5 d.c. was applied to
the samples.
methoxy-2-oxoethyl)-2-(4-methoxyphenyl)-4-oxo-
4,5-dihydro-1H-pyrrole-3-carboxylate (Ata3)
Recrystallized from 2-propanol, Yield 0.296 g, 63%, mp
206 ꢁC. 1H-NMR (400 MHz; DMSO-d6, ppm): d 7.29 (s, 1H,
OH), 7.14–6.54 (m, 8H, Ar–H), 3.94 (p, 2H, J ¼ 7.0 Hz, OCH2),
3.73, 3.55 (2 ꢂ s, 6H, 2 MeO), 2.91 (d, 1H, J ¼ 16.5 Hz,
CH2COOMe, Part A of AB system), 2.85 (s,6H, N(CH3)2), 2.45
(d, 1H, J ¼ 16.5 Hz, CH2COOMe, Part B of AB system), 1.01 (t,
3H, J ¼ 7.1 Hz, CH3). 13C-NMR (100 MHz; DMSO-d6, ppm): d
194.1 (CO, ketone), 178.9 (CO, ester), 168.9 (N-C¼C), 163.1
(CO, ester), 160.7, 149.7, 130.9, 129.8, 124.2, 123.0, 113.5,
112.1, 100.6 (C@C), 88.9 (N–C–OH), 58.7 (OCH2), 55.6, 52.1 (2
ꢂ OCH3), 40.3 (N(CH3)2), 39.5 (CH2), 14.6 (CH3). FTIR (ATR,
cmꢀ1): ꢀ 3390 (OH), 3078–2803 (aromatic and aliphatic CH),
2.1. General procedure for the synthesis of pyrrole-3-
one derivatives
1 mmol corresponding amines was added to furan-3-one
compounds (1.0 equiv.) in 1-propanol (30 mL). The mixture
was heated at reflux for 6 h. After that, the resulting solution
was evaporated under reduced pressure. Diethyl ether was
added to the residue to obtain the crude product that is 1738, 1714, 1647 (C ¼ O), 1608–1462 (C¼C, C ¼ N),

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
1242–1218 (C-O-C). HRMS: m/z (M þ H) calcd. for 1257–1245 (C-O-C). HRMS: m/z (M þ H) calcd. for C23H23NO7:
426.151; found: 426.148.
C25H28N2O7: 469.193; found: 469.162.
2.1.7.
Ethyl
2-(1-(4-carbamoylphenyl)-2-hydroxy-4-(4-
2.1.4.
Ethyl
2-(2-hydroxy-4-(4-methoxybenzoyl)-5-(4-
methoxybenzoyl)-5-(4-methoxyphenyl)-3-oxo-2,3-
dihydro-1H-pyrrol-2-yl)acetate (Ata7)
methoxyphenyl)-3-oxo-1-phenyl-2,3-dihydro-1H-
pyrrol-2-yl)acetate (Ata4)
Recrystallized from ethyl acetate, Yield 0.370 g, 68%, mp
Recrystallized from 2-propanol, Yield 0.314 g, 63%, mp
158 ꢁC, 1H-NMR (400 MHz; DMSO-d6, ppm): d 7.84–6.80 (m,
13H, Ar–H), 7.54 (s, 1H, OH), 4.04(q, 2H, J ¼ 6.9 Hz, OCH2),
1
206 ꢁC. H-NMR (400 MHz; DMSO-d6, ppm): d 7.96 (s, 1H, NH),
7.86–6.83 (m, 12H, Ar–H), 7.65 (s, 1H, OH), 7.41 (s, 1H, NH),
4.03 (q, 2H, OCH2), 3.84, 3.71 (2 ꢂ s, 6H, 2 MeO), 3.06 (d, 1H,
J ¼ 16.5 Hz, CH2COOMe, Part A of AB system), 2.59 (d, 1H,
J ¼ 16.5 Hz, CH2COOMe, Part B of AB system), 1.11 (t, 3H,
J ¼ 7.1 Hz, CH3). 13C-NMR (100 MHz; DMSO-d6, ppm): d 194.6
(CO, ketone), 188.4 (aroyl), 176.4 (CO, ester), 168.8 (amide),
167.4 (N-C¼C), 163.3, 161.4, 140.0, 133.1, 132.2, 132.0, 131.3,
128.7, 127.8, 114.4, 113.8, 112.4 (C@C), 89.7 (N–C–OH), 61.0
(OCH2), 55.9, 55.7 (2 ꢂ OCH3), 40.6 (CH2), 14.4 (CH3). FTIR
(ATR, cmꢀ1): ꢀ 3415 (OH), 3240-3190 (NH2) 3070–2840 (aro-
matic and aliphatic CH), 1728, 1718, 1698, 1667, 1625
(C ¼ O), 1600-1483 (C¼C, C ¼ N), 1248 (C-O-C). HRMS: m/z
(M þ H) calcd. for C30H28N2O8: 545.224; found: 545.187.
3.84, 3.70 (2 s, 6H,
2
MeO), 3.03 (d, 1H, J ¼ 16.3 Hz,
CH2COOMe, Part A of AB system), 2.54 (d, 1H, J ¼ 16.4 Hz,
CH2COOMe, Part B of AB system), 1.12 (t, 3H, J ¼ 7.1 Hz, CH3).
13C-NMR (100 MHz; DMSO-d6, ppm): d 194.5 (CO, ketone),
188.3 (CO, aroyl), 177.0 (CO, ester), 168.6 (N-C¼C), 163.2,
161.2, 137.2, 132.2, 131.3, 129.5, 128.6, 127.9, 122.2, 114.2,
113.7, 111.7 (C@C), 89.6 (N–C–OH), 61.0 (OCH2), 55.9, 55.7 (2
ꢂ OCH3), 40.5 (CH2), 14.4 (CH3). FTIR (ATR, cmꢀ1): ꢀ 3468
(OH), 3065–2837 (aromatic and aliphatic CH), 1724, 1704,
1687,1615 (C ¼ O), 1600–1475 (C¼C, C ¼ N), 1250–1234 (C-O-
C). HRMS: m/z (M þ H) calcd. for C29H27NO7: 502.182;
found: 502.179.
2.1.8. Methyl 2-(1-(4-carbamoylphenyl)-2-hydroxy-4-(4-
methoxybenzoyl)-5-(4-methoxyphenyl)-3-oxo-2,3-
2.1.5. Methyl 2-(2-hydroxy-4-(4-methoxybenzoyl)-5-(4-
methoxyphenyl)-3-oxo-1-phenyl-2,3-dihydro-1H-
pyrrol-2-yl)acetate (Ata5)
dihydro-1H-pyrrol-2-yl)acetate (Ata8)
Recrystallized from methanol, Yield 0.478 g, 90%, mp 214 ꢁC.
1H-NMR (400 MHz; DMSO-d6, ppm): d 8.00 (s, 1H, NH),
7.96–6.83 (m, 12H, Ar–H), 7.71 (s, 1H, OH), 7.46 (s, 1H, NH),
3.85, 3.71, 3.56 (3 ꢂ s, 9H, 3 MeO), 3.08 (d, 1H, J ¼ 16.4 Hz,
CH2COOMe, Part A of AB system), 2.61 (d, 1H, J ¼ 16.4 Hz,
CH2COOMe, Part B of AB system). 13C-NMR (100 MHz; DMSO-
d6, ppm): d 194.6 (CO, ketone), 188.4 (CO, aroyl), 176.4 (CO,
ester), 169.1 (CO, amide), 167.5 (N-C¼C), 163.3, 161.4, 139.9,
133.1, 132.2, 131.3, 128.7, 127.8, 122.0, 114.3, 113.8, 112.3
(C@C), 89.7 (N–C–OH), 56.0, 55.7, 52.3 (3 ꢂ OCH3), 40.3 (CH2).
FTIR (ATR, cmꢀ1): ꢀ 3400 (OH), 3334–3311 (NH2), 3075–2837
(aromatic and aliphatic CH), 1735, 1727, 1696, 1666, 1620
(C ¼ O), 1600–1477 (C¼C, C ¼ N), 1250 (C-O-C). HRMS: m/z
(M þ H) calcd. for C29H26N2O8: 531.172; found: 531.169.
Recrystallized from cꢁhloroform/cyclohexane, (1:4), Yield
0.342 g, 70%, mp 188 C (Ungoren et al., 2004). 1H-NMR
(400 MHz; DMSO-d6, ppm): d 7.85–6.80 (m, 13H, Ar–H), 7.60
(s, 1H, OH), 3.84, 3.70, 3.40 (3 ꢂ s, 9H, 3 ꢂ MeO), 3.05 (d, 1H,
J ¼ 16.5 Hz, CH2COOMe, Part A of AB system), 2.54 (d, 1H,
J ¼ 16.5 Hz, CH2COOMe, Part B of AB system). 13C-NMR
(100 MHz; DMSO-d6, ppm): d 194.6 (CO, ketone), 188.4 (CO,
aroyl), 176.9 (CO, ester), 169.1 (N-C¼C), 163.2, 161.2, 1137.1,
132.1, 132.1, 131.3, 129.5, 128.6, 127.9, 122.2, 114.2, 113.7,
111.6 (C@C), 89.6 (N–C–OH), 55.9, 55.7, 52.2 (3 ꢂ OCH3), 40.2
(CH2). FTIR (ATR, cmꢀ1): ꢀ 3360 (OH), 3074–2838 (aromatic
and aliphatic CH), 1728, 1656, 1629, 1607 (C ¼ O), 1600–1463
(C¼C, C ¼ N), 1251–1241 (C-O-C). HRMS: m/z (M þ H) calcd.
for C28H25NO7: 488.166; found: 488.160.
€
€
2.1.9.
Ethyl
1-(4-carbamoylphenyl)-5-hydroxy-5-(2-
2.1.6.
Ethyl
5-hydroxy-5-(2-methoxy-2-oxoethyl)-2-(4-
methoxy-2-oxoethyl)-2-(4-methoxyphenyl)-4-oxo-
4,5-dihydro-1H-pyrrole-3-carboxylate (Ata9)
methoxyphenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-
pyrrole-3-carboxylate (Ata6)
Recrystallized from methanol, Yield 0.356 g, 76%, mp 209 ꢁC.
1H-NMR (400 MHz; DMSO-d6, ppm): d 7.98 (s, 1H, NH),
7.76–6.88 (m, 12H, Ar–H), 7.59 (s, 1H, OH), 7.45 (s, 1H, NH),
3.97 (p, 2H, J ¼ 7.0 Hz, OCH2), 3.74, 3.39 (3 ꢂ s, 9H, 3 MeO),
2.99 (d, 1H, J ¼ 16.5 Hz, CH2COOMe, Part A of AB system),
2.2.54 (d, 1H, J ¼ 16.4 Hz, CH2COOMe, Part B of AB system),
1.04 (t, 3H, J ¼ 7.0 Hz, CH3). 13C-NMR (100 MHz; DMSO-d6,
ppm): d 194.0 (CO, ketone), 178.2 (CO, ester), 168.7 (CO,
ester), 167.4 (CO, amide), 162.9, 161.2, 139.4, 133.4, 131.2,
128.6, 128.5, 122.3, 113.8, 102.1 (C@C), 89.1 (N–C–OH), 59.1
(OCH2), 55.7, 52.2 (2 ꢂ OCH3), 39.7 (CH2), 14.6 (CH2). FTIR
(ATR, cmꢀ1): ꢀ 3442 (OH), 3324-3279 (NH2), 3050–2843 (aro-
Recrystallized from CCl4, Yield 0.294 g, 69%, mp 161 ꢁC. 1H-
NMR (400 MHz; DMSO-d6, ppm): d 7.48 (s, 1H, OH), 7.31–6.85
(m, 9H, Ar–H), 3.97 (m, 2H, OCH2), 3.73, 3.38 (2 ꢂ s, 6H, 2
MeO), 2.97 (d, 1H, J ¼ 16.5 Hz, CH2COOMe, Part A of AB sys-
tem), 2.50 (d, 1H, J ¼ 16.5 Hz, CH2COOMe, Part B of AB sys-
tem), 1.03 (t, 3H, J ¼ 7.1 Hz, CH3). 13C-NMR (100 MHz; DMSO-
d6, ppm): d 194.0 (CO, ketone), 178.6 (CO, ester), 168.8 (N-
C¼C), 163.0 (CO, ester), 161.0 136.6, 131.1, 129.4, 129.1,
128.2, 122.6, 113.6, 101.5 (C@C), 89.0 (N–C–OH), 58.9 (OCH2),
55.7, 52.1 (2 ꢂ OCH3), 39.6 (CH2), 14.6 (CH3). FTIR (ATR,
cmꢀ1): ꢀ 3350 (OH), 3069–2840 (aromatic and aliphatic CH),
1730, 1716, 1648 (C ¼ O), 1603–1440 (C¼C, C ¼ N), matic and aliphatic CH), 1708, 1683, 1643 (C ¼ O), 1607–1455

4
İ. ÇAPAN ET AL.
Table 1. Synthesis scheme and some properties of compounds Ata1-9.
(C¼C, C ¼ N), 1257, 1240 (C-O-C). HRMS: m/z (M þ H) calcd.
4. Results and discussion
for C24H24N2O8: 469.156; found: 469.161.
4.1. Synthesis and characterization
The target compounds (Ata1-9) were synthesized using
furan-3-one derivatives and various aromatic amines (Table
1). For this purpose, three different furan-3-one derivatives
were used. Furan-3-ones were prepared through Wittig reac-
tion of corresponding furan-2,3-diones and alkyl 2-(triphenyl-
k5-phosphaneylidene)acetate in benzene under reflux condi-
3. Computational details
The structures of a novel series of pyrrole-3-one derivatives
(Ata1-9) were optimized to the minimum energy states
using the Gaussian 09 W package program (Frisch, 2009),
DFT/B3LYP method and 6-311þþG(d,p) basis set. To NMR
calculations, the optimized structures were optimized again
in dimethyl sulfoxide (DMSO) solvent. The GIAO approach
€
€
tion (Sacmacl et al., 2012; Ungoren et al., 2004). The struc-
tures of all newly synthesized compounds were ascertained
1
using FTIR, H NMR, 13C NMR and mass spectral data.
1
was used for 13C and H-NMR and -NMR chemical shifts and
In this section, spectroscopic characterization will be
detailed by interpreting FTIR and NMR analyses with Ata1
molecule, one of the target compounds synthesized. The
FTIR, 1H NMR, 13C NMR and Hetcor analyses of Ata1 mol-
ecule, respectively, were interpreted and the signals of func-
tional groups and atoms in the molecule were analyzed. FTIR
spectra of all compounds were taken by ATR method. In the
FTIR spectrum of Ata1, a broad band belonging to OH
stretching vibrations starting from 3300 cmꢀ1 and aromatic
and aliphatic C-H stretching vibrations in the range of
3055–2845 cmꢀ1 were observed. Ata1 showed absorption
bands at 1723, 1650 and 1623 cmꢀ1 due to CO groups
stretching vibrations, respectively. In addition, some absorp-
tion bands of this compound were observed in the range of
1607–1463 cmꢀ1 due to C¼C stretching vibrations. Also in
the obtained computational results compared with the
experimental NMR data. The theoretical UV-Vis spectral data
of the title compounds were calculated by using TD-DFT/
B3LYP/6-311þþG(d,p) method/basis set in the DMF
(N,N–dimethylformamide) solvent. Major contributions to
electronic transitions in the next step were achieved with
the GaussSum 3.0 program (O’boyle et al., 2008). Later sec-
tion, molecular docking mechanism of Ata1-9 ligands with
two different receptor was obtained with AutoDock Vina
software program (Trott & Olson, 2010). In the last section,
drug-likeness, physicochemical and ADME/T properties of the
designed compounds were calculated with the help of
SwissADME and AdmetSAR 2.0 online tools (Yang
et.al., 2018).

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
Figure 1. 1H NMR spectra of compound Ata1.
Figure 2. 13C NMR spectra of compound Ata1.
this spectrum, there are bands belonging to C-O-C stretching was seen in diastereotopic CH2 protons adjacent to the
vibrations at 1245 and 1128 cmꢀ1
.
asymmetric carbon of pyrrole moiety. The part A of the sys-
1
Figure 1 shows the H-NMR spectrum of Ata1 compound tem consists of the peaks at ¼ 2.98 ppm, and the part B of
dissolved in DMSO-d6. Accordingly, the multiplet peaks were the system is the peaks at d ¼ 2.49 ppm. Methyl groups in
observed at d ¼ 7.83–6.59 ppm belonging to aromatic pro- the dimethylamino group were observed as singlets at
tons, and the singlet peak was seen at d ¼ 7.41 ppm due to 2.87 ppm. The triplet signal observed at 1.15 ppm corre-
proton of the OH group. The peaks were observed at sponds to three protons and belongs to methyl protons in
4.07 ppm corresponding to two protons and belonging to the ethoxy group.
methylene protons in the ethoxy group. Peaks belonging to
The 13C-NMR spectrum of Ata1 compound taken by dis-
protons in methoxy groups are observed as two singlet solving DMSO-d6 is given in Figure 2. Signals of carbonyl
peaks at d ¼ 3.84 and 3.70 ppm. In addition, the AB system groups in this molecule were observed at 194.5, 188.1 and

6
İ. ÇAPAN ET AL.
Figure 3. HETCOR spectra of compound Ata1.
peaks at 132.1–129.4 and 114.0–112.3 ppm are the aromatic
carbon signals, which are bonded with the aromatic proton
signals present at 7.83–6.59 ppm. The peak (a) at 14.5 ppm is
directly bonded to the triplet (–CH3) at 1.15 ppm. The peak
(b) at 60.9 ppm is directly bonded to the quartet (–CH2) at
4.08 ppm. The peak (c) at 55.9 ppm is directly bonded to the
singlet (–OCH3) at 3.84 ppm. The peak (d) at 55.6 ppm is dir-
ectly bonded to the singlet (–OCH3) at 3.70 ppm. The peak
(e) at 40.3 ppm is directly bonded to the singlet (–CH2) at
2.52 ppm. The peak (f) at 40.3 ppm is directly bonded to the
singlet (–N(CH3)2) at 2.87 ppm. The 1H NMR and 13C NMR
data of the Ata1 molecule describe all the carbon and
hydrogen atoms in the molecule. Spectroscopic analysis
data for the other synthesized compounds confirm the
structures of the corresponding compounds (See
Supplementary Material).
Figure 4. The variation of the real part of permittivity as
of frequency.
a function
175.5 ppm. The peaks seen between d ¼ 168.7–110.7 ppm are
the signals of aromatic, aliphatic C¼C carbon atoms. The sig-
nal of the optically active carbon atom was observed at
89.6 ppm. While a signal belonging to the carbon of
the OCH2 group was seen at 60.9 ppm, the signals of the
methoxy groups were presented at 55.9 and 55.6 ppm. The
signal belonging to the N(CH3)2 group was observed at
40.3 ppm among the solvent signals, while the signal of the
CH2 carbon atom adjacent to the carbonyl group was
located under the solvent peaks and was not observed.
HETCOR spectrum of Ata1 that is shown signals in the con-
tour plot with the chemical shifts of proton and carbons that
are directly bonded is compatible with 1H and 13C NMR
spectrums (Figure 3). The peaks at 194.5–132.4, 124.8, 122.6,
4.2. Dielectric properties of the samples
Dielectric spectroscopy is a powerful method for any materi-
als for valuable information about polarization behavior, con-
duction mechanism and dielectric relaxation (Maxwell, 1892).
Figure 4 shows the real part of the dielectric constant with
increasing angular frequency (w) plotted in a semi-log scale
in the range of 20 Hz–1 MHz for the synthesized samples.
When the graph is viewed, a strong decrease appears for the
dielectric permittivity values at the low-frequency region that
may be explained based on the Maxwell–Wagner model
€
(Kremer & Schonhals, 2002; Maxwell, 1892). In the model,
dielectric materials are thought to consist of conducting
grains separated by the resistive grain boundaries. After a
110.6 and 89.6 ppm are quaternary carbons and are not remarkable decrease, frequency-independent characteristics
result in any correlations (this is expected since quaternary were observed for all the samples. At 1 kHz frequency, the
carbons do not have protons directly attached (1JCH)). The Ata7 sample showed a maximum dielectric constant related

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
moment of pressing. We measured the dielectric properties
of samples immediately and 15 days after the pressing to
explore this suspect. The measurements showed less than
1% deviation from that of the initial measurement. Thus,
Ata1 was considered as a negative dielectric constant mater-
ial. It has a high electron density, and that may cause the
observed negative dielectric constant.
Figure 5 depicts the loss tangent graph of the samples.
The loss tangent is given by,
tan d ¼ ðe00=e0Þ
where e0 and e00 real and imaginary part of permittivity,
respectively. According to the graph, Ata1 and Ata5 showed
maximum dielectric losses at the low frequency. The dielec-
tric losses occur due to the absorption of applied energy,
which is generally utilized to rotate dipolar molecules. When
the molecular structure of an organic molecule is changed, it
produced different loss tangent curves. Thus, while the gen-
eral shape of the curves is similar, Ata1 presented different
characteristics.
Figure 5. The loss spectrum of the synthesized samples.
Figure 6 shows the conductivity-frequency graph of all
samples. All samples exhibited weak conductivity at low- and
middle-frequency regions. With the increasing frequency, an
increase in conductivity appears for all samples. Among
them, Ata3 and Ata1 stand out with their high conductivity
response in the high-frequency region. Since the dimethyla-
mino group is electron donating, it donates electrons to the
pyrrole ring. For this reason, Ata3 and Ata1 conductivity
may come to the fore at high frequencies.
4.3. H and 13C NMR chemical shift analyses
1
Figure 6. The ac conductivity spectrum of the synthesized samples.
The experimental records on the 13C- and H-NMR chemical
1
to the measured molecule’s polarization. However, in add-
ition to the contribution from molecular polarization,
molecular interactions and grain boundaries determine the
dielectric constant. The other samples showed similar dielec-
tric characteristics with dielectric constant values close to
each other except Ata1. Ata1 sample exhibited negative
dielectric values. There are many reasons for the negative
capacitance or dielectric permittivity, intentionally or unin-
tentionally doping with small size cations driven by the
applied voltage and accumulation at the interface (Wang &
Cai, 2012), static electricity of materials (Yan et al., 2013).
Alternatively, metamaterials exhibited negative dielectric per-
mittivity values (Li et al., 2009). Negative dielectric permittiv-
ity has been observed in the system containing free
electrons at the high frequency, but the same achieved at
low frequency, even desired frequency for polymer compos-
ite material (Ramasamy et al., 2014). This work proved that
all of the prepared organic structures were pure and did not
contain any cation. We also investigated the probability of
metal doping at the moment of pellet pressing procedure
from the metal compression chamber after pelleting. The
analysis results again exhibited that pressed samples did not
contain any metal doping. We tested samples’ static electri-
shifts of the compounds Ata1-9 dissolved in DMSO-d6 were
used in order to analyze magnetic spectral characterizations
of functional groups within their molecular structures. The
theoretical NMR results of these nine compounds were
obtained by using the GIAO method, B3LYP/6-311þþG(d,p)
level, IEFPCM solvent model and DMSO solvent within the
computational procedure. Some experimental and all com-
puted NMR chemical shift data for carbon and hydrogen
atoms within compounds were summarized in Tables S1
and S2.
The carbon atoms were connected by a p bond to the
electronegative oxygen atoms within carbonyl groups such
as ketone, aldehyde, ester, carboxylic acid and amide reson-
€
€
ate in the NMR region between 160 and 220 ppm (Gumus¸
et al., 2019; Koca et al., 2020). The ketone carbons (labeled
as the C5 in all compounds) within ring of 5-atoms were
found at 194.0–194.6 ppm (exp.)/197.8–206.3 ppm (calc.),
while the other ketone carbons (labeled as the C6, C10, C49)
in six compounds (Ata1, Ata2, Ata4, Ata5, Ata7 and Ata8)
resonated at 188.1–188.4 ppm as experimental and
198.2–199.4 ppm as theoretical. Similarly, the ester carbons
(labeled as the C14 in Ata1 and Ata2, the C6 and C14 in
Ata3, the C29 in Ata4, Ata5 and Ata7, the C10 and C25 in
city that can be reason the observed negative dielectric per- Ata6 and Ata9 and the C10 in Ata 8) in all compounds were
mittivity. The samples could gain static electricity at the obtained at the intervals of 163.0–178.9 ppm and

8
İ. ÇAPAN ET AL.
166.3–185.6 ppm as both experimental and theoretical, 343.05/0.2834/36% for Ata4, 354.23/0.1867/54% and 342.88/
respectively. The amide carbons (the C38, C19 and C31 0.2756/35% for Ata5, 340.66/0.0464/19% and 329.67/0.3565/
atoms, respectively) within the compounds Ata7, 8 and 9 79% for Ata6, 357.29/0.2105/52% and 345.25/0.3508/41% for
were recorded as resonance peak signals 168.5, 169.1 and Ata7, 349.42/0.3150/57% and 333.82/0.1562/24% for Ata8
167.4 ppm as experimental and 176.3, 175.9 and 175.6 ppm and 343.88/0.0767/30% and 334.35/0.3172/68% for Ata9
as computational. The carbons (labeled as the C4 in Ata1-3 with values of wavelength/oscillator strength/percentage
and 8 and the C2 in Ata4-7 and 9) within ring of 5-atoms contribution. As can be seen from charge localizations on
bonded of hydroxy groups in all nine compounds were HOMO and LUMO in Figure S26, they were mainly formed as
measured and computed at the intervals of 88.9–89.7 ppm bonding pi and anti-bonding pi molecular orbital styles of
and 97.7–91.7 ppm, respectively. As can be seen in Table S1, aromatic groups, respectively. These HOMO!LUMO elec-
ꢄ
the methyl and ethyl carbons within the compounds were tronic transitions can be interpreted as p!p character.
LUMO (lowest unoccupied molecular orbital) and HOMO
(highest occupied molecular orbital) that are known as FMOs
measured and computed as resonance signals within upfield
region below 61 and 70 ppm, respectively.
The NMR resonance frequency signals for hydroxyl pro- play an important role in determining intramolecular elec-
tons (the H43, H42, H37, H40, H39, H34, H43, H24 and H37 tronic transitions and many molecular electronic features in a
atoms, respectively) within all the compounds Ata1-9 were molecular (Fukui, 1982; Geerlings et al., 2003; Parr & Pearson,
experimentally recorded at 7.50 0.21 ppm. These values 1983; Pearson, 1986; Zhan et al., 2003). Some global reactiv-
may indicate a weak character O–HꢃꢃꢃO intramolecular hydro- ity parameters defined in Table 3 were computed depending
gen bond. The computed NMR values for these hydroxyl pro- on LUMO and HOMO energy values of the compounds Ata1-
tons were obtained at the interval 5.22–6.75 ppm. The 9. ELUMO, EHOMO and jEHOMO - ELUMOj values were obtained as
protons on the nitrogen atoms of the amide groups the ꢀ2.045, ꢀ5.556 and 3.510 eV for Ata1, ꢀ2.053, ꢀ5.553 and
compounds Ata7, 8 and 9 were assigned to NMR signals in 3.500 eV for Ata 2, ꢀ2.113, ꢀ5.575 and 3.462 eV for Ata3,
the region of 7.41–8.00 ppm, while they were computed at ꢀ2.231, ꢀ6.411 and 4.180 eV for Ata4, ꢀ2.238, ꢀ6.417 and
values between 5.26 and 6.05 ppm. The experimental and 4.179 eV for Ata5, ꢀ2.173, ꢀ6.505 and 4.332 eV for Ata6,
compute NMR chemical shifts for the methyl and ethyl pro- ꢀ2.315, ꢀ6.353 and 4.038 eV for Ata7, ꢀ2.268, ꢀ6.450 and
tons within the compounds were found in region below 4.07 4.182 eV for Ata8 and ꢀ2.278, ꢀ6.528 and 4.250 eV for Ata9.
and 4.28 ppm, respectively (Table S2).
The order within the energy band gaps jEHOMO - ELUMOj of
the compounds is Ata3<Ata2<Ata1<Ata7 <Ata5<Ata4
<Ata8<Ata9<Ata6. It is well known that the smaller the
energy band gap of molecules, the more easily molecule can
be excited, or vice versa. Moreover, according to low or large
values of energy band gap, molecule is called as chemically
soft or hard. According to this, the compound Ata 3 is softer
and easier excitable than others. Likewise, the orders
within LUMOs and HOMOs of the compounds are
Ata7<Ata9<Ata8<Ata5<Ata4<Ata6<Ata3<Ata2<Ata1
and Ata9<Ata6<Ata8<Ata5<Ata4<Ata7 <Ata3<Ata1<
Ata2, respectively. According to these results computed of
LUMO and HOMO, the highest ionization potential (I ¼
–EHOMO) and electron affinity (A ¼ –ELUMO) values are for the
compounds Ata9 and Ata7, whereas their lowest values
belong to the compounds Ata2 and Ata1, respectively. The
chemical potentials (l ¼ –(I þ A)/2) for the compounds were
computed as ꢀ3.801 eV for Ata1, ꢀ3.803 eV for Ata2,
ꢀ3.844 eV for Ata3, ꢀ4.321 eV for Ata4, ꢀ4.328 eV for Ata5,
ꢀ4.339 eV for Ata6, ꢀ4.334 eV for Ata7, ꢀ4.359 eV for Ata8
and ꢀ4.403 eV for Ata9.
4.4. UV-Vis. spectroscopic and FMOs analyses
Intramolecular charge transfer properties of the compounds
Ata1-9 were researched by the TD-DFT method at the
B3LYP/6-311þþG(d,p) computational level. The computed
absorption wavelengths and related parameters are listed in
Table 2. GaussSum 3.0.1 software (O’boyle et al., 2008) used
to obtain the percentages with major contributions of elec-
tronic transitions corresponding to the computed wave-
lengths. Th experimental UV spectra of the compounds were
recorded in n,n-dimethylformamide (DMF) solvent. They were
given in Figure S25.
The experimental UV spectra of the compounds contain
absorption bands within 264–379-nm region. The UV absorp-
tion wavelengths in mentioned this region can correspond
ꢄ
to the intra-molecular p!p electronic transition, which
could result from the presence of conjugated groups in the
compounds. The UV wavelengths were computed at the
intervals 421.60–325.62 nm for Ata1, 422.88–325.35 nm for
Ata2, 429.95–297.34 nm for Ata3, 354.31–325.32 nm for
Ata4, 354.23–325.70 nm for Ata5, 340.66–268.42 nm for
Ata6, 357.29–326.70 nm for Ata7, 349.42–325.72 nm for Ata8
4.5. Nonlinear optical properties
and 343.88–283.46 nm for Ata9. The most likely electronic The optical properties of matter can be expressed as the
excitation that can occur within a molecular system is from reaction of the electrons within it to an electric field. As it is
HOMO to LUMO because the energy difference between known, the electric field vector of the light sent on the mat-
HOMO and LUMO is less compared with other molecular ter polarizes it. The polarity of an atom or molecule is a
orbital transitions. In our study, the possible HOMO!LUMO measure of how easily nuclei and electrons can move from
electronic transitions for the compounds Ata1-9 were com- equilibrium states and it is an electrical characteristic of mat-
puted at 421.60/0.0936/97% for Ata1, 422.88/0.0975/97% for ter. The design of molecules with nonlinear optical (NLO)
Ata2, 429.95/0.0659/99% for Ata3, 354.31/0.1812/53% and properties is
a
current research topic in modern

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
9
Table 2. The computed UV spectral parameters of the compounds.
Ata1
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
421.60
370.93
337.85
333.33
325.62
Ata2
0.0936
0.0481
0.1252
0.1387
0.2041
2.9408
3.3425
3.6698
3.7196
3.8076
H ! L(97%)
H ! L þ 1(93%)
H-1 ! L(42%), H-4 ! L(31%), H-1 ! L þ 1(10%)
H-4 ! L(49%), H-1 ! L(22%), H-4 ! L þ 1(11%)
H-4 ! L þ 1(39%), H-1 ! L(31%), H-2 ! L(12%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
422.88
372.35
338.50
333.26
325.35
Ata 3
0.0975
0.0488
0.1343
0.1137
0.2021
2.9319
3.3298
3.6627
3.7203
3.8108
H ! (97%)
H ! L þ 1(93%)
H-1 ! L(46%), H-4 ! L(28%), H-1 ! L þ 1(11%)
H-4 ! L(48%), H-1 ! L(14%), H-4 ! L þ 1(12%), H-4 ! L(11%)
H-4 ! L þ 1(35%), H-1 ! L(34%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
429.95
332.73
323.60
303.74
297.34
Ata4
0.0659
0.1232
0.2732
0.1234
0.0590
2.8837
3.7263
3.8314
4.0820
4.1698
H ! (99%)
H-3 ! L(52%), H-1 ! L(41%)
H-1 ! L(57%), H-3 ! L(38%)
H-4 ! L(93%)
H ! L þ 1(84%), H ! L þ 3(12%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
354.31
343.05
338.76
329.28
325.32
Ata5
0.1812
0.2834
0.1242
0.0696
0.0309
3.4993
3.6142
3.6599
3.7653
3.8112
H ! (53%), H-3 ! L(35%)
H-3 ! L(50%), H ! (36%)
H-4 ! L(64%), H-4 ! L þ 1(18%)
H-1 ! L(51%), H ! L þ 1(15%), H-4 ! L þ 1(10%)
H-1 ! L(42%), H ! L þ 1(20%), H-4 ! L(16%), H-4 ! L þ 1(11%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
354.23
342.88
339.04
329.75
325.70
Ata6
0.1867
0.2756
0.1309
0.0699
0.0273
3.5001
3.6160
3.6569
3.7599
3.8067
H ! (54%), H-3 ! L(34%)
H-3 ! L(51%), H ! (35%)
H-4 ! L(68%), H-4 ! L þ 1(16%)
H-1 ! L(56%), H ! L þ 1(13%)
H-1 ! L(37%), H ! L þ 1(23%), H-4 ! L(14%), H-4 ! L þ 1(13%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
340.66
329.67
325.09
276.30
268.42
Ata7
0.0464
0.3565
0.1508
0.0072
0.0079
3.6395
3.7609
3.8139
4.4873
4.6191
H-4 ! L(69%), H ! (19%)
H ! (79%), H-4 ! L(14%)
H-1 ! L(87%)
H-3 ! L(76%)
H-4 ! L(89%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
357.29
345.25
341.25
333.54
326.70
Ata8
0.2105
0.3508
0.0920
0.1139
0.0085
3.4701
3.5911
3.6332
3.7172
3.7951
H ! (52%), H-3 ! L(33%)
H ! (41%), H-3 ! L(38%)
H-4 ! L(61%), H-4 ! L þ 1(15%), H-3 ! L(10%)
H-1 ! L(80%)
H ! L þ 1(26%), H-4 ! L þ 1(22%), H-2 ! L þ 1(16%), H-4 ! L(15%), H-1 ! L(11%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
349.42
343.37
333.82
329.96
325.72
Ata9
0.3150
0.1132
0.1562
0.1459
0.1232
3.5483
3.6108
3.7141
3.7575
3.8065
H ! (57%), H-3 ! L(20%)
H-3 ! L(27%), H-4 ! L(26%), H ! (14%)
H ! (24%), H ! L þ 1(16%), H-3 ! L(16%), H-4 ! L þ 1(15%), H-1 ! L(10%)
H-4 ! L(58%), H-1 ! L(20%), H-3 ! L(14%)
H-1 ! L(57%), H ! L þ 1(14%)
kcalc. (nm)
f
DE (eV)
Computed major transitions in MOs
343.88
334.35
330.05
291.73
283.46
0.0767
0.3172
0.2328
0.0267
0.1092
3.6055
3.7082
3.7565
4.2500
4.3740
H-4 ! L(58%), H ! (30%)
H ! (68%), H-4 ! L(27%)
H-1 ! L(94%)
H ! L þ 1(88%)
H-1 ! L þ 1(86%)
kcalc.: computed wavelength, f: oscillator strength, DE: excitation energy, MO: molecular orbital.
communication technology and optical data storage. Bipolar properties of the molecules arise from the delocalized p-elec-
molecules with acceptor–donor groups are the most trons moving through the molecule. Increasing conjugation
researched NLO materials. NLO materials are categorized as in the molecule leads to an increase in nonlinear optical
semiconductor layered structures. Therefore, many types of properties. When we look at the literature (Hinchliffe &
ꢁ
inorganic, organic and organometallic molecular systems are Soscun M, 1994), we notice that there is a reciprocal relation-
being studied for NLO activity. The nonlinear optical ship between the polarizability of molecules and the HOMO-

10
İ. ÇAPAN ET AL.
Table 3. HOMOs and LUMOs energy values and other related parameters computed in DMSO solvent of the title compounds.
Parameters (eV)
Ata1
Ata2
Ata3
Ata4
Ata5
Ata6
Ata7
Ata8
Ata9
ELUMO
EHOMO
–2.045
–5.556
3.510
5.556
2.045
1.755
0.285
3.801
–3.801
4.115
2.165
–2.053
–5.553
3.500
5.553
2.053
1.750
0.286
3.803
–3.803
4.132
2.173
–2.113
–5.575
3.462
5.575
2.113
1.731
0.289
3.844
–3.844
4.268
2.221
–2.231
–6.411
4.180
6.411
2.231
2.090
0.239
4.321
–4.321
4.466
2.067
–2.238
–6.417
4.179
6.417
2.238
2.089
0.239
4.328
–4.328
4.482
2.071
–2.173
–6.505
4.332
6.505
2.173
2.166
0.231
4.339
–4.339
4.347
2.004
–2.315
–6.353
4.038
6.353
2.315
2.019
0.248
4.334
–4.334
4.653
2.147
–2.268
–6.450
4.182
6.450
2.268
2.091
0.239
4.359
–4.359
4.542
2.084
–2.278
–6.528
4.250
6.528
2.278
2.125
0.235
4.403
–4.403
4.561
2.072
Energy band gap
Ionization potential
Electron affinity
Chemical hardness
Chemical softness
Electronegativity
Chemical potential
Electrophilicity index
Maximum charge transfer index
LUMO energy range. The smaller the HOMO-LUMO energy of the Ata3 compound is more easily polarized than the aro-
difference of the molecule, the easier the electron distribu-
tion can be directed and the greater the polarization.
Therefore, it will not be surprising that b is large in a mol-
ecule with a small HOMO-LUMO energy range and such a
molecule can be considered as a material with nonlinear
optical properties. However, it should be noted that the
HOMO-LUMO energy range is not a sufficient predictor for
the b value of the molecule. Another way to increase the
nonlinear optical properties of a molecule is to add donor
and acceptor groups to the molecule. If the delocalization of
the p electron cloud on the molecule increases, the polariz-
ability value of the molecules increases (Verbiest et al., 1997;
Wolff & Wortmann, 1999). Theoretical and experimental stud-
ies show that the first- and second-order hyper-polarizability
of molecules is significantly affected by the environment.
In this section as theoretically, the mean polarizabili-
ty(atotal) and its components, the anisotropy of polarizability
(Da), the first-order hyper-polarizability (b0) and its compo-
nents and the dipole moments (lx, ly, lz) of Ata1-9 mole-
cules were computed with B3LYP model and 6-311þþG(d,p)
basis set. For reference NLO material urea molecule, these
matic ring, so it is expected that the order will come out in
this way. Secondly, the order of the first-order hyper-polariz-
abilities (b0) was obtained as follows: Ata8 b0 > Ata7
b0 > Ata3 b0 > Ata9 b0 > Ata5 b0 > Ata4 b0 > Ata2
b0 > Ata6 b0 > Ata1 b0. In light of the literature information
given above, it is expected for a molecule with a small
HOMO-LUMO energy range to have higher b. But in our
molecular system, the b value of the Ata8 molecule is
greater than the others. The expected result is Ata3 accord-
ing to the literature (Verbiest et al., 1997; Wolff & Wortmann,
1999). As a consequence the b values of pyrroles containing
amide group were found to be high. However, it should be
noted that the HOMO-LUMO energy range is not a sufficient
predictor for the b value of the molecule. In other words,
increasing the ground state charge asymmetry of the mol-
ecule by attaching acceptor and donor groups to the ends
of the molecule will increase the first-order hyper-polarity
value. As the third, the order of the mean polarizability
(atotal
)
is Ata1
a
total > Ata7 total > Ata2
a
a
a
total > Ata8
total > Ata9
a
a
total > Ata4
a
total > Ata5 atotal > Ata3
total > Ata6 atotal. Finally, the order of anisotropy of polariz-
parameters (atotal
,
Da and b0) was reported as
ability (Da) was found as follows: Ata7 Da > Ata1 Da > Ata8
Da > Ata4 Da > Ata5 Da > Ata2 Da > Ata9 Da > Ata3
Da > Ata6 Da.
5.07643717 ꢂ 10ꢀ24 esu,
2.13568262 ꢂ 10ꢀ24 esu
and
7.2228469891 ꢂ 10ꢀ31 esu, respectively and the urea mol-
ecule is a pretty good reference for organic materials. For
our computations, the used equations are follows:
4.6. Molecular electrostatic potential
1
3
atotal
¼
a
xx þ ayy þ azz
(1)
ð
Þ
Molecular electrostatic potential (MEP) analysis is a useful
method that shows the charge distributions of molecular sys-
tems, including biomolecules and drugs, in three dimensions
and is often used to determine chemical reactivities, hydro-
gen bond interactions, electrophilic and nucleophilic regions
(Luque et al., 2000; Scrocco & Tomasi, 1973). MEP analysis is
very important in showing molecular size, shape and posi-
tive, negative, neutral electrostatic potential regions simul-
taneously and in investigating the relationship between
physicochemical property and molecular structure. In add-
ition, MEP is related to the molecule’s dipole moment, elec-
tronegativity, partial charges and chemical reactivity region.
It provides a visual method for understanding the relative
polarity of a molecule. The positive electrostatic potential
corresponds to the repulsion of the proton by the atomic
nucleus in regions of low electron density, while the nega-
tive electrostatic potential corresponds to the attraction of
h
i
1=2
1
2
2
2
pffiffiffi
Da ¼
ðaxxꢀayyÞ þ ðayyꢀazzÞ þ ðazzꢀaxxÞ þ 6a2xz þ 6ax2y þ 6ay2z
2
(2)
1=2
h
i
2
2
2
b0 ¼ ðbxxx þ bxyy þ bxzzÞ þ ðbyyy þ byzz þ byxxÞ þ ðbzzz þ bzxx þ bzyy
Þ
(3)
(4)
1=2
ltotal ¼ ðl2x þ ly2 þ l2z Þ
The obtained NLO values of Ata1-9 molecules were pre-
sented in Table S3; additionally, their comparison with urea
molecule was given in Table S4. From Table S3 and S4, we
can say that the order of the dipole moment magnitudes is
total > Ata2 total > Ata1
total > Ata4 ltotal > Ata8
total > Ata7 ltotal. The groups donating electrons to the pyr-
role ring increase the electron density in the ring, which
increases the dipole moment in the ring. In the order of
as follows: Ata3
l
l
l
l
total > Ata6
total > Ata9
l
l
total > Ata5
l
Ata3 > Ata2 > Ata1, the ester group in the fourth position the proton by the concentrated electron density of the

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
11
Figure 7. The MEP analysis of the Ata1-9 compounds at B3LYP/6-311þþG(d,p) level.
molecule. The different electrostatic potential values on the focused on the O9, O32 and O11 atoms, which are the most
MEP surface are represented by different colors: Red, blue reactive parts of the molecules. On the other hand, the posi-
and green are the most negative, most positive and zero tive regions are focused over hydrogen atoms (with normal
blue distribution) for Ata1, Ata2, Ata3, Ata4, Ata5 and Ata6
molecules; additionally for Ata7, Ata8 and Ata9 molecules,
dark blue points (positive regions) were focused on H67-H68,
H32-H33 and H54-H55 molecules, respectively. These points
indicate a possible nucleophilic attack site. As a result, we
can say that the positive and negative regions provide infor-
mation about the region where the compound can have
intermolecular interactions.
electrostatic potential regions, respectively. Identifying these
regions means determining intramolecular and intermolecu-
lar interaction regions. Increases in potential are identified in
the order of red < orange < yellow < green < blue. The value
of the electrostatic potential is largely responsible for the
binding of a substrate to the receptor binding sites because
the receptor and the corresponding ligands recognize each
other at the molecular surfaces.
In this section, the MEP surfaces of Ata1-9 were calcu-
lated by DFT-B3LYP/6-311 þ G(d,p) level over the optimized
4.7. Molecular docking study
ꢄ
structures by using chk files and their MEP surfaces and
potential scales are shown in Figure 7. The potential color
scales of Ata1-9 molecules were calculated in the range
between ꢀ6.596e-2 and 6.596e-2 for Ata1; in the range
between ꢀ6.486e-2 and 6.486e-2 for Ata2, in the
range between ꢀ8.815e-2 and 8.815e-2 for Ata3, in
the range between ꢀ6.327e-2 and 6.327e-2 for Ata4, in the
range between ꢀ6.306e-2 and 6.306 for Ata5, in the range
between ꢀ6.328e-2 and 6.328e-2 for Ata6, in the range
between ꢀ6.045e-2 and 6.045e-2 for Ata7, in the
range between ꢀ5.814e-2 and 5.814e-2 for Ata8 and in the
range between ꢀ5.986e-2 and 5.986e-2 for Ata9 molecule.
For Ata1, Ata2 and Ata3 molecules, it can be clearly seen
that the negative region is mainly localized over the O13,
O8, O15 atoms; for Ata4, Ata5 and Ata6 molecules, it can
be clearly seen that the negative region is mainly localized
over the O11 and O9 atom; for Ata7 molecule, it can be
clearly seen that the negative region is mainly focused on
the O11, O9 and O39 atom; for Ata8 molecule, it can be
Molecular docking plays a leading role in drug design, and
many docking programs are used for these theoretical stud-
ies. The docking process is a program that examines the
interactions and movements between ligand and protein
during binding. For the docking, ligands and proteins with a
known three-dimensional structure are needed. In this part,
the molecular docking studies of Ata1-9 ligands were inves-
tigated by the AutoDock Vina program (Trott & Olson, 2010).
Primarily, the receptors or targets were determined with bio-
logical activity program-PASS website (Filimonov et al., 2014;
Filimonov et. al., 2014), and Pass analysis results for Pa > Pi
of the title ligands are given Table 4. According to PASS
online results, our title molecules have two important activity
as CYP2H substrate (PDB: 3TDA) and antieczematic (PDB:
3RZE) activity. PDB structures for CYP2H substrate and anti-
eczematic were downloaded from RCSB (Protein Data Bank)
(Berman et. al., 2003) according to the determined activities.
Later, on two proteins heteroatoms involving the ligands,
clearly seen that the negative region is mainly focused on ions and water molecules were removed and polar hydrogen
the O6, O50, O11 and O20 atoms; and for Ata9 molecule, it atoms were added. The optimized geometries of Ata1-9 mol-
can be clearly seen that the negative region is mainly ecules were used for PDB format as ligand. In this step, all

12
İ. ÇAPAN ET AL.
Table 4. Pass analysis results for Pa > Pi of the title compounds.
Ata1
Ata2
Ata3
Activity
Pa
Pi
Activity
Pa
Pi
Activity
Pa
Pi
0.800 0.017 CYP2H substrate
0.782 0.022 Antieczematic
0.483 0.018 Antibacterial
0.418 0.028 Hþ-exporting ATPase inhibitor
0.413 0.037 P-glycoprotein substrate
0.431 0.062 Antiviral (Rhinovirus)
Ata4
0.835 0.012 CYP2H substrate
0.690 0.049 Antieczematic
0.496 0.017 Antibacterial
0.422 0.034 P-glycoprotein substrate
0.448 0.077 HIF1A expression inhibitor
0.406 0.045 Antimetastatic
Ata5
0.877 0.008 CYP2H substrate
0.754 0.029 Antieczematic
0.554 0.024 Analeptic
0.550 0.049 CYP3A2 substrate
0.485 0.018 Antibacterial
0.520 0.055 CYP3A substrate
Ata6
Pa
Pi
Activity
Pa
Pi
Activity
Pa
Pi
Activity
0.837 0.012 Antieczematic
0.666 0.045 CYP2H substrate
0.558 0.071 Phosphatase inhibitor
0.777 0.024 Antieczematic
0.731 0.029 CYP2H substrate
0.542 0.045 HIF1A expression inhibitor
0.827 0.013 CYP2H substrate
0.817 0.015 Antieczematic
0.590 0.020 Analeptic
0.529 0.057 Acetylcholine neuromuscular blocking agent 0.560 0.069 Phosphatase inhibitor
0.533 0.019 Histamine release stimulant
0.550 0.049 CYP3A2 substrate
0.489 0.034 Histamine release stimulant
0.477 0.034 Antiviral (Rhinovirus)
Ata7
0.500 0.036 Antinociceptive
0.589 0.130 Gluconate 2-dehydrogenase (acceptor) inhibitor 0.553 0.073 Phosphatase inhibitor
Ata8 Ata9
Activity
Pa
Pi
Activity
Pa
Pi
Activity
Pa
Pi
0.783 0.022 Antieczematic
0.581 0.077 CYP2H substrate
0.433 0.024 Antibacterial
0.693 0.048 Antieczematic
0.650 0.050 CYP2H substrate
0.449 0.022 Antibacterial
0.770 0.022 CYP2H substrate
0.767 0.026 Antieczematic
0.593 0.079 Nootropic
0.507 0.104 Phosphatase inhibitor
0.423 0.040 Antimetastatic
0.434 0.060 Antiviral (Rhinovirus)
0.504 0.106 Phosphatase inhibitor
0.433 0.037 Antimetastatic
0.464 0.070 HIF1A expression inhibitor
0.510 0.030 Analeptic
0.521 0.094 Phosphatase inhibitor
0.430 0.024 Antibacterial
preparations for both ligands and targets were made by with binding energy, gas constant (1.9872036 ꢂ 10ꢀ3 kcal/mol)
Discover Studio Visualizer 4.0 (DSV 4.0) software (http://www.
3dsbiovia.com/). Active residues of target proteins were
determined as follows: For 3RZE active residues are
ARG1145, ASN1144, PRO1143, THR1142, ARG1080, ARG1076,
ASN1055, ASN1053, ARG1014, GLU1011, TYR458, HIS450,
PHE435, PHE432, TYR431, TRP428, ASN198, LYS191, LYS179,
ASP178, TRP158, ILE115, THR112, SER111, TYR108 and
ASP107; for 3TDA (A chain) active residues are PHE483,
GLY445, LEU444, CYS443, ARG441, SER437, PHE436, PRO435,
ASP422, LEU399, HIS376, VAL374, GLN364, THR313, THR309,
ALA305, SER304, LEU302, ASP301, ALA300, GLU287, GLU273,
ASP270, HIS258, HIS246, GLN244, GLU216, ARG132, TRP128,
PHE120 and ARG101. Therefore, the grid parameters were
also determined considering these active residues as follows:
112 ꢂ 92 ꢂ 102 Å3 x,y,z dimensions, 0.375 Å space and 15.751,
and room temperature (298.15 K), respectively).
According to the affinity binding energies, the best bind-
ings were determined between Ata7 and Ata8 compounds
and antieczematic/3RZE protein with same ꢀ7.4 kcal/mol
energy, 3.76496 lM inhibition constant and six hydrogen
bonding for Ata7 and four hydrogen bonding for Ata8 as
shown in Table 5. Additionally, molecular docking results as
3D (a) and 2D (b) forms are shown in Figure 8 (Ata7-3RZE
interactions).
Finally, the respective docking parameters such as binding
energy value, number of hydrogen bonds and inhibition con-
stants involved in bonding against receptor CYP2H sub-
strate/3TDA (A chain) are reported in Table 6. In silico
molecular docking from Table 6, results reveal that Ata1
molecule under investigation exhibit excellent binding
energy ꢀ8.1 kcal/mol containing one hydrogen bond with
amino acid residue THR54 of CYP2H substrate/3TDA (A chain)
and its inhibition constant is 1.1552 lM. On the other hand,
the most hydrogen bonds (the number of hydrogen bond-
ings) were seen in the interaction between Ata9 ligand and
CYP2H substrate/3TDA (A chain) receptor and its inhibition
constant is 12.2706 lM. Additionally, molecular docking
results as 3D (a) and 2D (b) shapes are shown in Figure 9
(Ata1-3TDA (A chain) interactions).
33.517,
26.546
x,y,z
centers
for
Ata1-9 þ 3RZE;
126 ꢂ 114 ꢂ 116 Å3 x,y,z dimensions, 0.375 Å space and 5.282,
23.83, 3.291 x,y,z centers for Ata1-9 þ 3TDA (A chain). As to
be in molecular docking studies in the literature (de Lima
et al., 2017; Ea de Lima et al., 2016; Kuca et al., 2018), via
help of AutoDock Vina program, the molecular docking
result outputs computed for 10 different conformational
poses of the ligand compounds Ata 1-9 docked into the tar-
get receptor macromolecules (3RZE and 3TDA) are listed in
Tables 5 and 6, respectively. For molecular docking analysis,
the starting ground state molecular conformational forms of
the ligand compounds were obtained by using DFT-B3LYP/6-
311þþG(d,p) computational level of theoretical model. The
comments on the interaction results were performed for the
best conformational poses with the lowest interacting ener-
gies obtained of the ligand compounds docked into the tar-
get macromolecules 3RZE and 3TDA. Additionally, in these
tables inhibition constants and the number of hydrogen
bonding were given in the bottom lines. Here, the inhibition
constants for docking interactions were computed by
Although we cannot say the statement precisely because
we do not have experimental data, these results concluded
that the compounds are potent inhibitor for antieczematic/
3RZE and CYP2H substrate/3TDA (A chain).
4.8. Drug-likeness and physicochemical properties
Drug-likeness and physicochemical properties are very
important in drug design. The pharmacokinetic parameters
were first put forward in theory in 1997 when Lipinski et al.
Ki ¼ exp(DG/RT) equation (DG, R and T are the docking published five rules based on the investigation of the

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
13
Table 5. AutoDock Vina results of the binding affinity and RMSD values of different poses in Antieczematic/3RZE protein inhibitor of the title compounds.
Ata1-3RZE
rmsd l.b.
Ata2-3RZE
rmsd l.b.
Ata3-3RZE
rmsd l.b.
Mode
affinity (kcal/mol)
rmsd u.b.
affinity (kcal/mol)
rmsd u.b.
affinity (kcal/mol)
rmsd u.b.
1
2
3
4
5
6
7
8
–6.9
–6.4
–6.4
–6.1
–6.0
–5.8
–5.8
–5.7
–5.7
–5.7
0.000
36.374
18.169
36.589
16.841
19.423
20.537
18.705
19.457
12.575
0.000
39.990
21.565
40.193
19.948
22.228
23.928
22.482
21.976
16.901
–6.9
–6.7
–6.2
–6.2
–6.1
–6.0
–6.0
–6.0
–6.0
–5.9
0.000
16.807
14.929
2.016
0.000
21.233
17.776
2.756
–6.4
–6.3
–6.2
–5.7
–5.5
–5.3
–5.3
–5.2
–5.2
–5.2
0.000
1.858
2.084
18.424
46.390
22.672
20.912
3.105
42.483
43.627
0.000
6.353
6.128
22.204
49.031
26.335
23.580
7.210
43.863
46.792
3.165
5.061
19.245
26.785
46.768
25.958
15.809
22.188
32.037
49.553
31.127
20.009
9
10
Inhibition constant:8.75514 lM
Number of hydrogen bonding: 4
Inhibition constant:5.27669 lM
Number of hydrogen bonding: 2
Ata5-3RZE
Inhibition constant:20.3594 lM
Number of hydrogen bonding: 5
Ata6-3RZE
Ata4-3RZE
Mode
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
1
2
3
4
5
6
7
8
9
–7.2
–6.5
–6.3
–6.3
–6.0
–6.0
–5.9
–5.7
–5.7
–5.7
0.000
2.330
2.357
0.000
4.982
6.778
–7.2
–6.4
–6.3
–6.2
–6.1
–6.1
–6.0
–5.9
–5.9
–5.9
0.000
2.507
36.319
16.637
2.425
36.945
33.829
18.059
3.117
0.000
6.012
39.356
20.868
8.263
39.957
37.092
20.695
8.597
–6.1
–5.9
–5.8
–5.8
–5.7
–5.7
–5.6
–5.5
–5.5
–5.4
0.000
40.909
18.080
18.260
40.747
41.058
18.511
2.726
0.000
43.869
20.476
21.015
43.888
44.207
20.999
3.690
2.107
6.055
14.105
15.588
17.721
39.910
19.769
40.409
17.368
20.016
20.237
43.071
21.879
43.426
18.571
29.984
20.723
34.841
10
15.342
20.033
Inhibition constant:5.27669 lM
Number of hydrogen bonding: 2
Inhibition constant:5.27669 lM
Number of hydrogen bonding: 2
Ata8-3RZE
Inhibition constant:33.7806 lM
Number of hydrogen bonding: 0
Ata9-3RZE
Ata7-3RZE
Mode
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
1
2
3
4
5
6
7
8
9
–7.4
–6.6
–6.6
–6.6
–6.5
–6.4
–6.4
–6.3
–6.3
–6.0
0.000
15.301
4.830
35.333
2.710
36.606
36.373
16.188
16.800
27.869
0.000
17.588
8.366
39.715
7.471
40.887
40.944
19.004
22.022
31.770
–7.4
–7.2
–6.8
–6.6
–6.5
–6.3
–6.2
–6.2
–6.1
–6.1
0.000
2.225
1.880
12.882
36.330
3.004
26.600
2.825
0.000
6.816
5.546
17.421
40.259
7.008
32.019
7.504
–6.6
–6.5
–5.8
–5.7
–5.7
–5.6
–5.5
–5.5
–5.5
–5.5
0.000
2.293
0.000
5.341
17.479
37.023
28.736
25.759
42.950
17.664
22.902
20.032
20.873
39.869
31.893
29.448
46.022
21.097
26.062
22.936
46.690
2.749
49.446
7.242
10
Inhibition constant:3.76496 lM
Number of hydrogen bonding: 6
Inhibition constant:3.76496 lM
Number of hydrogen bonding: 4
Inhibition constant:14.5266 lM
Number of hydrogen bonding: 3
physicochemical properties of 2245 drugs in the World Drug reference range) are in agreement with the five rule of
Index (WDI) database approved for Phase II clinical studies Lipinski. Cytochromes P450 (CYP) are enzymes that play an
important role in the breakdown of drugs to be excreted
from the body (Hollenberg, 2002). Their inhibition causes a
delay in the excretion of drugs from the body (Kirchmair
et al., 2015). The five main enzymes of this system (CYP1A2,
(Lipinski et al., 1997). If we summarize these rules as follows:
ꢅ
ꢅ
ꢅ
MlogP ꢆ 5;
Molecular weight (MW) ꢆ 500 g/mol;
Number of H-bond acceptor (HBA) ꢆ 10 and number of CYP2C19, CYP2C9, CYP2D6 and CYP3A4) play an important
H-bond donors (HBD) ꢆ 5;
role in rendering harmless therapeutic molecules. According
to the conducted study as in silico, the potentials of Ata1-9
molecules to affect these enzyme activities were presented
in Table S5. From these results, we can say that the synthe-
sized compounds have no potential to affect the activities of
these enzymes. From the Table S5 aqueous solubility (Ali log
ꢅ
ꢅ
Number of rotatable bonds (nRot) ꢆ 10;
Topological Polar Surface Area (TPSA)< 140 Å2.
In this section, the pharmacokinetic parameters of Ata1-9
were obtained and tabulated as in Table S5 in accordance
with the criteria defined above. These parameters were S) values were obtained as ꢆ 0. As a result, we can say that
obtained with the help of SwissADME web page (http:// target molecules (Ata1-9) possess a good pharmacoki-
netic profile.
www.swissadme.ch/). In addition, bioavailability radars and
predicted Boiled Egg plot were created by taking these rules
into consideration and are shown in Figures 10 and 11,
respectively. According to the obtained results, the synthe-
sized Ata1-9 compounds meet these criteria in other words
as can be seen the theoretical ADME results of the synthe-
4.9. Prediction of ADMET and related properties
In this section, AdmetSAR analysis of the Ata1-9 compounds
was performed with the help of AdmetSAR 2.0 web page
sized compounds (except Ata1, Ata2, Ata4, Ata5, Ata7 and (http://lmmd.ecust.edu.cn/admetsar2/) and the some import-
Ata8 molecular weights in these compounds fall outside the ant selected results were given as in Table S6. It is

14
İ. ÇAPAN ET AL.
Table 6. AutoDock Vina results of the binding affinity and RMSD values of different poses in CYP2H substrate/3TDA (A chain) protein inhibitor of the
title compounds.
Ata1-3TDA (A chain)
Ata2-3TDA (A chain)
Ata3-3TDA (A chain)
Mode
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
1
2
3
4
5
6
7
8
–8.1
–8.0
–7.7
–7.6
–7.4
–7.1
–7.0
–6.9
–6.9
–6.7
0.000
1.347
4.373
3.459
3.809
3.517
19.541
22.606
5.150
18.914
0.000
2.371
9.195
6.810
8.264
–7.7
–7.5
–7.1
–7.0
–6.8
–6.6
–6.3
–6.2
–5.9
–5.8
0.000
3.304
3.313
20.624
3.170
5.461
39.813
28.306
29.196
31.175
0.000
8.415
8.941
23.362
6.308
9.891
42.822
33.567
33.597
35.819
–6.7
–6.5
–6.5
–6.5
–6.5
–6.5
–6.3
–6.3
–6.0
–5.9
0.000
3.050
4.136
2.598
1.386
4.966
4.222
4.092
3.534
1.877
0.000
8.060
8.345
3.660
5.894
8.816
7.692
8.213
5.805
6.104
8.660
23.113
26.256
10.651
22.159
9
10
Inhibition constant:1.1552 lM
Number of hydrogen bonding: 1
Inhibition constant:2.26913 lM
Number of hydrogen bonding: 2
Ata5-3TDA (A chain)
Inhibition constant:12.2706 lM
Number of hydrogen bonding: 2
Ata6-3TDA (A chain)
Ata4-3TDA (A chain)
Mode
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
1
2
3
4
5
6
7
8
9
–7.1
–7.1
–7.0
–6.8
–6.8
–6.3
–6.0
–6.0
–5.9
–5.8
0.000
2.755
2.984
5.215
3.832
28.437
9.291
17.990
28.043
15.805
0.000
6.509
5.340
8.285
7.669
32.518
14.951
21.973
32.615
20.044
–7.1
–7.1
–7.0
–6.7
–6.6
–6.3
–6.3
–6.2
–6.2
–6.1
0.000
2.758
2.808
0.000
6.103
5.753
–6.8
–6.6
–6.4
–6.1
–6.0
–6.0
–5.9
–5.8
–5.7
–5.7
0.000
2.808
2.445
16.483
5.269
38.348
5.381
16.755
15.323
33.114
0.000
3.837
5.176
18.957
8.062
41.362
8.070
19.384
19.043
36.650
5.507
8.549
15.911
16.734
7.896
16.398
22.245
17.133
18.671
19.810
11.021
18.660
24.871
18.763
10
Inhibition constant:6.24687 lM
Number of hydrogen bonding: 1
Inhibition constant:6.24687 lM
Number of hydrogen bonding: 1
Ata8-3TDA (A chain)
Inhibition constant:10.3649 lM
Number of hydrogen bonding: 0
Ata9-3TDA (A chain)
Ata7-3TDA (A chain)
Mode
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
affinity (kcal/mol)
rmsd l.b.
rmsd u.b.
1
2
3
4
5
6
7
8
9
–7.3
–7.2
–7.0
–6.8
–6.3
–6.2
–6.2
–6.2
–6.1
–6.0
0.000
3.203
3.560
16.618
34.486
22.972
24.043
16.449
17.025
35.168
0.000
6.140
7.110
23.224
37.752
25.230
26.167
22.864
22.062
39.533
–7.3
–7.2
–7.1
–7.0
–6.9
–6.6
–6.3
–6.2
–6.2
–6.2
0.000
2.698
3.446
21.230
3.103
0.000
9.024
7.937
25.207
7.704
11.298
31.900
45.105
8.699
–6.7
–6.3
–6.1
–5.9
–5.9
–5.8
–5.7
–5.7
–5.4
–5.3
0.000
33.795
26.430
33.746
34.774
25.447
29.512
1.869
0.000
35.791
29.614
38.243
38.341
28.753
32.563
2.332
6.586
26.523
41.976
4.697
30.923
8.329
34.608
11.281
10
35.962
39.692
Inhibition constant:4.45719 lM
Number of hydrogen bonding: 3
Inhibition constant:4.45719 lM
Number of hydrogen bonding: 2
Inhibition constant:12.2706 lM
Number of hydrogen bonding: 6
Figure 8. (a) 3D and (b) 2D molecular docking results of the Ata-7 for PDB: 3RZE.
determined that all the compounds indicate negative oral administration, and all compounds are non-carcinogenic.
response for blood–brain barrier (BBB) criteria, but Ata5 mol- From the Table S6, it is determined that Ata1, Ata2, Ata3,
ecule indicates positive response. This output shows us that Ata4, Ata5 and Ata6 compounds indicate inhibitor effect for
the Ata5 molecule can pass the BBB. All the compounds P-glycoprotein, but Ata7, Ata8 and Ata9 molecules indicate
indicate III category acute oral toxicity; therefore, it can be non-inhibitor effect. In line with the information obtained
predicted that these molecules are relatively harmless for from the literature (Amin, 2013), we can say that the

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
15
Figure 9. (a) 3D and (b) 2D molecular docking results of the Ata-1 for PDB: 3TDA (A chain).
Figure 10. The bioavailability radars for the analyzed compounds.
inhibition of P-glycoprotein can prevent the absorption, property for human ether-a-go-go-related gene (hERG).
permeability and retention of the compounds or drugs. On Finally, human intestinal absorption values were obtained
the other hand, all compounds indicate weak inhibitor positive for all compounds.

16
İ. ÇAPAN ET AL.
Figure 11. Boiled-Egg model of Ata1-9 compounds.
5. Conclusions
Author contributions
All authors have made essential contributions to this study. Establishing
In summary, nine novel pyrrol-3-one derivatives were suc-
cessfully synthesized, and their structures were characterized
_
_
_
the outline of the study: IK, YS; synthesis and characterization: IC¸, MG, IK;
dielectric spectroscopy experiments: HC¸; theoretical and molecular dock-
1
by FT-IR, H NMR, 13C NMR and HRMS techniques. The pro-
_
ing studies: YS, HG; manuscript drafting; IK, YS, HC¸. All authors read and
duced organic samples’ experimental dielectric properties
showed that Ata1 and Ata3 have different dielectric proper-
ties. It was observed that Ata1 has negative dielectric values
at a relatively high-frequency range. This observation may be
related to electron-donating and electron-accepting groups
in the molecule structure. To support experimental spectro-
scopic results (NMR and UV), the theoretical calculations
were carried out with the DFT-B3LYP/6-311þþG(d,p) model-
method/level for Ata1-9 compounds. Over the optimized
structures within the DMF solvent HOMO and LUMO distribu-
tions were obtained the theoretical UV results were sup-
ported and the theoretical results were found to be
consistent with the experimental data. With the help of MEP
analysis, the electrophilic and nucleophilic attack points on
approved the final manuscript.
Funding
The authors would like to thank Science and Technology Practice &
Research Centre of Bozok University for financial support (Project No:
6602c-SMYO/20-357).
ORCID
_
Irfan C¸apan
http://orcid.org/0000-0002-9555-1555
http://orcid.org/0000-0001-9262-7940
http://orcid.org/0000-0003-2258-859X
http://orcid.org/0000-0002-8373-6990
http://orcid.org/0000-0001-8836-8667
http://orcid.org/0000-0001-7873-159X
€
€
Mehmet Gumu¸s
Halil Gokce
Hidayet C¸etin
€
the Ata1-9 molecules were determined and analyzed. From Yusuf Sert
the NLO results, we can say that as a consequence the first-
_
Irfan Koca
order hyper-polarizability values of pyrroles containing amide
group were found to be high. Later, antieczematic and
References
CYP2H substrate properties of the Ata1-9 molecule were
researched with the help of online PASS analysis and
Autodock Vina program. These results concluded that the
compounds are potent inhibitor for antieczematic/3RZE and
CYP2H substrate/3TDA (A chain). When the MEP diagrams of
the studied ligands were examined, it was observed that the
electron-rich regions were on oxygen atoms. In molecular
docking studies, ligands formed hydrogen bonds by bonding
to proteins from these regions, which were also observed in
MEP diagrams. Finally, from drug-Likeness, physicochemical
and ADME/T results show that Ata1-9 compounds were
found to have good pharmacokinetic profile.
€
€
Aksu, K., Ozgeris¸, B., & Tumer, F. (2019). Synthesis and -characterization
of new N-substituted 2-aminopyrrole derivatives. Organic
Communications, 12, 38–42.
Amin, M. L. (2013). P-glycoprotein inhibition for optimal drug delivery.
Drug Target Insights, 7, DTI. S12519. https://doi.org/10.4137/DTI.
S12519
Berman, H. M., Henrick, K., Nakamura, H. (2003). Announcing the world-
wide Protein Data Bank, Nature Structural Biology,10(12), 980.
Bhardwaj, V., Gumber, D., Abbot, V., Dhiman, S., & Sharma, P. (2015).
Pyrrole: A resourceful small molecule in key medicinal hetero-aro-
matics. RSC Advances, 5(20), 15233–15266. https://doi.org/10.1039/
C4RA15710A
ꢂ
Dassault Systemes BIOVIA, Discovery Studio Modeling Environment,
ꢂ
Release 2017, San Diego: Dassault Systemes, 2016. http://www.3dsbio-
via.com
Daina, A., Michielin, O., Zoete, V. (2017). SwissADME: A free web tool to
evaluate pharmacokinetics, drug-likeness and medicinal chemistry
friendliness of small molecules. Scientific Reports, 7, 42717.
Disclosure statement
All authors declare that they have no conflict of interests.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
17
de Lima, W. E. A., Francisco, A., da Cunha, E. F., Radic, Z., Taylor, P., Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997).
Franc¸a, T. C., & Ramalho, T. C. (2017). Mechanistic studies of new
oximes reactivators of human butyryl cholinesterase inhibited by
cyclosarin and sarin. Journal of Biomolecular Structure & Dynamics,
35(6), 1272–1282. https://doi.org/10.1080/07391102.2016.1178173
Ea de Lima, W., F Pereira, A., A de Castro, A., Ff da Cunha, E., & C
Ramalho, T. (2016). Flexibility in the molecular design of acetylcholin-
esterase reactivators: Probing representative conformations by che-
mometric techniques and docking/QM calculations. Letters in Drug
Design & Discovery, 13, 360–371.
Experimental and computational approaches to estimate solubility
and permeability in drug discovery and development settings.
Advanced Drug Delivery Reviews, 23(1–3), 3–25. https://doi.org/10.
1016/S0169-409X(96)00423-1
ꢁ
Luque, F. J., Lopez, J. M.,
& Orozco, M. (2000). Perspective on
“Electrostatic interactions of a solute with a continuum. A direct util-
ization of ab initio molecular potentials for the prevision of solvent
effects. Theoretical Chemistry Accounts, 103(3–4), 343–345. https://doi.
org/10.1007/s002149900013
Filimonov, D., Lagunin, A., Gloriozova, T., Rudik, A., Druzhilovskii, D., Maxwell, J. C. (1892). A Treatise on Electricity and Magnetism. Clarendon.
Pogodin, P., & Poroikov, V. (2014). Prediction of the biological activity O’boyle, N. M., Tenderholt, A. L., & Langner, K. M. (2008). Cclib: A library
spectra of organic compounds using the PASS online web resource.
Chemistry of Heterocyclic Compounds, 50(3), 444–457. https://doi.org/
10.1007/s10593-014-1496-1
for package-independent computational chemistry algorithms. Journal
of Computational Chemistry, 29(5), 839–845. https://doi.org/10.1002/
jcc.20823
Filimonov, D. A., Lagunin, A. A., Gloriozova, T. A., Rudik, A. V., Parr, R. G., & Pearson, R. G. (1983). Absolute hardness: Companion par-
Druzhilovskii, D. S., Pogodin, P. V., Poroikov, V. V. (2014). Prediction of
the biological activity spectra of organic compounds using the PASS
online web resource. Chemistry of Heterocyclic Compounds,50(3),
444–457.
Frisch, M. J. (2009). Gaussian 09, Revision D. 01. Gaussian Inc.
Fukui, K. (1982). Role of frontier orbitals in chemical reactions. Science
(New York, N.Y.), 218(4574), 747–754. https://doi.org/10.1126/science.
218.4574.747
ameter to absolute electronegativity. Journal of the American
Chemical Society, 105(26), 7512–7516. https://doi.org/10.1021/
ja00364a005
Pearson, R. G. (1986). Absolute electronegativity and hardness correlated
with molecular orbital theory. Proceedings of the National Academy of
Sciences of the United States of America, 83(22), 8440–8441. https://
doi.org/10.1073/pnas.83.22.8440
Qin, M., Tian, Y., Han, X., Cao, Q., Zheng, S., Liu, C., Wu, X., Liu, L., Meng,
Y., Wang, X., Zhang, H., & Hou, Y. (2020). Structural modifications of
indolinones bearing a pyrrole moiety and discovery of a multi-kinase
Geerlings, P., De Proft, F., & Langenaeker, W. (2003). Conceptual density
functional theory. Chemical Reviews, 103(5), 1793–1874. https://doi.
org/10.1021/cr990029p
inhibitor with potent antitumor activity. Bioorganic
Chemistry, 28(11), 115486. https://doi.org/10.1016/j.bmc.2020.115486
Rafailovich, M. H. (2014).
& Medicinal
Gholap, S. S. (2016). Pyrrole: An emerging scaffold for construction of
valuable therapeutic agents. European Journal of Medicinal Chemistry, Ramasamy, R. P., Yang, K.,
&
110, 13–31. https://doi.org/10.1016/j.ejmech.2015.12.017
Polypropylene–graphene–a nanocomposite that can be converted
into a meta-material at desired frequencies. RSC Advances, 4(85),
44888–44895. https://doi.org/10.1039/C4RA05814C
_
€
€
€
Gumus¸, M., Sert, Y., Yalkı n, A., Gokce, H., & Koca, I. (2019). Synthesis,
experimental and theoretical characterization of novel pyrimidine-5-
carboxamides. ChemistrySelect, 4(16), 4695–4708. https://doi.org/10. Sac¸macı, M., Ungoren, S¸., & Akc¸amur, Y. (2006). Preparation and charac-
€
€
1002/slct.201900780
terization of novel pyrrol-3-ones attached to alpha/beta-amino acids,
esters and amides. Amino Acids, 31(4), 397–401. https://doi.org/10.
1007/s00726-006-0340-z
ꢁ
Hinchliffe, A., & Soscun M, H. J. (1994). Ab initio studies of the dipole
polarizabilities of conjugated molecules: Part 2. Journal of Molecular
Structure: Theochem, 304(2), 109–120. https://doi.org/10.1016/S0166- Sac¸macı, M., Ungoren, S¸. H., Akc¸amur, Y., Arıcı, C., & Ulku, D. (2005). 2, 4,
€
€
€
€
1280(96)80003-0
5-Substituted furan-3 (2H)-ones: Synthesis, reactions with amino acid
and hydrazine derivatives. Heteroatom Chemistry, 16(3), 235–241.
https://doi.org/10.1002/hc.20115
Hollenberg, P. F. (2002). Characteristics and common properties of inhibi-
tors, inducers, and activators of CYP enzymes. Drug Metabolism
Reviews, 34(1–2), 17–35. https://doi.org/10.1081/dmr-120001387
Sacmacl, M., Bolukbasl, H., & Sahin, E. (2012). Reactions of some furan-3-
ones with 2, 3-diaminopyridine and its derivatives. Bulletin of the
Korean Chemical Society, 33(1), 90–94. https://doi.org/10.5012/bkcs.
2012.33.1.90
€
Kirchmair, J., Goller, A. H., Lang, D., Kunze, J., Testa, B., Wilson, I. D., Glen,
R. C., & Schneider, G. (2015). Predicting drug metabolism: Experiment
and/or computation? Nature Reviews. Drug Discovery, 14(6), 387–404.
https://doi.org/10.1038/nrd4581
Scrocco, E.,
Concepts II.
structural characterization of pyrrole heterocyclic systems bearing Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and
& Tomasi, J. (1973). Topics in current chemistry. New
_
€
€
Koca, I., Sac¸macı, M., Yılmaz, F., & Ungoren, S¸H. (2014). Synthesis and
amino acid units: Novel pyrrol-3-ones, pyrrolo [1, 2-a][3, 1] benzoxa-
zines, and pyrrolo [2, 1-b][1, 3] oxazoles. Journal of Heterocyclic
Chemistry, 51(1), 212–218. https://doi.org/10.1002/jhet.1509
accuracy of docking with a new scoring function, efficient optimiza-
tion, and multithreading. Journal of Computational Chemistry, 31(2),
455–461. https://doi.org/10.1002/jcc.21334
_
€
€
€
ꢀ
€
€
€
€
Koca, I., Yigitcan, S., Gumus¸, M., Gokce, H., & Sert, Y. (2020). A new series Ungoren, S¸., Sacmaci, M., Akcamur, Y., Arici, C., & Ulku, D. (2004).
of sulfa drugs containing pyrazolyl acylthiourea moiety: Synthesis,
experimental and theoretical spectral characterization and molecular
docking studies. Journal of Molecular Structure, 1204, 127479. https://
doi.org/10.1016/j.molstruc.2019.127479
Koca, I., & Yildirim, I. (2012). Synthesis and spectroscopic characterization
of pyrrole-2, 3-diones and their following reactions with 1, 2-aromatic
Synthesis of new 2, 3-dihydrofuran-3-one derivative and its reactions
with some primary amines. Journal of Heterocyclic Chemistry, 41(2),
151–155. https://doi.org/10.1002/jhet.5570410203
Vengatesh, G., Sundaravadivelu, M., & Muthusubramanian, S. (2020).
Iodine mediated rearrangement of tetraarylpiperidin-4-ones:
Synthesis, structure analysis and biological studies of 5-aryl-2-
methoxy-2, 4-diphenyl-1H-pyrrole-3-ones. Journal of Molecular
Structure, 1199, 126980. https://doi.org/10.1016/j.molstruc.2019.126980
Verbiest, T., Houbrechts, S., Kauranen, M., Clays, K., & Persoons, A. (1997).
Second-order nonlinear optical materials: Recent advances in chromo-
phore design. Journal of Materials Chemistry, 7(11), 2175–2189.
https://doi.org/10.1039/a703434b
_
diamines. Organic Communications, 5, 135.
€
Kremer, F., & Schonhals, A. (2002). Broadband dielectric spectroscopy.
Springer Science & Business Media.
Kuca, K., Musilek, K., Jun, D., Zdarova-Karasova, J., Nepovimova, E.,
Soukup, O., Hrabinova, M., Mikler, J., Franca, T. C. C., Da Cunha,
E. F. F., De Castro, A. A., Valis, M., & Ramalho, T. C. (2018). A newly
developed oxime K203 is the most effective reactivator of tabun- Wang, X., & Cai, C. (2012). A possible mechanism for the negative capaci-
inhibited acetylcholinesterase. BMC Pharmacology and Toxicology,
19(1), 1–10. https://doi.org/10.1186/s40360-018-0196-3
Li, B., Sui, G., & Zhong, W. H. (2009). Single negative metamaterials in
unstructured polymer nanocomposites toward selectable and control-
tance observed in organic devices. arXiv Preprint arXiv:12107904.
Wolff, J. J., & Wortmann, R. (1999). Organic materials for second-order
non-linear optics. In: Advances in physical organic chemistry (vol. 32,
pp. 121–217). Elsevier.
lable negative permittivity. Advanced Materials, 21(41), 4176–4180. Yang, H., Lou, C., Sun, L., Li, J., Cai, Y., Wang, Z., Li, W., Liu, G., Tang, Y.,
https://doi.org/10.1002/adma.200900653 (2018) admetSAR 2.0: Web-service for prediction and optimization of

18
İ. ÇAPAN ET AL.
chemical ADMET properties. Bioinformatics, bty707. http://lmmd.ecust. Zhan, C.-G., Nichols, J. A., & Dixon, D. A. (2003). Ionization potential, elec-
edu.cn/admetsar2
tron affinity, electronegativity, hardness, and electron excitation
energy: Molecular properties from density functional theory orbital
energies. The Journal of Physical Chemistry A, 107(20), 4184–4195.
https://doi.org/10.1021/jp0225774
Yan, H., Zhao, C., Wang, K., Deng, L., Ma, M., & Xu, G. (2013). Negative
dielectric constant manifested by static electricity. Applied Physics
Letters, 102(6), 062904. https://doi.org/10.1063/1.4792064