Synthesis, characterization, DFT and molecular docking studies for novel 1,5-diphenylpenta-1,4-dien-3-one O-benzyl oximes

Article abstract of DOI:10.1007/s13738-019-01697-0

The main objectives of this study are: (a) to synthesize novel 1,5-diphenylpenta-1,4-dien-3-one O-benzyl oximes in an efficient way, (b) to investigate the synthesized molecules computationally via DFT calculations, (c) to compare computationally obtained data with experimental results and (d) to perform molecular docking calculations for the newly synthesized compounds and heat shock protein HSP90A N-terminal domain to determine the binding affinities of the investigated molecules and to reveal possible receptor–ligand interactions. In the first part of the study, syntheses and characterizations of the investigated compounds have been carried out. In this part, the target compounds have been synthesized and characterized successively. In the synthesis of target compounds from corresponding oximes, ultrasound has been used alternatively and results showed that the usage of ultrasound considerably increases the reaction rate and the efficiency. In the second part, detailed density functional theory calculations have been performed on the investigated compounds with the use of Becke, three-parameter, Lee–Yang–Parr hybrid functional and various basis sets. In this part, geometry optimizations, frequency analyses, NMR spectral analyses, frontier molecular orbital calculations, and molecular electrostatic potential map calculations have been performed. In NMR spectral analyses, both continuous set of gauge transformations (CSGT) and gauge-independent atomic orbital (GIAO) methods have been used and the obtained results with the use of various basis sets have been compared. Results showed that in NMR calculations, GIAO method is more successful than CSGT method and can provide satisfactory results even with small basis sets. In the third part of the study, molecular docking calculations have been performed on the investigated compounds and HSP90A N-terminal domain. Results showed that investigated molecules show a good binding affinity for HSP90A N-terminal domain. The binding affinities were found to be in the range of ? 8.7 to ? 10.1?kcal/mol.

Full text of DOI:10.1007/s13738-019-01697-0

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01697-0
ORIGINAL PAPER
Synthesis, characterization, DFT and molecular docking studies
for novel 1,5‑diphenylpenta‑1,4‑dien‑3‑one O‑benzyl oximes
Taner Erdogan1
Received: 14 January 2019 / Accepted: 20 May 2019
© Iranian Chemical Society 2019
Abstract
The main objectives of this study are: (a) to synthesize novel 1,5-diphenylpenta-1,4-dien-3-one O-benzyl oximes in an ef-
cient way, (b) to investigate the synthesized molecules computationally via DFT calculations, (c) to compare computation-
ally obtained data with experimental results and (d) to perform molecular docking calculations for the newly synthesized
compounds and heat shock protein HSP90A N-terminal domain to determine the binding afnities of the investigated mol-
ecules and to reveal possible receptor–ligand interactions. In the frst part of the study, syntheses and characterizations of the
investigated compounds have been carried out. In this part, the target compounds have been synthesized and characterized
successively. In the synthesis of target compounds from corresponding oximes, ultrasound has been used alternatively and
results showed that the usage of ultrasound considerably increases the reaction rate and the efciency. In the second part,
detailed density functional theory calculations have been performed on the investigated compounds with the use of Becke,
three-parameter, Lee–Yang–Parr hybrid functional and various basis sets. In this part, geometry optimizations, frequency
analyses, NMR spectral analyses, frontier molecular orbital calculations, and molecular electrostatic potential map calcula-
tions have been performed. In NMR spectral analyses, both continuous set of gauge transformations (CSGT) and gauge-
independent atomic orbital (GIAO) methods have been used and the obtained results with the use of various basis sets have
been compared. Results showed that in NMR calculations, GIAO method is more successful than CSGT method and can
provide satisfactory results even with small basis sets. In the third part of the study, molecular docking calculations have
been performed on the investigated compounds and HSP90A N-terminal domain. Results showed that investigated molecules
show a good binding afnity for HSP90A N-terminal domain. The binding afnities were found to be in the range of −8.7
to −10.1 kcal/mol.
Keywords 1,5-Diphenylpenta-1,4-dien-3-one · Oxime ether · Computational chemistry · Molecular docking ·
Sonochemistry · HSP90A
Introduction
is a chalcone, and its derivatives are important molecules in
organic chemistry, too. Oxime forms of 1,5-diphenylpenta-
1,4-dien-3-ones are also useful compounds in heterocyclic
chemistry for constructing various heterocycles [14–16].
The extant literature contains reports on the synthesis of
1,5-diphenylpenta-1,4-dien-3-one and its oxime forms
[17–19], but the oxime ether forms of these compounds have
not been studied yet.
Chalcones and related compounds are important structures
in organic and pharmaceutical chemistry. They can act as
anticancer, antitubercular, antiviral, antifungal, antibacte-
rial agents, etc. [1–13]. 1,5-Diphenylpenta-1,4-dien-3-one
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01697-0) contains
supplementary material, which is available to authorized users.
HSP90 plays an important role in folding, stabilization,
and maturation of the substrate client proteins involved in cell
growth, diferentiation, and survival [20]. HSP90 is highly
expressed in most tumor cells and plays a key role in the pro-
liferation, malignant transformation, and progression of cancer
cells. Inhibition of HSP90 can regulate target and signal path-
ways essential for tumor cell survival and proliferation [20].
* Taner Erdogan
taner.erdogan@kocaeli.edu.tr
1
Department of Chemistry and Chemical Processing
Technologies, Kocaeli Vocational School, Kocaeli
University, 41140 Kocaeli, Turkey
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
This has made HSP90 an attractive target for cancer therapy,
and inhibition of this protein has been a source of inspiration
for many studies in the literature [21–35].
In a previous study by Joshi et al. [28], some 1,3,5-tria-
zine derivatives have been studied and the binding afni-
ties have been determined for HSP90. For mono-substituted
1,3,5-triazines, they have obtained the binding afnities in
the range of −7.6 to −10.5 kcal/mol. For di-substituted and
tri-substituted derivatives, the binding afnities were found
to be in the range of −9.1 to −11.4 kcal/mol and −10.6 to
−12.1 kcal/mol, respectively.
In another study from the literature, Lee and Seo [36]
have studied on a series of 1,3,5-triazine derivatives. In this
study, experimental and molecular docking calculations have
been performed and it was reported that the binding energy
of 4-chloro-6-(2,6-dimethylphenoxy)-1,3,5-triazin-2-amine
is found to be −6.78 kcal/mol.
Mahanta et al. [30] studied Geldanamycin and its ana-
logues as HSP90 inhibitors for the treatment of breast can-
cer. In the study, ten diferent Geldanamycin analogues were
designed and molecular docking calculations have been per-
formed. Binding afnities of the investigated compounds
were found to be in the range of −7.75 to −9.64 kcal/mol.
In this study, novel 1,5-diphenylpenta-1,4-dien-3-one
O-benzyl oximes (5a–j) have been synthesized via the ultra-
sound-assisted reaction of 1,5-diphenylpenta-1,4-dien-3-one
oxime with corresponding aryl halides. Reaction pathway is
given in Fig. 1.
Fig. 1 Reaction pathway
oxime (4), 1,5-diphenylpenta-1,4-dien-3-one (3) was reacted
with hydroxylammonium chloride in pyridine. In the next
step, 1,5-diphenylpenta-1,4-dien-3-one oxime (4) was con-
verted to its oxime ether forms via the reaction between
oxime (4) and corresponding aryl halides. Bandelin Son-
orex ultrasonic bath was used for the ultrasound-assisted
reactions. NMR and LC–MS spectra were taken on Varian
Mercury AS400 and Waters 2695 Alliance Micromass ZQ,
respectively.
In the second part of the study, the synthesized mol-
ecules have been investigated computationally. All cal-
culations have been performed using DFT approach by
B3LYP method, and 6-31G(d), 6-31G(d,p), 6-311G(d,p),
6-311+G(d,p) and 6-311++G(d,p) basis sets have been
used. In the computational studies, Gaussian 09 Rev.D.01
[37], Avogadro 1.1.1 [38], and GaussView 5 [39] software
packages have been used. In the third part of the study,
molecular docking calculations have been performed on the
synthesized molecules and HSP90A N-terminal domain.
HSP90 inhibitors can be used in the treatment of cancer [20].
Therefore, in this study, heat shock protein was selected as
target receptor and molecular docking calculations have been
focused on this protein. Molecular docking calculations have
been performed using AutoDock Tools [40, 41], AutoDock
Vina [42], and UCSF Chimera [43] software packages, and
Discovery Studio Visualizer [44] was used for the visualiza-
tion of the ligand–receptor interactions.
1,5‑Diphenylpenta‑1,4‑dien‑3‑one (3)
To a solution of benzaldehyde (0.10 mol, 10.6 g) and ace-
tone (0.05 mol, 2.9 g) in ethanol (25 mL), an aqueous solu-
tion of NaOH (0.12 mol, 4.8 g) was added dropwise. After
15 min of stirring, formed solids were fltered, washed with
water, and air-dried. Crude product was purifed by recrys-
tallization from ethyl acetate.
1,5‑Diphenylpenta‑1,4‑dien‑3‑one oxime (4)
The solution of 1,5-diphenylpenta-1,4-dien-3-one (3)
(0.020 mol, 4.68 g) and hydroxylammonium chloride
(0.030 mol, 2.09 g) in pyridine (25 mL) was refuxed for 6 h.
After completion of the reaction, the solution was allowed
to cool to the room temperature. The solution was added
dropwise to the vigorously stirred cold HCl solution (10%).
Experimental
1,5-Diphenylpenta-1,4-dien-3-one (3) has been synthesized
via the condensation reaction between benzaldehyde and ace-
tone. In the synthesis of 1,5-diphenylpenta-1,4-dien-3-one
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Journal of the Iranian Chemical Society
The formed solids were collected and used for the next step
128.11, 127.85, 127.34, 127.00, 122.49, 117.61, 76.67; m/z
without further purifcation.
(ESI–MS): 340.58 [M–H]+.
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(2‑chlorobenzyl) oxime (5b)
Synthesis
of 1,5‑diphenylpenta‑1,4‑dien‑3‑one
O‑benzyl oximes (5a–j)
Oily; Yield: %80; 1H NMR (CDCl3, 400 MHz) δ 7.57–7.25
(m, 15H), 7.15 (d, J= 16.4 Hz, 1H), 7.13 (d, J= 16.8 Hz,
1H), 6.90 (d, J = 16.4 Hz, 1H), 5.40 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ 154.90, 137.44, 136.49, 136.24,
135.70, 135.15, 133.11, 129.40, 129.37, 129.04, 128.86,
128.79, 128.72, 128.48, 127.36, 127.01, 126.74, 122.30,
117.45, 73.71; m/z (ESI–MS): 374.62 [M–H]+.
Method A
To a solution of 1,5-diphenylpenta-1,4-dien-3-one oxime (4)
(2 mmol, 0.500 g) in THF (10 mL), sodium hydride (60%,
2 mmol, 0.080 g) was added at room temperature. After
5 min of stirring, aryl halide (2 mmol) was added portion-
wise at room temperature. The reaction was completed in
the range of 2–4 h of stirring at room temperature, gener-
ally. After completion of the reaction, a small amount of
methanol was added and solvent was evaporated, then dis-
tilled water was added and extracted with dichloromethane.
Organic phase was dried over sodium sulfate, fltered, and
the solvent was evaporated. Purifcation achieved by column
chromatography on silica gel and eluted with hexane–ethyl
acetate (20:1). Further purifcation has been achieved by
preparative TLC on silica gel and eluted with hexane–ethyl
acetate (10:1). Similar procedure has been used in a previ-
ous study [45].
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(4‑chlorobenzyl) oxime (5c)
Oily; Yield: 84%; 1H NMR (CDCl3, 400 MHz) δ 7.54–7.49
(m, 4H), 7.40–7.26 (m, 11H), 7.11 (t, J=17 Hz, 2H), 6.89
(d, J=16 Hz, 1H), 5.22 (s, 2H) 13C NMR (CDCl3, 100 MHz)
δ 154.73, 137.38, 136.47, 136.36, 136.19, 135.13, 129.46,
129.05, 128.78, 128.72, 128.58, 128.49, 127.33, 127.00,
122.29, 117.44, 75.74; m/z (ESI–MS): 374.54 [M–H]+.
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(4‑bromobenzyl) oxime (5d)
Oily; Yield: 78%; 1H NMR (CDCl3, 400 MHz) δ 7.55–7.50
(m, 6H), 7.41–7.26 (m, 9H), 7.11 (t, J = 17.2 Hz, 2H),
6.89 (d, J = 16 Hz, 1H), 5.21 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 154.75, 137.40, 136.89, 136.47, 136.19, 135.15,
131.54, 129.78, 129.06, 128.79, 128.73, 128.50, 127.34,
127.02, 122.28, 121.81, 117.44, 75.76; m/z (ESI–MS):
418.58 [M–H]+.
Method B
To a solution of 1,5-diphenylpenta-1,4-dien-3-one oxime (4)
(2 mmol, 0.500 g) in THF (10 mL), sodium hydride (60%,
2 mmol, 0.080 g) was added at room temperature. After
1 min of sonication, aryl halide (2 mmol) was added and
sonicated for 20 min. After 20 min of sonication, a small
amount of methanol was added and solvent was evaporated,
then distilled water was added and extracted with dichlo-
romethane. Organic phase was dried over sodium sulfate, fl-
tered, and the solvent was evaporated. Purifcation achieved
by column chromatography on silica gel and eluted with
hexane–ethyl acetate (20:1). Further purifcation has been
achieved by preparative TLC on silica gel and eluted with
hexane–ethyl acetate (10:1). Similar procedure has been
used in a previous study [46].
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(2,4‑dichlorobenzyl) oxime (5e)
Oily; Yield: 80%; 1H NMR (CDCl3, 400 MHz) δ 7.55–7.25
(m, 14H), 7.14 (d, J=16 Hz, 1H), 7.12 (d, J=16.8 Hz, 1H),
6.88 (d, J = 16 Hz, 1H), 5.33 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 155.13, 137.62, 136.40, 136.15, 135.35, 134.41,
133.98, 133.75, 130.31, 129.63, 129.21, 129.12, 129.04,
128.81, 128.72, 128.55, 127.36, 127.08, 127.06, 127.03,
122.09, 117.30, 73.05; m/z (ESI–MS): 408.53 [M–H]+.
(1E,4E)‑1,5‑diphenylpenta‑1,4‑dien‑3‑one O‑benzyl oxime
(5a)
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(2,6‑dichlorobenzyl) oxime (5f)
Oily; Yield: 82%; 1H NMR (CDCl3, 400 MHz) δ 7.55–7.26
(m, 16H), 7.15 (d, J= 16.4 Hz, 1H), 7.10 (d, J= 16.8 Hz,
1H), 6.91 (d, J=16 Hz, 1H), 5.29 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 154.47, 137.80, 137.20, 136.57, 136.29,
134.93, 128.97, 128.76, 128.71, 128.47, 128.43, 128.42,
Oily; Yield: 80%; 1H NMR (CDCl3, 400 MHz) δ 7.52–7.20
(m, 14H), 7.16 (d, J=16.4 Hz, 1H), 7.08 (d, J=16.8 Hz,
1H), 6.89 (d, J=16 Hz, 1H), 5.54 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 154.77, 137.27, 137.20, 136.59, 136.32, 134.95,
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Journal of the Iranian Chemical Society
132.66, 130.12, 129.90, 128.90, 128.71, 128.69, 128.42,
128.38, 127.33, 127.02, 122.34, 117.44, 70.92; m/z (ESI–MS):
408.55 [M–H]+.
Computational studies
Optimized structures and single‑point energies
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(2‑bromobenzyl) oxime (5g)
Optimized structures of the investigated molecules have
been determined using DFT approach by B3LYP method.
Frequency analysis has also been carried out to confrm
that there is no imaginary frequency and each of the opti-
mized structures corresponds to a global minimum. Before
geometry optimization, a conformational search has been
done with the use of genetic algorithm search option and
the obtained structure was used as a starting geometry in
the geometry optimization calculation. For instance, the
optimized structure and selected geometric parameters of
compound 5a, calculated with 6-311++G(d,p) basis set, are
given in Fig. 2 and Table 1. Optimized structures and the
calculated geometric parameters of all other compounds are
given in Supplementary Material.
Oily; Yield: 78%; 1H NMR (CDCl3, 400 MHz) δ 7.59–7.18
(m, 15H), 7.15 (d, J=16.4 Hz, 1H), 7.13 (d, J=16.8 Hz,
1H), 6.91 (d, J=16 Hz, 1H), 5.36 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 154.97, 137.46, 137.31, 136.48, 136.24, 135.17,
132.63, 129.47, 129.11, 129.05, 128.80, 128.71, 128.49,
127.36, 127.01, 122.83, 122.27, 117.47, 75.89; m/z (ESI–MS):
418.50 [M–H]+.
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(3‑chlorobenzyl) oxime (5 h)
Oily; Yield: 78%; 1H NMR (CDCl3, 400 MHz) δ 7.56–7.26
(m, 15H), 7.12 (t, J=16.4 Hz, 2H), 6.89 (d, J=16.4 Hz,
1H), 5.23 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 154.83,
139.97, 137.46, 136.46, 136.18, 135.21, 134.28, 129.70,
129.06, 128.79, 128.72, 128.50, 128.09, 127.94, 127.35,
127.02, 126.05, 122.26, 117.42, 75.70; m/z (ESI–MS): 374.61
[M–H]+.
Single-point energy (SPE) is described as the sum of elec-
tronic energy and the nuclear repulsion energy of a molecule
at a specifed nuclear confguration. SPEs of the compounds
5a–j have been calculated and are given in Table 2. As can
be seen from Table 2, the calculated energies are decreasing
with the increasing size of the basis set. The lowest energies
have been obtained for 5d and 5g. When 6-311+G(d,p) and
6-311++G(d,p) basis sets were used, the lowest energies
have been obtained for 5d. On the other hand, the usage of
6-31G(d), 6-31G(d,p) and 6-311G(d,p) basis sets causes the
lowest energies to be obtained for 5g, which is related to the
use of difuse functions in the calculations.
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(4‑fuorobenzyl) oxime (5i)
Oily; Yield: 80%; 1H NMR (CDCl3, 400 MHz) δ 7.54–7.26
(m, 4H), 7.43–7.26 (m, 9H), 7.16–7.05 (m, 4H), 6.90 (d,
J=16.4 Hz, 1H), 5.23 (s, 2H); 13C NMR (CDCl3, 100 MHz)
δ 163.74, 154.60, 137.30, 136.50, 136.22, 135.05, 133.59,
130.03, 129.95, 129.02, 128.77, 128.72, 128.47, 127.32,
127.00, 122.37, 117.50, 115.38, 115.17, 75.88; m/z (ESI–MS):
358.56 [M–H]+.
In Table 3, calculated energies of the geometric isomers
of compound 3 are given. It was found that the energy of
the (E,E)-isomer is lower than the energies of both (Z,E)-
and (Z,Z)-isomers. This results also explain why the
(1E,4E)‑1,5‑Diphenylpenta‑1,4‑dien‑3‑one
O‑(3,4‑dichlorobenzyl) oxime (5j)
Oily; Yield: 78%; 1H NMR (CDCl3, 400 MHz) δ 7.55–7.15
(m, 14H), 7.12 (d, J=16 Hz, 1H), 7.09 (d, J=16.4 Hz, 1H),
6.87 (d, J=16.4 Hz, 1H), 5.19 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 155.04, 138.23, 137.60, 136.39, 136.11, 135.38,
130.41, 129.98, 129.12, 128.80, 128.72, 128.55, 127.35,
127.31, 127.03, 122.10, 117.30, 74.99; m/z (ESI–MS): 408.44
[M–H]+.
Fig. 2 Optimized structure of compound 5a
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Journal of the Iranian Chemical Society
Table 1 Selected geometric parameters of compound 5a
Atoms
Bond lengths (Å)
Atoms
Bond angles (°)
Atoms
Dihedral angles (°)
5C–7C
7C–8C
8C–9C
9C–10C
10C–12C
12C–13C
9C–11N
11N–19O
19O–20C
20C–21C
1.465
1.347
1.463
1.474
1.343
1.466
1.298
1.395
1.441
1.504
5C–7C–8C
7C–8C–9C
126.9
124.3
120.6
124.3
126.8
112.8
109.1
107.8
4C–5C–7C–8C
5C–7C–8C–9C
177.9
179.4
149.8
177.6
168.2
−4.6
177
175.4
−179.9
93.1
8C–9C–10C
9C–10C–12C
10C–12C–13C
9C–11 N–19O
11 N–19O–20C
19O–20C–21C
8C–9C–10C–12C
9C–10C–12C–13C
10C–12C–13C–18C
8C–9C–11N–19O
10C–9C–11N–19O
9C–11N–19O–20C
11N–19O–20C–21C
19O–20C–21C–22C
Table 2 Calculated energies for
compounds 5a–j
Compounds
Energies (eV)
opt1a
opt2b
opt3c
opt4d
opt5e
5a
5b
5c
5d
5e
5f
−28,765.088
−41,272.122
−41,271.342
−98,728.443
−53,777.490
−53,777.405
−98,728.469
−41,271.339
−31,465.369
−53,777.447
−28,765.979
−41,272.122
−41,272.190
−98,729.292
−53,778.294
−53,778.212
−98,729.323
−41,272.188
−31,466.216
−53,778.252
−28,767.035
−41,273.181
−41,273.240
−98,730.999
−53,779.353
−53,779.269
−98,801.747
−41,279.090
−31,473.259
−53,785.893
−28,772.478
−41,279.404
−41,279.459
−98,802.164
−53,786.354
−53,786.273
−98,802.101
−41,279.454
−31,473.720
−53,786.292
−28,772.486
−41,279.414
−41,279.467
−98,802.173
−53,786.365
−53,786.287
−98,802.109
−41,279.462
−31,473.730
−53,786.300
5g
5h
5i
5j
a6-31G(d), b6-31G(d,p), c6-311G(d,p), d6-311+G(d,p), e6-311++G(d,p)
Table 3 Calculated energies for the isomers of 3 with 6-311++G(d,p)
computational and experimental data. In Table 3, the more
the green color, the better the agreement between experi-
mental and computational data. As can be seen from Table 4
and Fig. 3, GIAO method is generally more successful than
CSGT method and satisfactory results can be obtained even
with small basis sets. The best basis set for GIAO method
was found to be 6-31G(d,p). For CSGT method, it needs to
be used larger basis sets for acceptable results.
basis set
Energies (hartree) Energies (kcal/mol) Relative ener-
gies (kcal/
mol)
(E,E)-3 −731.62,774
(Z,E)-3 −731.62,098
−460,925.47
−460,921.22
−460,914.73
0.00
4.25
10.75
(Z,Z)-3
−731.61,068
Frontier molecular orbital and global reactivity
descriptors
(E,E)-isomer is the only product in the synthesis of com-
pound 3.
FMO energies of the investigated molecules have been deter-
mined and are given in Fig. 4, Fig. 5 and also in Table 5.
HOMO–LUMO gap values, calculated with 6-311++G(d,p)
basis set, vary between 3.7345 and 3.7688 eV. Since the
larger HOMO–LUMO gap corresponds to a more stable
structure, it can be said that the stability order of the com-
pounds 5a–j is as follows: 5j>5f>5g>5e>5h>5d>5b>
5a>5c>5i, and 5j is the most stable compound.
NMR spectral analysis
NMR spectral analyses have been carried out at the same
level of theory with both CSGT and GIAO methods. Exper-
1
imental and computationally obtained H NMR data are
1
given in Table 4 for 5a. Absolute errors for calculated H
NMR chemical shifts for compound 5a are represented in
Fig. 3 and also a color scale from red to green is applied
to Table 4 in order to emphasize the agreement between
Ionization potentials (I), electron afnities (A), chemical
softnesses (S), chemical hardnesses (η), electronic chemical
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Journal of the Iranian Chemical Society
Table 4 Calculated and experimental 1H NMR chemical shifts for compound 5a
Exp.
csgt1a csgt2b csgt3c csgt4d csgt5e csgt6f giao1a giao2b giao3c giao4d giao5e giao6f
27-H 7.55-7.25 4.65 5.20 6.88 6.39 6.45 7.19 7.16 7.35 7.73 7.46 7.47 7.52
28-H 7.55-7.25 4.56 5.10 6.80 6.30 6.36 7.15 7.07 7.26 7.78 7.39 7.37 7.45
29-H 7.55-7.25 4.65 5.20 6.88 6.39 6.45 7.19 7.16 7.35 7.73 7.46 7.47 7.52
30-H 7.55-7.25 4.53 5.10 6.99 6.50 6.57 7.39 7.24 7.46 7.97 7.69 7.66 7.69
31-H 7.55-7.25 4.53 5.10 6.99 6.50 6.57 7.39 7.24 7.46 7.97 7.69 7.66 7.69
32-H 7.55-7.25 3.61 4.21 6.35 5.89 5.94 6.81 6.47 6.69 7.21 7.04 7.03 7.09
33-H
34-H
35-H
7.15
6.91
7.1
4.38 5.10 7.23 6.72 6.78 7.50 7.44 7.78 8.24 7.99 8.00 7.95
3.72 4.42 6.51 6.07 6.12 6.97 6.73 7.00 7.58 7.27 7.27 7.29
4.18 4.79 6.89 6.43 6.48 7.30 7.12 7.33 7.80 7.59 7.63 7.63
36-H 7.55-7.25 4.58 5.16 7.12 6.65 6.70 7.55 7.32 7.54 8.07 7.85 7.86 7.88
37-H 7.55-7.25 4.68 5.23 6.99 6.50 6.55 7.31 7.22 7.40 7.88 7.54 7.51 7.56
38-H 7.55-7.25 4.56 5.11 6.86 6.37 6.42 7.22 7.10 7.29 7.68 7.39 7.36 7.48
39-H 7.55-7.25 4.68 5.23 6.99 6.50 6.55 7.31 7.22 7.40 7.88 7.54 7.51 7.56
40-H 7.55-7.25 4.58 5.16 7.12 6.65 6.70 7.55 7.32 7.54 8.07 7.85 7.86 7.88
41-H
42-H
5.29
5.29
3.20 3.55 5.13 4.30 4.35 5.03 5.15 5.21 5.49 5.20 5.17 5.24
3.20 3.55 5.13 4.30 4.35 5.03 5.15 5.21 5.49 5.20 5.17 5.24
43-H 7.55-7.25 4.77 5.29 7.18 6.73 6.79 7.56 7.35 7.56 8.10 7.80 7.79 7.80
44-H 7.55-7.25 4.73 5.27 7.09 6.61 6.66 7.41 7.26 7.44 7.95 7.66 7.65 7.69
45-H 7.55-7.25 4.70 5.22 7.06 6.56 6.62 7.39 7.22 7.39 8.01 7.66 7.65 7.70
46-H 7.55-7.25 4.73 5.27 7.09 6.61 6.66 7.41 7.26 7.44 7.95 7.66 7.65 7.69
47-H 7.55-7.25 4.77 5.29 7.18 6.73 6.79 7.56 7.35 7.56 8.10 7.80 7.79 7.80
a6-31G(d), b6-31G(d,p), c6-311G(d,p), d6-311+G(d,p), e6-311++G(d,p), f6-311++G(2d,p)
Fig. 3 Absolute errors of calculated 1H NMR chemical shifts
potentials (μ), electronegativities (χ), and electrophilicity
indexes (ω) have been determined and are given in Table 5.
Ionization potentials can be calculated using Eq. (1) and cor-
respond to minimum energies required to remove an electron
from atoms or molecules. Electron afnity is described as
the energy released when an electron is added to a neutral
molecule in gaseous state and can be calculated using Eq. (2)
[47]. Additionally, chemical softness, chemical hardness,
electronegativity, electrophilicity index, and electronic chemi-
cal potential can be calculated using Eqs. (3)–(7) [48–54].
I = −EHOMO
(1)
A = −ELUMO
(2)
ꢀ = (I + A)∕2
(3)
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Journal of the Iranian Chemical Society
Fig. 4 HOMO and LUMO orbitals and HOMO–LUMO gaps for compounds 5a–e
Fig. 5 HOMO and LUMO orbitals and HOMO–LUMO gaps for compounds 5f–j
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Journal of the Iranian Chemical Society
Table 5 Global reactivity descriptors of the compounds 5a–j calculated with 6-311++G(d,p) basis set
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
LUMO
HOMO
Gap
I
A
χ
η
S
μ
ω
−2.1113
−5.8548
3.7435
5.8548
2.1113
3.9831
1.8717
0.5343
−3.9831
4.2380
−2.1179
−5.8662
3.7484
5.8662
2.1179
3.9920
1.8742
0.5336
−3.9920
4.2516
−2.1908
−5.9326
3.7418
5.9326
2.1908
4.0617
1.8709
0.5345
−4.0617
4.4089
−2.1913
−5.9430
3.7516
5.9430
2.1913
4.0672
1.8758
0.5331
−4.0672
4.4092
−2.1856
−5.9462
3.7606
5.9462
2.1856
4.0659
1.8803
0.5318
−4.0659
4.3960
−2.1268
−5.8924
3.7655
5.8924
2.1268
4.0096
1.8828
0.5311
−4.0096
4.2695
−2.1154
−5.8788
3.7633
5.8788
2.1154
3.9971
1.8817
0.5314
−3.9971
4.2453
−2.1908
−5.9487
3.7579
5.9487
2.1908
4.0697
1.8789
0.5322
−4.0697
4.4075
−2.1788
−5.9133
3.7345
5.9133
2.1788
4.0461
1.8672
0.5355
−4.0461
4.3836
−2.2411
−6.0099
3.7688
6.0099
2.2411
4.1255
1.8844
0.5307
−4.1255
4.5160
ligands have been obtained using DFT approach by B3LYP
method with the use of 6-311++G(d,p) basis set before
molecular docking studies. The preparation of the recep-
tor and the ligands has been performed using UCSF Chi-
mera. Before docking studies, all non-standard residues of
the receptor and solvent have been removed. For incomplete
side chains, Dunbrack 2010 rotamer library [58] has been
used and hydrogens and Gasteiger charges have been added
to the receptor. The binding afnities of the compounds 5a–j
were found to be in the range of − 8.7 to − 10.1 kcal/mol
and are given in Fig. 7. The highest binding afnities have
been obtained for 5c, 5d, and 5i. On the other hand, 5e and
5f have the lowest binding afnities. Receptor surface and
receptor–ligand interactions for compound 5c, which shows
the highest binding afnity, are given in Fig. 8 and for all
other compounds in Fig. 9.
ꢀ = (I − A)∕2
S = 1∕ꢀ
(4)
(5)
(6)
(7)
ꢀ = −(I + A)∕2
ꢀ = ꢁ2∕2ꢂ
Chemical hardness is described as a measure of the resist-
ance of a molecule to a change in its electronic confguration
[55]. Chemical hardnesses of the compounds 5a–j showed a
similar trend to the HOMO–LUMO gap values. Electrophi-
licity index is described as a measure of electrophilic power
[48]. A good electrophile is characterized by a high elec-
trophilicity index value, and in opposite, good nucleophiles
have lower values. The order of the electrophilic power of
compound 5a–j is as follows: 5j>5d>5c>5h>5e>5i>
5f>5b>5g>5a.
Molecular electrostatic potential (MEP) maps are useful
tools for determination and representation of the electron
densities of the investigated molecules. MEP maps of the
newly synthesized molecules with the use of 6-311++G(d,p)
basis set are given in Fig. 6. As can be seen from Fig. 6, the
negative charge was located dominantly on the nitrogen and
the oxygen atoms of the oxime group.
Results and discussion
In this study, novel 1,5-diphenylpenta-1,4-dien-3-one O-ben-
zyl oximes (5a–j) have been synthesized via the reaction
of 1,5-diphenylpenta-1,4-dien-3-one oxime (4) with cor-
responding aryl halides. Additionally, the same reactions
have also been carried out with the assistance of ultrasound.
Results showed that the usage of ultrasound considerably
increases the reaction rate and the efciency.
Molecular docking calculations
Molecular docking analyses have been carried out on the
synthesized compounds to determine binding afnities of
the investigated molecules and to reveal possible recep-
tor–ligand interactions between 5a–j and HSP90A N-termi-
nal domain using AutoDock Tools [40, 41], AutoDock Vina
[42], and UCSF Chimera [43] software packages. Discovery
Studio Visualizer [44] has been used for the visualization
and the representation of the docking results. The crystal
structure of HSP90A was obtained from RCSB Protein Data
Bank (PDB:3QDD) [56, 57]. The optimized structures of
In the synthesis of 1,5-diphenylpenta-1,4-dien-3-one (3),
(E,E)-isomer is the only product as expected, because of its
more stable structure. The DFT studies also support this
observation. The energy of (E,E)-isomer is lower than both
the energies of (E,Z)- and (Z,Z)-isomers. The relative ener-
gies of the (E,E)-, (E,Z)- and (Z,Z)-isomers were found to
be 0, 4.25, and 10.75 kcal/mol, respectively.
In NMR spectral analyses, it was found that GIAO
method is more successful than CSGT method for the
investigated molecules, and GIAO method can provide
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Journal of the Iranian Chemical Society
Fig. 6 Molecular electrostatic potential maps of the synthesized compounds
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Journal of the Iranian Chemical Society
to good binding afnity for HSP90A. The binding afni-
ties of the investigated molecules were found to be in the
range of −8.7 to −10.1 kcal/mol. The results showed that
the investigated molecules, especially 5c, 5d, and 5i, show
a good binding afnity for HSP90A N-terminal domain
and can be promising structures as HSP90 inhibitor. It was
observed that compounds 5c, 5d, and 5i showed the high-
est binding afnities. On the other hand, the lowest binding
afnities have been obtained for the compounds 5e and 5f.
Conclusion
In conclusion, in this study, novel 1,5-diphenylpenta-1,4-
dien-3-one O-benzyl oximes have been synthesized, char-
acterized, and computationally investigated via DFT cal-
culations. Geometry optimizations, frequency analyses,
NMR spectral analyses, FMO calculations, and MEP map
calculations have been performed. In NMR spectral analy-
ses, both CSGT and GIAO methods have been used and
the results showed that GIAO method is more successful
than CSGT method. In addition to conventional method,
ultrasound-assisted method was also used for the synthe-
sis of oxime ethers, alternatively. The results showed that
the usage of ultrasound increases the reaction rate and the
reaction efciency, considerably. Additionally, molecular
Fig. 7 Binding afnities of compounds 5a–j
satisfactory results even with small basis sets and does not
require high computer resources. The best basis set was
found to be 6-31G(d,p) for GIAO method. Additionally, it
was observed that CSGT method becomes more successful
with the use of larger basis sets. For CSGT method, the best
results have been obtained with 6-311++G(2d,p) basis set.
Similar results have been obtained in the previous studies
[45, 46, 59].
In the molecular docking studies, the interactions between
HSP90A N-terminal domain and compounds 5a–j have been
investigated. The investigated compounds showed moderate
Fig. 8 Molecular docking results for compound 5c
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Journal of the Iranian Chemical Society
Fig. 9 Molecular docking results for compounds 5a, 5b, and 5d–j
Funding This work was fnancially supported by Kocaeli Univer-
sity Scientifc Research Projects Unit. Project No: 2018/058HD. The
authors acknowledge Kocaeli University for the fnancial support.
docking calculations have been performed to determine
binding afnities of the synthesized molecules for heat shock
protein HSP90 and promising results have been obtained.
The binding afnities were found to be in the range of −8.7
to −10.1 kcal/mol.
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