Synthesis, spectroscopic characterization, DFT computations, nonlinear optical profile and molecular docking study of a novel chalcone derivative

Journal Pre-proof Synthesis, spectroscopic characterization, DFT computations, nonlinear optical profile and molecular docking study of a novel chalcone derivative Serdal Kaya, Halil Gökce, Tayfun Arslan, Gökhan Alpaslan PII:

S0022-2860(19)31379-1

DOI:

https://doi.org/10.1016/j.molstruc.2019.127270

Reference:

MOLSTR 127270

To appear in:

Journal of Molecular Structure

Received Date: 25 March 2019 Revised Date:

15 October 2019

Accepted Date: 21 October 2019

Please cite this article as: S. Kaya, H. Gökce, T. Arslan, Gö. Alpaslan, Synthesis, spectroscopic characterization, DFT computations, nonlinear optical profile and molecular docking study of a novel chalcone derivative, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/ j.molstruc.2019.127270. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Graphical Abstract

Synthesis, Spectroscopic Characterization, DFT Computations, Nonlinear Optical Profile and Molecular Docking Study of a Novel Chalcone Derivative Serdal Kayaa, Halil Gökce b,*, Tayfun Arslana, Gökhan Alpaslanb a b

Department of Chemistry, Faculty of Arts and Sciences, Giresun University, 28200 Giresun, Turkey Vocational School of Health Services, Giresun University, 28200 Giresun, Turkey

A novel chalcone derivative, (E)-1-(3-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (Tx), was synthesized and its spectroscopic characterization was done by using the experimental FT-IR, Laser-Raman, UV-Vis. and NMR spectroscopic techniques. To support experimental spectroscopic data, computational analyses were performed with DFT/B3LYP method at the 6311G++(d,p) basis set. The assignments of fundamental vibrational modes were defined in terms of PED% by using VEDA4xx software. HOMO, LUMO and UV-Vis. spectral analyses were used for determination of molecular electronic transitions. By considering the computed HOMO and LUMO energy values, some global reactivity descriptors were theoretically investigated. MEP surface mapping was used to determine the nucleophilic and electrophilic reactive sites within the compound Tx. Thermodynamic features of the compound were theoretically studied within gas phase. The static polarizabilities and first order hyperpolarizabilities were used to investigate nonlinear optical (NLO) profile of the compound. The protein-ligand interactions for the compound Tx docked into a breast cancer resistance protein ATP-binding cassette sub-family G member 2 (PDB ID: 6FFC) were investigated with the molecular docking analysis.

Keywords: DFT/B3LYP computations • Molecular structure • Spectroscopic studies • Electronic properties • Termochemical anaysis • NLO features • Molecular docking study

1. Introduction Fatal and common breast cancer among female worldwide occurs with the uncontrolled proliferation of the milk-channel and milk-forming cells in the breast tissue [1]. Its main reason is that it is age-related. Other important factors are parity, which is the number of all pregnancies of a woman, and low rate infant breastfeeding [2]. Depending on the stage of the disease, the characteristics of the patient and its overall health, surgery may include one or more of the treatment options such as radiation, hormone, chemotherapy or targeted therapies. However, the most common problem in cancer chemotherapy is the multidrug resistance (MDR) of cancer cells

*

Corresponding Author. E-mail: [email protected], [email protected] (H. Gökce).

1

[3]. Previous studies have reported that MDR is associated with ATP-binding cassette (ABC) transporters,

which

are

P-glycoprotein

(P-gp/ABCB1),

multidrug

resistance

protein

1

(MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) [3-5]. The treatment of this type of cancer is very important. One of the methods of treatment is to eliminate these resistant cancer cells by using the multidrug ABC transporters [5]. When the literature was investigated, it was determined that chalcones analogues with various substituents (-OH, -OCH3, -Cl, -Br) on the ring A and B of the chalcone skeleton and Tariquidar-related chalcones compounds inhibited by interacting with breast cancer resistance protein (ABCG2) [4,6] (Figure 1). Chalcones based a myriad of heterocyclics have been synthesized bearing azo, sulfonamide and hydroxy groups and some of them have been studied for their biological activity [7,8]. Furthermore, they have been used widespreadly in pharmaceutical and medicinal areas such as carbonic anhydrase inhibitor, anticancer, anti-HIV activity, antiproliferative and antifungal [9-13].

Figure 1. Some chalcone derivatives as ABCG2 inhibitors.

This work is a characterization study on molecular structure, spectroscopic, electronic (HOMO, LUMO and MEP), thermochemical and non-linear optical features of a novel synthesized chalcone derivative (E)-1-(3-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (Tx) by using experimental and computational methods. Additionally, the protein-ligand interactions between a breast cancer resistance protein ATP-binding cassette sub-family G member 2 (PDB ID: 6FFC) and the compound Tx were determined via the molecular docking study. In the literature, there is no a detailed study on structural, spectral, electronic, thermochemical and non-linear optical features of this chalcone derivative. The experimental analyses was performed by using FT-IR, Laser-Raman, NMR and UV spectroscopic techniques, while the quantum chemical computations on the electronic structure of the compound were performed with the B3LYP/6-311G++(d,p) level. In the literature, there are in many researches including combined experimental and theoretical analyses on synthesis, characterization, structural, spectral, electronic, thermodynamic, magnetic, non-linear optical and molecular docking studies of organic, inorganic, polymeric and metal complex compounds [14-19].

2

2. Experimental procedures 2.1. Synthesis of (E)-1-(3-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (3 or Tx) All reagents were purchased from Sigma Aldrich and used without further purification. Ketone 1 (210.2 mg, 1.0 mmol) and aldehyde 2 (122.1 mg, 1.0 mmol) was dissolved in 10 mL ethanol. To this mixture, sodium hydroxide (60%, 5 mL) was added at 0-5 °C. The reaction mixture was stirred at the same temperature for 24 h. The progress of reaction was monitored by TLC. After completion of the reaction, reaction mixture was poured into the iced water and acidified with dil. HCl until precipitating a yellow solid. After completion of the reaction, crude product was crystallized from EtOH/H2O (1:1) to give yellow crystals of compound 3 (Tx) in quantitative yield. The synthetic route of the new compound (E)-1-(3-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (Tx) is given in Scheme 1 [13]. The structures of the compound were confirmed by spectroscopic analysis. Yield: 310.0 mg, 98%. M.P.: 93-95 °C; 1H NMR (400 MHz, CDCl3): δ 8.30 (A part of AB system, J = 15.9 Hz, 1H, H29), 7.88 (B part of AB system, J = 15.9 Hz, 1H, H28), 7.64 (qt, J = 2.1 Hz, 1H, H27), 7.58 (d, J = 7.9 Hz, 1H, H24), 7.36 (t, J = 7.9 Hz, 1H, H25), 7.09 (dd, J = 7.9 Hz and 2.1 Hz, 1H, H26), 6.36 (br, 1H, -OH), 6.14 (s, 2H, H30 and H31), 3.91 (s, -OCH3, 6H, H32, H33, H34, H38, H39 and H40), 3.88 (s, -OCH3, 3H, H35, H36 and H37); 13C NMR (100 MHz, CDCl3): δ 192.2, 163.3, 161.9, 156.3, 140.7, 136.6, 129.6, 121.8, 120.8, 119.5, 115.2, 106.6, 90.5, 55.8, 55.4. HRMS (TOF-ESI): m/z calc. for [M+H]+: 315.1227; found: 315.1257, ∆ = 9.5 ppm (see Figure S1 within supporting information).

Scheme 1. Synthesis step of (E)-1-(3-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one.

2.2. Spectral analysis details To analyze vibrational properties of the compound Tx, Laser-Raman (100-4000 cm-1) and Fourier Transform Infrared (FT-IR) (400-4000 cm-1) spectra were recorded by using Renishaw Invia Raman Microscope Spectrophotometer and JASCO FT/IR-6600 Fourier Transform Infrared Spectrometer, respectively. The accumulation and resolution for FT-IR spectrum is 64 and 4 cm-1, while the resolution, scan number and excitation laser line for Laser-Raman spectrum are 4 cm-1, 100 and a diode laser at 785 nm, respectively. 1H-, 13C-, DEPT-90, COSY, 1H-13C HMQC and 1H-13C HMBC NMR spectra of the compound Tx dissolved in CDCl3 (chloroform-d) were measured with Bruker 3

Biospin-Avance III 400 MHz NMR spectrometer at the temperature of 295 K. The NMR chemical shifts were recorded at frequency values of 400 MHz (for protons) and 100 MHz (for carbons) in ppm level relative to tetramethylsilane (TMS). The UV-Vis. electronic absorption spectrum of the compound Tx dissolved in chloroform was measured by using UV-6100 Double Beam Spectrophotometer in the region of 190-1100 nm at the room temperature with spectral bandwidth of 2 nm. Melting points were determined by using a Barnstead electro-thermal 9200 series digital apparatus.

3. Computation procedures Quantum chemical computations for structural geometry, vibrational frequencies, 1H and 13C NMR chemical shifts, UV-Vis. spectral features, HOMO and LUMO analyses, MEP surface mapping and thermochemical properties and non-linear optical quantities of the compound Tx were made via the B3LYP functional [20,21] in Density Functional Theory (DFT) method by using the 6-311G++(d,p) basis set. All electronic structure computations and visualizations of all computed characters were performed by using Gaussian 09W [22] and GaussView5 [23] software packages, respectively. The calculated harmonic vibrational frequency values were multiplied by 0.983 (0-1700 cm-1) and 0.958 (1700-4000 cm-1) for the B3LYP/6-311G++(d,p) computational level [24]. For computations of NMR and UV spectral parameters, the initial molecular structure of the compound Tx was optimized in chloroform by using IEF-PCM [25] solvation model. Then, 1H and 13C NMR chemical shifts for the compound Tx were computed by using GIAO method [26-28] and the same solvation model. Likewise, UV-Vis. spectral features were obtained at the same solvation model with the TDDFT/B3LYP/6-311G++(d,p) computational level [29]. To confirm intra-molecular electronic transitions, HOMOs and LUMOs examinations were performed by using the optimized molecular structure within chloroform. MEP surface of the compound Tx under investigation was used to determine electrophilic and nucleophilic reactive attack sites. NLO features at the static state were obtained by using keyword polar=enonly at the B3LYP/6-311G++(d,p) computational level. Molecular docking study was performed with AutoDock Vina program software suite [30] to predict protein-ligand interactions between the compound Tx with a breast cancer resistance protein ATP-binding cassette sub-family G member 2 (PDB ID: 6FFC).

4. Results and discussion 4.1. Optimize molecular geometry The optimized molecular geometry (depicted in Figure 2) and the computed structural geometry parameters (listed in Table S1 (Supporting Information)) of the compound Tx were obtained with the B3LYP/6-311G++(d,p) level. The compound Tx under investigation was formed from R1=34

hydroxyphenyl and R2=2,4,6-trimethoxyphenyl groups bonded to α,β-unsaturated carbonyl (R1-COCH=CH-R2) group. The C7-C6 and C9-C10 bond lengths between α,β-unsaturated carbonyl group and the other two groups (R1 and R2) connected to it were computed as 1.5102 Å and 1.4498 Å, while the C7=O19, C8=C9 and C7-C8 bond lengths within α,β-unsaturated carbonyl group of the compound Tx were calculated as 1.2261 Å, 1.3533 Å and 1.4766 Å, respectively. Similarly, the CO bond lengths in 2,4,6-trimethoxyphenyl group of the compound Tx were computed as 1.3573 Å, 1.3604 Å and 1.3585 Å for C11-O21, C13-O23 and C15-O22 bond lengths and 1.4226 Å, 1.4225 Å and 1.4231 Å for C18-O21, C17-O-23 and C16-O22 bond lengths. These values computed aforementioned for the compound Tx are in good agreement with bond lengths of similar groups within 1-(2-fluorophenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one [31], 1-phenyl-3-(2,4,6trimethoxyphenyl)prop-2-en-1-one [32], (E)-1-(4-methoxyphenyl)-3-(2,4,6trimethoxyphenyl)prop2-en-1-one [33], (E)-1-(4-bromophenyl)-3-(2,4,6trimethoxyphenyl)prop-2-en-1-one [34] and (2E)1-(pyridin-2-yl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one [35] molecules. Additionally, Alen et al. [36] computed values of 1.352 Å, 1.357 Å and 1.360 Å (for Cring-O bond lengths) and 1.420 Å, 1.419 Å and 1.417 Å for the O-CH3 bond lengths in methoxy groups of (E)-1-(2,4,6trimethoxyphenyl)pent-1-en-3-one molecule with the B3LYP/cc-pVTZ level. Likewise, these C-O bond lengths for a similar molecular system containing 2,4,6-trimethoxyphenyl group were reported as 1.390 Å, 1.385 Å and 1.383 Å (for Cring-O bond lengths) and 1.451 Å, 1.453 Å and 1.456 Å (for Cmethyl-O bond lengths) with the B3LYP/6-31++G(d,p) computational level [37].

Figure 2. The optimized molecular geometry of the compound Tx.

The C1-C6-C7-C8 dihedral angle value was computed as 163.10°, whereas the C8-C9-C10C11 torsional angle was found as 178.61°. It can be seen from the calculated values of these two dihedral angles that the compound Tx deviates from the plane in which the α,β-unsaturated 5

carbonyl group is located with 179.39° of the C7-C8-C9-C10 angle. That is, the compound Tx is a non-planar molecule. A similar comment can be also made by looking at torsional angle value between the planes formed by two aromatic rings. Namely, the dihedral angle value between C1-C6 ring plane and C10-C15 one was obtained as 29.59°. The C5-C6-C7, C6-C7-C8, C7-C8-C9, C8-C9C10 and C9-C10-C11 bond angles were computed at values of 122.69°, 118.28°, 119.55°, 130.76° and 118.27°, respectively. The C-O-C bond angles of the methoxy groups were computed at the interval of 119.10°-119.87°.

4.2. Analyses of vibrational frequencies The experimental and computed vibrational wavenumbers, IR and Raman intensities, Raman scattering activities and vibrational mode assignments for the compound Tx were listed in Table S2 (Supporting Information). Figures 3 and 4 indicate the measured and simulated IR and Raman spectra of the compound Tx, respectively. The position of the OH stretching band may vary depending on the intensity of the intra- and inter-molecular hydrogen bonding interactions. The OH stretching bands within phenols and alcohols can be observed at the interval 3200-3450 cm-1 and above 3450 cm-1 region at presence and absence of intra- and inter-molecular hydrogen bonding interactions, respectively [38-43]. If the intensity of the interactions increases, the position of this band can shifts below 3200 cm-1 region. In our study, the OH stretching band was observed at 3186 cm-1 in FT-IR spectrum and calculated at 3675.1 cm-1. This value of the experimental vibrational frequency may indicate a weak intermolecular hydrogen bonding interaction within the crystal packing of the compound Tx. The OH in-plane bending (δHOC) modes were detected at 1463.2 (calc.) cm-1, 1182 (IR)-1181 (R) (exp.)/1181.5 (calc.) cm-1 and 1164.5 (calc.) cm-1, while the OH out-of-plane bending (τHOCC) mode was observed at 292 cm-1 in Laser-Raman spectrum and computed at 290.1 cm-1 with PED contribution of 93%.

6

Figure 3. Experimental (red) and simulated (balck) IR spectra of the compound Tx.

Figure 4. Experimental (red) and simulated (balck) Raman spectra of the compound Tx.

The aromatic CH stretching vibrations observe in the region of 3000-3100 cm-1, whereas the symmetric and asymmetric CH3 stretching vibrations of methyl groups appear at the range of 28003000 cm-1 [38-42]. The CH stretching vibrations for aromatic groups of the compound Tx were observed at 3013 cm-1 and 3093 cm-1. They were computed at the interval of 3112.3-3016.9 cm-1. Similarly, the CH stretching modes in α,β-unsaturated carbonyl group were calculated at 3128.0 cm1

and 3049.6 cm-1. Six asymmetric stretching vibrations and three symmetric ones of three methyl

groups were obtained in 2970-2941 (IR) (exp.)/3007.5-2940.5 (calc.) cm-1 and 2885-2839 (IR) (exp.)/2885.5-2882.5 (calc.) cm-1 regions, respectively. The scissoring modes of the methyl groups 7

were determine at the intervals of 1472-1411 cm-1 in IR spectrum, 1467-1416 cm-1 in Laser-Raman one and 1480.7-1423.5 cm-1 with the B3LYP/6-311G++(d,p) computational level. Likewise, the rocking and torsional vibrations of the methyl groups were detected at 1221 (IR)-1217 (R) (exp.)/1208.3 (calc.) cm-1, 1186.7 (calc.) cm-1, 1179.7 (calc.) cm-1, 1148.4 (calc.) cm-1, 1147.1 (calc.) cm-1 and 1146.1 (calc.) cm-1 for rocking modes and 275 (R) (exp.)/275.1 (calc.) cm-1, 259.5 (calc.) cm-1 and 239 (R) (exp.)/237.7 (calc.) cm-1 for torsional modes. Additionally, the CH in-plane and out-of-plane bending modes within aromatic rings and α,β-unsaturated carbonyl group of the compound Tx were summarized in Table S2 (Supporting Information). The skeletal C=C stretching vibrations of aromatic groups give bands in 1430-1625 cm-1 region [38-43]. Moreover, the aromatic groups can give rise to CC stretching vibrations as mixed with the other vibrational modes in 1000-1450 cm-1 region [38-43]. In this connection, the bands obtained at 1614 (IR)-1617 (R) (exp.)/1621.6 (calc.) cm-1, 1596.5 (calc.) cm-1 and 1545 (IR)-1543 (R)/1573.0 (calc.) cm-1 were assigned to skeletal C=C stretching vibrations in aromatic groups of the compound Tx. Similarly, the experimental and computed vibrational wavenumbers reported as combined with the other vibrational modes at 1463.2 (calc.) cm-1, 1331 (IR) (exp.)/1330.2 (calc.) cm-1, 1301 (IR) (exp.)/1306.0 (calc.) cm-1, 1182 (IR)-1181 (R) (exp.)/1181.5 (calc.) cm-1, 1084 (IR) (exp.)/1088.5 (calc.) cm-1, 1061 (IR)-1065 (R) (exp.)/1066.2 (calc.) cm-1 and 996 (IR)-998 (R) (exp.)/995.0 (calc.) cm-1 were also assigned to aromatic CC stretching vibrations. The most important characteristic bands of chalcone derivatives are the C=O and C=C stretching modes in α,β-unsaturated carbonyl group of the compound Tx. In our study, these vibrational bands were found at 1634 (IR)-1631 (R) (exp.)/1634.9 (calc. with PED contribution of 64%) cm-1 for C=O stretching mode and 1581 (IR)-1584 (R) (exp.)/1586.3 (calc. with 26% contribution of PED) cm-1 for C=C one. These vibrational modes are in good agreement with our previous studies on chalcone derivatives [44,45]. The vibrational frequency values and their assignments for the CO stretching modes of -OH (hydroxy) and -OCH3 (methoxy) groups on aromatic rings of the compound Tx were listed in Table S2 (Supporting Information).

4.3. Analyses of NMR chemical shifts The 1H-,

13

C- and 2D (DEPT-90, COSY, 1H-13C HMQC and 1H-13C HMBC) NMR spectra

measured in CDCl3 of the compound Tx were given in Figures S2-S8 (Supporting Information). By using the optimized structural geometry in chloroform with IEF-PCM model of the compound Tx, the NMR chemical shifts were computed at the B3LYP/6-311G++(d,p) level with GIAO method by using same solvation model quantities. The experimental and computed 1H and 13C NMR chemical shifts were also listed in Table 1.

8

Table 1. The experimental and calculated 1H- and 13CNMR chemical shifts (with respect to TMS as an internal reference, all values in ppm) of the compound Tx. Atoms δexp. δcal. Atoms δexp. δcal. C1 120.8 127.3 H24 7.58 7.84 C2 129.6 135.9 H25 7.36 7.52 C3 119.5 122.8 H26 7.09 7.14 C4 156.2 165.5 H27 7.64 7.81 C5 115.2 121.0 H28 7.88 8.24 C6 140.7 151.2 H29 8.32 9.10 C7 192.2 198.1 H30 6.14 6.01 C8 121.8 122.8 H31 6.14 6.02 C9 136.6 144.4 H32 3.91 3.98 C10 106.6 113.0 H33 3.91 3.91 C11 161.8 170.9 H34 3.91 4.53 C12 90.5 96.0 H35 3.88 3.81 C13 163.3 172.8 H36 3.88 3.81 C14 90.5 89.8 H37 3.88 4.20 C15 161.8 173.2 H38 3.91 3.76 C16 55.8 57.9 H39 3.91 4.41 C17 55.4 59.0 H40 3.91 3.84 C18 55.8 58.7 H41 6.36 4.50

The H24 and H25 protons gave resonance signals at 7.58 ppm (as a doublet) and 7.36 ppm (as a triplet) with value 7.7 Hz and 7.9 Hz of coupling constants, while they were computed at 7.84 ppm and 7.52 ppm, respectively. The H26 was experimentally recorded as doublets of doublet at 7.09 ppm with the value of coupling constants 2.2 Hz and 8.0 Hz splitting by the H25 and H27 protons and its calculated resonance signal is theoretically obtained at 7.14 ppm. The H27 proton that is splitting by the H24 and H26 protons was occurred at 7.64 ppm as a quasitriplet signal within the most downfield aromatic proton region because of the electronegative oxygen atom and being at the β-position of carbonyl group. The calculated value of this proton is found at 7.81 ppm. It can be clearly seen the presence of the AB spin system with trans configuration in 1H NMR spectrum of the compound Tx. The B part (H28) of the AB system is observed at 7.88 ppm as doublet with value 15.9 Hz of coupling constant which shows the trans configuration of the double bond due to neighborhood with oxygen atom of methoxy group. The A part (H29 atom) of the AB system is appeared as doublet at 8.32 ppm, which is a high chemical shift for an olefinic proton resulting from both being at the position of α,β-unsaturated system and making hydrogen bond interaction with oxygen atoms of carbonyl and methoxy groups. Additionally, it is also located in the deshielding zone of both carbonyl group and aromatic ring. The calculated values of the H28 and H29 were found at 8.24 ppm and 9.10 ppm, respectively. The H30 and H31 aromatic protons which have the same chemical environment are observed at 6.14 ppm as a singlet signal within the experimental 1H NMR spectrum. They were theoretically detected as the resonance signals at 6.02 ppm for the H30 proton and 6.01 ppm for the H31 one. Because of the β-position of the neighboring double bond, methoxy protons of H32, H33, H34, H39, H40 and H41 are experimentally detected at 3.91 ppm as 9

a singlet, while the H35, H36 and H37 methoxy protons are observed as resonance signal at 3.88 ppm as a singlet. These protons were theoretically calculated at the interval of 3.81-4.53 ppm. Finally, The H41 phenolic proton resonates at 6.36 ppm as a broad singlet signal in the experimental 1H-NMR spectrum. However the computed value for this proton was obtained at 4.50 ppm. This may indicate that the inter-molecular hydrogen bond interactions may occur through this group within the crystal package of the compound Tx. The C7 carbon signal in carbonyl group was found at 192.2 ppm (exp.) and 198.1 ppm (calc.) within downfield region of the

13

C-NMR spectrum as expected. There are four carbon

resonance signals for the C4, C11, C13, and C15 aromatic carbon atoms. They have higher chemical shift values than the other aromatic carbons due to the electronegative property of the O20, O21, O23 and O22 oxygen atoms. Among these carbons, the C13 carbon resonated at 163.3 ppm, while the C11 and C15 carbons resonated at 161.8 ppm according to the DEPT-90 spectrum. In addition to this, the C4 carbon resonated at 156.2 ppm as expected and in the 1H-13C HMBC spectrum it correlates with the H25 proton over 3-bonds. According to the calculations, these carbons gave resonance signals at 172.8, 170.9, 161.8 and 156.2, respectively. Since one another downfielded carbon signals neighboring the carbonyl group is the C6 carbon atom, it was observed as resonance signal at 140.7 ppm in the 1H-13C HMBC spectrum and it correlates with the H25 proton over 3-bonds. The computation results show that its resonance signal is at 151.2 ppm. From the 1H-13C HMQC spectra, resonance signals of the olefinic protons can be easily understood that the C8 and C9 carbons gave resonance signals at 121.8 ppm and 136.6 ppm, respectively. In the theoretical results, the C8 carbon gave the resonance signal at 122.8 ppm and the C8 carbon was found at 144.4 ppm. In the 1H-13C HMQC spectrum, the C2 carbon, which resonated at 129.6 ppm, gave a correlation with the H25 signal. The C2 carbon atom was theoretically obtained as a resonance signal at 135.9 ppm. The 1H-13C HMQC spectra also indicated that the C1, C3 and C5 carbons resonated at 120.9 ppm, 119.5 ppm and 115.2 ppm by the correlation of these carbons with the H24, H26 and H27 protons, respectively. In the same order, these carbons gave resonance signals at 122.8 ppm, 127.3 ppm and 121.0 ppm according to the calculation results. The C10 carbon atom gave a resonance signal at 106.6 ppm. This chemical shift value is low for an aromatic proton. It is caused from the inductively electron donation ability of the oxygen atom over the conjugation. Oxygen atoms shift the resonance signal of the C10 carbon atom to the high field while α-β-unsaturated carbonyl group shifts it to the low field of the spectra. The resonance signal also proved by the 1H-13C HMBC spectra. In the 1H-13C HMBC spectra, the C10 carbon atom correlates with the H30 and H31 proton signal over the 3-bonds. In the theoretical spectra, the C10 carbon atom gave a resonance signal at 113.3 ppm. Another highfielded (low chemical shift value) resonance signal belongs to the C12 and C14 atoms. This causes from three-oxygen atom at the α10

position to the C12 and C14 carbon atoms. As a result, these carbon atoms resonated at 90.5 ppm in experimental spectrum, while they were computed at 96.0 ppm and 89.8 ppm, respectively. Finally, in the experimental spectrum, the C16, C17 and C18 carbons resonated at 55.8 ppm, 55.4 ppm and 55.8 ppm and they were computed as resonance signal at 57.9 ppm, 59.0 ppm and 58.7 ppm, respectively. As a conclusion, there is no distinct difference between experimental and theoretical NMR chemical shifts. They support each other for giving resonance signals in both 1H- and

13

C-

NMR analysis.

4.4. FMO analysis and UV-Vis. spectroscopic study Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) that are known as frontier molecule orbitals (FMOs) are important for understanding electronic transitions and charge transfers in molecular systems. Additionally, they are also used for determination of many molecular electrical and electronic features [46-55]. In this connection, depending on HOMO and LUMO energy values, some quantum mechanical descriptors (or some global reactivity descriptors) such as energy band gap |EHOMO-ELUMO|, ionization potential (I = EHOMO), electron affinity (A = -ELUMO), chemical hardness (η = (I-A)/2), chemical softness (ζ = 1/2η), electronegativity (χ = (I+A)/2), chemical potential (µ = -(I+A)/2), electrophilicity index (ω = µ2/2η) and maximum charge transfer index (∆Nmax. = -µ/η) for the compound Tx were computed and listed in Table 2.

Table 2. Quantum chemical descriptors computed of the compound Tx. Parameters (eV) Values ELUMO -2.2727 EHOMO -5.8948 3.6221 Energy bandgap |EHOMO−ELUMO| 5.8948 Ionization potential (I = −EHOMO) 2.2727 Electron affinity (A = −ELUMO) 1.8111 Chemical hardness (η = (I−A)/2) 0.2761 Chemical softness (ζ = 1/2η) Electronegativity (χ = (I+A)/2) 4.0838 -4.0838 Chemical potential (µ = −(I+A)/2) 4.6042 Electrophilicity index ( ω = µ2/2η) 2.2549 Maximum charge transfer index (∆Nmax. = −µ/η)

The HOMOs (H, H-1, H-2, H-3 and H-4) and LUMOs (L and L+1) investigations of the compound Tx were analyzed with the RB3LYP/6-311G++(d,p) level in chloroform by using IEFPCM solvation model. Their simulated plots and the energy values of each were depicted in Figure 5. The HOMO and LUMO energy values and the energy difference between them were computed as -5.8948 eV, -2.2727 eV and 3.6221 eV, respectively. As can be seen from Figure 5, the H, H-1, 11

H-2 and H-4 were mostly localized over bonding π (or e1g) molecular orbitals of aromatic and C=C- groups, whereas the L and L+1 were mainly placed on anti-bonding π (or e2u) molecular orbitals of these groups. The charge transfers or molecular electronic transitions from H, H-1, H-2, and H-4 to L and L+1 are character of π→π*.

Figure 5. HOMOs and LUMOs plots of the compound Tx.

The experimental UV-Vis. spectrum of the compound Tx dissolved in chloroform was obtained to determine electronic transitions and charge transfers between molecular groups in the molecule. To support the experimental UV-Vis. spectroscopic electronic absorption wavelengths, the theoretical UV-Vis. electronic features (wavelengths, excitation energies, oscillator strengths and possible electronic transitions) of the compound Tx were computed with the TD12

DFT/RB3LYP/6-311G++(d,p) computational level in chloroform solvent by using IEF-PCM solvation model. The simulated and experimental UV-Vis. spectra of the compound Tx were given in Figure 6. Additionally, Table 3 includes the experimental and computed UV-Vis. spectral parameters and electronic transitions corresponding to wavelengths. The percentage major contributions of electronic transitions corresponding to the calculated UV-Vis. wavelengths were computed via GaussSum 3.0.1 program package [56].

Figure 6. Experimental (black) and simulated (blue) UV-Vis. spectra of compound Tx. Table 3. The UV-Vis. spectroscopic parameters of the compound Tx. λexp. (nm) (Abs.) Transition λcal. (nm) f ∆E (eV) Major contributions of transitions 366 (2.2211) π→π* 382.76 0.8556 3.2392 H→L (98%) π→π* 369.50 0.0208 3.3554 H-3→L (76%), H-1→L (13%) π→π* 343.96 0.0315 3.6046 H-2→L (63%), H-1→L (34%) π→π* 334.67 0.0138 3.7047 H-1→L (50%), H-2→L (28%), H-3→L (20%) 256 (1.2086) π→π* 276.14 0.1494 4.4899 H-4→L (76%), H→L+1 (16%) 238 (1.0662) π→π* 270.66 0.1107 4.5808 H→L+1 (80%), H-4→L (13%) ∆E, Excitation energy; f; oscillator strength; Abs, Absorbance.

The electronic absorption wavelengths emerged at 238 nm, 256 nm and 366 nm in the region of 200-400 nm of the recorded UV-Vis. spectrum of the compound Tx can be corresponded to π→π* electronic transition. This transition can be resulted from aromatic rings and olefinic -C=Cgroup. Because, these molecular groups contain bonding and anti-bonding π molecular orbitals in electronic structure. Six excited states for the compound Tx were computed at 382.76 nm, 369.50 nm, 343.96 nm, 334.67 nm, 276.14 nm and 270.66 nm with values 0.8556, 0.0208, 0.0315, 0.0138, 0.1494 and 0.1107 of oscillator strengths, respectively. The percentage major contributions of electronic transitions corresponding to these computed wavelengths H→L (98%) for 382.76 nm, H3→L (76%) and H-1→L (13%) for 369.50 nm, H-2→L (63%) and H-1→L (34%) for 343.96 nm, H-1→L (50%), H-2→L (28%) and H-3→L (20%) for 334.67 nm, H-4→L (76%) and H→L+1 13

(16%) for 276.14 nm and H→L+1 (80%) and H-4→L (13%) for 270.66 nm. As emphasized in HOMO and LUMO studies, it can be seen from the experimental and theoretical UV-Vis. spectral studies that the electronic transitions corresponding to all wavelengths are character of π→π*.

4.5. MEP surface analysis Molecular electrostatic potential (MEP) [57] surface was performed to predict electrophilic and nucleophilic reactive attack sites of the compound Tx. These sites can be used for determination of interactions regions. The MEP mapping of the compound Tx were drawn with the B3LYP/6-311G++(d,p) computational level. A MEP surface is presented with different colors from red to blue. The red points on surface indicate electrophilic reactive attack sites that are negative values of electrostatic potential, whereas the blue points symbolize nucleophilic reactive attack sites which are positive values of electrostatic potential. The green points are neutral regions of electrostatic potential. Additionally, the orange-yellow and light blue points present partial negative and partial positive regions on surface. Figure 7 shows the MEP surface plotted from two different points of view of the compound Tx. The negative electrostatic potential points were placed with value of -8.029 e-2 over the O19 atom in α,β-unsaturated carbonyl group of the molecule. Similarly, the partial negative were localized around the centers of the two aromatic rings at the interval of (1.500 e-2)-(-3.900 e-2). The positive electrostatic points were localized on the other all hydrogen atoms and particularly H41 atom (+6.838 e-2) in -OH group of phenol ring. These negative and positive electrostatic potential regions may indicate the presence of intermolecular interactions within the experimental X-Ray crystal packing and molecular docking study. Additionally, the partial negative electrostatic potential values around the aromatic ring centers may also found out the presence of π interactions.

Figure 7. MEP surface plotted from different points of view of the compound Tx.

14

4.6. Thermochemical analysis Thermodynamic features of the compound Tx were computed at the DFT/B3LYP/6-311G++(d,p) level at temperature of 298.15 Kelvin, under 1 atm pressure and within gas phase. The calculated thermochemical features were listed in Table S3 (Supporting Information). Depending on electronic, translational, rotational and vibrational partition functions, the total molecular electronic energy (E0 = Ee + Et + Er + Ev) of the compound Tx was computed as -1073.12295534 Hartrees with the RB3LYP/6-311G++(d,p) level. The zero-point vibrational energy (ZPVE) was calculated as 203.94529 kcal/mol. The zero-point correction, thermal correction to energy, thermal correction to enthalpy and thermal correction to Gibbs free energy values were computed as 0.325008, 0.347310, 0.348254 and 0.271705 Hartree/particle, respectively. Sum of the total molecular electronic energy value with these computed correction values give sum of electronic and zeropoint energies (-1072.797948 Hartree/particle), sum of electronic and thermal energies (1072.775645 Hartree/particle), sum of electronic and thermal enthalpies (-1072.774701 Hartree/particle) and sum of electronic and thermal free energies (-1072.851250 Hartree/particle). The total values for thermal energy, heat capacity and entropy were computed as 217.940 kcal/mol, 83.418 cal/mol×K and 161.111 cal/mol×K, respectively. As seen from Table S3 (Supporting Information), the major contributions to these quantities come from vibrational part with values of 216.163 kcal/mol (for thermal energy), 77.457 cal/mol×K (for heat capacity), 161.111 cal/mol×K (for entropy), whereas the minor contributions result from electronic part with values 0.000 cal/mol×K. This result indicates importance of vibrational analysis studies of molecular systems. The rotation constants used in microwave investigations were computed as 0.47899, 0.11173 and 0.09150 GHz for the compound Tx.

4.7. Nonlinear optical analysis There are potential applications in fields such as switching, computing, interconnections, telecommunications, information processing, modulation, data storage, signal processing, dynamic image processing and sensor protection of optical industry of nonlinear optical (NLO) materials. Additionally, NLO materials use in various photonic technologies of opto- and micro-electronics [58]. Therefore, the research of high performance NLO materials has been a popular topic of study. For the compound Tx, the dipol moment (µ), the polarizabilities (α) and the first-order hyperpolarizabilities (β) at the static state were computed by using keyword polar=enonly with the B3LYP/6-311G++(d,p) level. The µ, α and β quantities in terms of x, y and z components were listed in Table S4 (Supporting Information). The µ total, αtotal, ∆α and β0 quantities were obtained via the following equations [58]; 15


 = (
 +
 +
)/  = ∆ =

1 √2

1  +  +   3  /

( −  ) + ( −  ) + ( −  ) + 6 + 6 + 6 

/

 = ( +  +  ) + ( +  +  ) + ( +   +   ) 

The static µ total, αtotal, ∆α and β0 values of the compound Tx were calculated as 2.3093318 Debye, 40.1634421×10-24 esu, 36.0629812×10-24 esu and 339.8154261×10-31 esu, respectively. The urea is a common molecule used in NLO research. So, the NLO parameters of compounds can be compared with those the urea. The static µ total, αtotal, ∆α and β0 quantities with the B3LYP/6311G++(d,p) computational level of urea were found as 1.5264225 Debye, 5.04773248×10-24 esu, 2.1118099×10-24 esu and 7.5880127×10-31 esu, respectively. If these values of the compound Tx are compared with these parameters of the urea, we see that they are approximately 1.513, 7.957, 17.708 and 44.783 times greater than those of the urea, respectively. The obtained these results show that the compound Tx exhibits a good NLO feature and may be used as a suitable NLO material.

4.8. Molecular docking study AutoDock Vina [30] program package was used to investigate the binding modes at different poses of the compound Tx docked into a breast cancer resistance protein ATP-binding cassette sub-family G member 2 (PDB ID: 6FFC). High resolution crystal structure of protein ATP-binding cassette sub-family G member 2 (PDB ID: 6FFC) were supplied from the RCSB Protein Data Bank website [59], while the optimized molecular structure in gas phase of the compound Tx was used as ligand molecule. The .pdb files of the protein and ligand molecules were arranged via Discover Studio Visualizer (DSV) program [60]. Additionally, the presented plots for protien-ligand interactions for the best binding mode of the compound Tx docked into the macromolecule 6FFC were obtained with DSV program. The research space volume was chosen within the region where the active sites of the macromolecule 6FFC were located. This volume was adjusted within the grid size of 50Å×50Å×80Å at value 0.375 Å of spacing. The macromolecule 6FFC structure of ATP-binding cassette sub-family G member 2 that is a breast cancer resistance protein is composed of two protein chains. The ligand molecule was docked into α-helix region containing active sites between 16

these two chains. Table S5 (Supporting Information)includes the binding affinities and their RMSD values calculated for ten different binding modes of the compound Tx docked into the macromolecule 6FFC. The binding affinity for the best binding mode of the compound Tx docked into the macromolecule 6FFC was found as -9.10 kcal/mol with values 0.000 Å of RMSD. According to the computed RMSD values in molecular docking studies, an ideal docking analysis can be possible with obtaining of RMSD values up to 2 Å [61]. Visualizations of interactions between the conformational mode at the best pose of the compound Tx docked into its and the macromolecule 6FFC were depicted in Figure 8. According to molecular docking analysis, there are one carbon hydrogen bond, one unfavorable acceptor-acceptor, two pi-pi stacked and one pi-alkyl interactions between the macromolecule 6FFC and the compound Tx. The carbon hydrogen bond interaction (C-H…OTHR(B)435) was formed between =O atom of residue THR(B)435 and the methyl CH group of the ligand molecule with value 2.85 Å of interaction distance. The unfavorable acceptor-acceptor interaction (=O…OTHR(A)435) was occurred between oxygen atom in -OH group of residue THR(A)435 and and =O atom in α,β-unsaturated carbonyl group of the compound Tx with value of 2.95 Å of interaction distance. Similarly, the pi-pi stacked interactions (π…πPHE(A)439 interaction with value of 4.47 Å and π…πPHE(B)439 interaction with value of 4.06 Å) were obtained between the aromatic groups of residues PHE439 in A and B chains of the macromolecule 6FFC and the 2,4,6-trimethoxyphenyl group of the ligand molecule, while the pi-alkyl interaction was found between delocalized pi electrons of the aromatic group of residue VAL(B)546 of the macromolecule 6FFC with delocalized pi electrons of the phenol ring of the compound Tx with value 3.80 Å of interaction distance.

Figure 8. Visualizations of protein-ligand interactions of the compound Tx docked into a breast cancer resistance protein ATP-binding cassette sub-family G member 2 (PDB ID: 6FFC).

17

5. Conclusion A novel synthesized chalcone derivative, (E)-1-(3-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop2-en-1-one (Tx), was characterized by using experimental and computational methods. The structural properties such as bond lengths and bond angles were theoretically investigated by the molecular geometry analysis. The trans configuration form and the most important spectral bands of the α,β-unsaturated carbonyl group within the compound Tx were analyzed by NMR and vibrational (IR and Raman) spectroscopic techniques. The nature and origin of the intra-molecular electronic transitions were confirmed via investigation of electronic properties such as HOMO, LUMO and UV-Vis. spectral analyses. Some quantum mechanical descriptors were theoretically determined for the compound Tx. The electrophilic and nucleophilic reactive attack sites, the information about inter-molecular interactions and probable binding sites of the studied compound were obtained by using MEP surface analysis. The thermodynamic features such as entropy, enthalpy, heat capacity, total energy, thermal free energy, rotational constants etc. were theoretically determined for the compound within gas phase. The compound Tx may be used as a suitable NLO material in optical researches according to values of the static µ total, αtotal, ∆α and β0. Noteworthy values of binding affinity and inter-molecular interactions obtained with molecular docking analysis can show that the compound Tx may be used as an effective molecule against breast cancer.

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Highlights • Protein-ligand interactions were studied via molecular docking analysis. • Spectral properties were investigated using both experimental and theoretical methods. • All computations were performed with DFT/B3LYP/6-311G++(d,p) level.

• Electronic charge transitions were determined by UV-Vis. and HOMO-LUMO analyses. • MEP, NLO and thermodynamic analyses were theoretically studied.

1

Declaration of interests X The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. X The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

No funding.