Synthesis, crystal structure, Hirshfeld surface analysis, spectroscopic characterization, reactivity study by DFT and MD approaches and molecular docking study of a novel chalcone derivative

Accepted Manuscript Synthesis, crystal structure, Hirshfeld surface analysis, spectroscopic characterization, reactivity study by DFT and MD approaches and molecular docking study of a novel chalcone derivative Suhana Arshad, Renjith Raveendran Pillai, Dian Alwani Zainuri, Nuridayanti Che Khalib, Ibrahim Abdul Razak, Stevan Armaković, Sanja J. Armaković, C. Yohannan Panicker, C. Van Alsenoy PII:

S0022-2860(17)30123-0

DOI:

10.1016/j.molstruc.2017.01.080

Reference:

MOLSTR 23385

To appear in:

Journal of Molecular Structure

Received Date: 9 September 2016 Revised Date:

27 January 2017

Accepted Date: 27 January 2017

Please cite this article as: S. Arshad, R.R. Pillai, D.A. Zainuri, N.C. Khalib, I.A. Razak, S. Armaković, S.J. Armaković, C.Y. Panicker, C. Van Alsenoy, Synthesis, crystal structure, Hirshfeld surface analysis, spectroscopic characterization, reactivity study by DFT and MD approaches and molecular docking study of a novel chalcone derivative, Journal of Molecular Structure (2017), doi: 10.1016/ j.molstruc.2017.01.080. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

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Graphical abstract:

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Title of the paper: “Synthesis, Crystal Structure, Hirshfeld Surface Analysis, Spectroscopic Characterization, Reactivity Study by DFT and MD approaches and Molecular Docking Study of a novel chalcone derivative.”

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In this work, a new chalcone derivative, (E)-1-(4-bromophenyl)-3-(4(trifluoromethyl)phenyl)prop-2-en-1-one is synthesized and structurally characterized by single crystal XRD. Hirshfeld surface analysis was carried out in order to establish a quantitative insight into the intermolecular interactions. The FT-IR spectrum was recorded and interpreted in details with the aid of Density Functional Theory (DFT) calculations and Potential Energy Distribution (PED) analysis. In order to investigate local reactivity properties of the title molecule, we have conducted DFT calculations of average local ionization energy surface and Fukui functions which were mapped to the electron density surface. In order to predict the open air stability and possible degradation properties, within DFT approach, we have also calculated bond dissociation energies. To determine which atoms of title molecule have pronounced interactions with water molecules, we have calculated radial distribution functions obtained after molecular dynamics simulations. In order to understand how the title molecule inhibits and hence increases the catalytic efficiency of MOA-B enzyme, molecular docking study was performed to fit the title compound into the binding site of MOA-B enzyme.

ACCEPTED MANUSCRIPT Synthesis, Crystal Structure, Hirshfeld Surface Analysis, Spectroscopic Characterization, Reactivity Study by DFT and MD approaches and Molecular Docking Study of a novel chalcone derivative. Suhana Arshada , Renjith Raveendran Pillaib, Dian Alwani Zainuria, Nuridayanti Che Khaliba, Ibrahim Abdul Razaka, Stevan Armakovićc, Sanja J. Armakovićd, C. Yohannan Panickerb, C. a

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Van Alsenoye X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM,

Penang, Malaysia. b

Department of Physics, TKM College of Arts and Science, Karicode, Kollam, Kerala.

University of Novi Sad, Faculty of Sciences, Department of Physics, Trg D. Obradovića 4,

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c

21000 Novi Sad, Serbia. d

University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and

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Environmental Protection, Trg D. Obradovića 3, 21000 Novi Sad, Serbia. e

Department of Chemistry, University of Antwerp, B2610, Antwerp, Belgium.

*

Author for correspondence: Email: [email protected]

Phone: +918281560152

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Abstract

In the present study, the title compound named as (E)-1-(4-bromophenyl)-3-(4(trifluoromethyl)phenyl)prop-2-en-1-one was synthesized and structurally characterized by single-crystal X-ray diffraction. The compound crystallizes in monoclinic crystal system in

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P21/c space group, unit cell parameters a = 16.7629 (12) Å, b = 13.9681 (10) Å, c = 5.8740 (4) Å, β = 96.3860 (12)˚ and Z = 4. Hirshfeld surface analysis revealed that the molecular

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structure is dominated by H···H, C···H/H···C, Br···F/F···Br and F···F contacts. The FT-IR spectrum was recorded and interpreted in details with the aid of Density Functional Theory (DFT) calculations and Potential Energy Distribution (PED) analysis. Average local ionization energies (ALIE) and Fukui functions have been used as quantum-molecular descriptors to locate the molecule sites that could be of importance from the aspect of reactivity. Degradation properties have been assessed by calculations of bond dissociation energies (BDE) for hydrogen abstraction and the rest of the single acyclic bonds, while molecular dynamics (MD) simulations were used in order to calculate radial distribution functions and determine the atoms with significant interactions with water. In order to understand how the title molecule inhibits and hence increases the catalytic efficiency of

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ACCEPTED MANUSCRIPT MOA-B enzyme, molecular docking study was performed to fit the title compound into the binding site of MOA-B enzyme. Keywords: DFT; Chalcones; XRD; FT-IR; Molecular Dynamics, Molecular Docking.

1.

Introduction

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In recent years, chalcone and its substituted derivatives plays a significant role in pharmaceutical chemistry. Indeed, antimalarial [1], antitubercular [2], anticancer [3], antioxidant [4] and antifungal [5] agents bearing chalcone fragment have been widely used as therapeutically important drugs. The potential drug, echinatin, used for the treatment of

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leishmaniasis [6] is a well known naturally occurring chalcone derivative. Another naturally occurring chalcones include larrein [7], sappanchalcone [8], crotaoprostin [9] and flavokawain [10]. Recently, Otvos et al. [11] reported the continuous-flow synthesis of

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deuterium-labelled antidiabetic chalcones. Replacement of C–H or C–OH bonds by C–F bond were widely accepted since such substitutions results in alterations in physicochemical properties and biological activities of organic compounds, without introducing much major steric changes [12]. Because of this, fluorine substitution has been attracted by many researchers to develop wide range biologically active materials. Nakamura et al. [13]

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synthesized a series of fluorinated chalcones, evaluated their biological activities and found that the potencies of these compounds were comparable or better than that of the well-known compound 3,4-dihydroxychalcone. Javier Rojas et al. [14] reported the effect of fluorinated chalcone derivatives on nitric acid production. Kooriyaden et al. [15] investigated the

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influence of trifluoromethyl groups in the crystal packing motif of the metalloporphyrins using Hirshfeld surface analysis. With the aim of developing new antimalarial drugs, Boechat

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et al. [16] have reported the design and synthesis of a series of trifluoromethyl-substituted benzenesulfonamide derivatives. A combined experimental and computational studies of (E)2-(((4-bromo-2-(trifluoromethoxy)phenyl)imino)methyl)-4-nitrophenol

was

reported

by

Tamer et al. [17].

In view of the significant applications of organofluorine derivatives, here we are

reporting the crystal structure of a newly synthesized chalcone derivative containing a trifluoromethyl group. The molecular structure and spectroscopic properties were investigated by single crystal X-ray diffraction and infrared (IR), 1H and

13

C NMR

techniques. Intermolecular interactions in the crystal structure of the title compound were studied in detail using Hirshfeld surface analysis. Principles of molecular modeling are frequently employed in order to predict important reactive properties of various molecules 2

ACCEPTED MANUSCRIPT [18–21]. These predictions offer possibilities not only to understand behaviour of such molecules in organism, but also to understand how their degradation can be induced. In order to investigate local reactivity properties of the title molecule, we have conducted DFT calculations of average local ionization energy surface and Fukui functions which were mapped to the electron density surface. In particular, in this work we have used DFT

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calculations of bond dissociation energies (BDE), since this parameter is correlated with autoxidation sensitivity of molecule. On the other side, sensitivity towards hydrolysis mechanism of molecule was investigated by calculating radial distribution functions (RDFs), as obtained after molecular dynamic simulations. In order to explore possible binding mode

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of the title compound towards MAO-B isoform of the enzyme, molecular docking study was performed to fit the compound into binding site of the enzyme, which consists of a substrate cavity extends from the covalently bound redox cofactor flavin adenine dinucleotide (FAD)

2.

Experimental

2.1.

Synthesis and Crystal Growth

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to the entrance cavity and an aromatic cage.

Synthesis of (E)-1-(4-bromophenyl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one Standard Claisen–Schmidt condensation method was used to prepare the compound

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which is easy and simple to conduct as well as inexpensive, not sensitive to oxygen and water; which make it easy to operate at room temperature and it can be readily used in laboratory

[22].

Commercially

available

4-bromoacetophenone

(1

mol)

and

4-

(trifluoromethyl)benzaldehyde (1 mol) were used to prepare the title compound. The

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reactants were dissolved in 20 ml of methanol solution and stirred continuously. Catalytic amount of NaOH was added to the solution drop-wise. The reaction mixture was then stirred

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for about 5–6 hours at room temperature. The resultant crude products were filtered, washed successively with distilled water and recrystallized from acetone to get the corresponding chalcone (Scheme 1). The repeated crystallization yield light yellow plate crystals (CCDC No.: 1013208) as shown in Fig.S1, given as supplementary information. Structure of the synthesized compound was characterized by single crystal XRD, 1H NMR,

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C NMR, and

FT-IR. The FT-IR spectrum was recorded in the 4000‒400 cm-1 region with a PerkinElmer Spectrum GX Frontier Spectrophotometer using KBr pellet. 1H and 13C NMR spectra were recorded at 500 MHz, in DMSO‒d6, on Bruker 500MHz Avance III spectrometer. The chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS) internal reference.

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2.2.

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Scheme 1. Synthetic route of the title compound X-Ray Crystallography Analysis

Data collection on single crystal suitable for X-ray analysis was performed on APEXII Duo CCD area-detector using MoKα radiation (λ = 0.71073 Å). Data collection was performed using the APEX2 software [23], whereas the cell refinement and data reduction were performed using the SAINT software [23]. The crystal structure was solved by direct

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method using the program SHELXTL [24] and refined by full-matrix least squares technique on F2. Absorption correction was applied to the final crystal data using the SADABS software [23]. All geometrical calculations were carried out using the program PLATON

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[24]. The molecular graphics were drawn using SHELXTL [23] and Mercury program [25]. The non-hydrogen atoms were refined anisotropically. All the hydrogen atoms were positioned geometrically (C–H = 0.93 Å) and refined using riding model Uiso(H) = 1.2

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Ueq(C). In the final refinement, the most disagreeable reflections were omitted (1 0 0 and 7 3 3). A summary of crystal data and relevant refinement parameters of the title compound is given in Table 1. 3.

Computational Details

Geometry optimization and vibrational frequency calculations of the title compound were carried out with Guassian09 software package [26], using the three-parameter hybrid functional of Becke based on the correlation functional of Lee, Yang, and Parr (B3LYP) [27]. The 6-311+G(d,p) basis set was assigned to all atoms in the title molecule. We have used a scaling factor of 0.9688 for vibrational frequencies, since the B3LYP functional tends to overestimate the fundamental vibrational modes [28]. The assignments of wavenumbers were 4

ACCEPTED MANUSCRIPT carried out using the potential energy distribution (PED) analysis with the help of GAR2PED software [29] and animation option of the Gaussview program [30]. In order to obtain all possible conformations of the title molecule, MD simulations have been performed with MacroModel program [31]. DFT calculations of ALIE, Fukui functions and bond dissociation energies (BDE) have been performed using the Jaguar 9.0

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program [32]. Investigation of the influence of solvent (water) was conducted by MD simulations in Desmond program [33–35]. Used MacroModel, Jaguar and Desmond programs are implemented in the Schrödinger Materials Science Suite 2015-4. All input and output files were manipulated by Maestro graphical user interface for Schrödinger Materials

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Science Suite 2015-4. All MD simulations were performed with OPLS 2005 force field [36]. For MD simulations in MacroModel default values for parameters were chosen and for MD simulations in Desmond an NPT ensemble class was used, with cut off distance of 12 Å and

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simulation time of 10 ns. The temperature was set to 300 K, while pressure was set to 1.0235 bar. Time step in RESPA integrator [37] was set to 2.0 fs. Solvent was treated within simple point charge [38] model, while the whole system was modelled by placing one molecule in cubic box with ~3000 water molecules.

All DFT calculations have been performed by B3LYP exchange-correlation

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functional [39] and 6-31g(d,p) basis set for ALIE and noncovalent interactions, 6-31+g(d,p) basis set for the Fukui functions and 6-311g(d,p) basis set for the calculations of BDE. Conformers obtained by the MacroModel program, total of 10 structures, have been optimized at B3LYP/6-31g(d) level of theory and then the five lowest energy conformers

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were further again optimized at B3LYP/6-31g(d,p) level of theory with increased integral accuracy and finer grid density, followed by frequency calculations in order to assure that

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true ground states were located. Finally, the lowest energy conformation among these five was chosen for the detailed DFT calculations and MD simulations. The method of Johnson [40, 41] was employed, also as implemented in Jaguar 9.0 program, for the determination of intramolecular noncovalent interactions. 4. 4.1.

Results and Discussion Description of the Crystal Structure

The single crystal of the compound was obtained from slow evaporation in acetone at room temperature. The compound crystallizes in monoclinic crystal system in P21/c space group, unit cell parameters a = 16.7629 (12) Å, b = 13.9681 (10) Å, c = 5.8740 (4) Å, β = 96.3860 (12)˚ and Z = 4. Selected bond lengths and angles of the compound are summarized in a table and given in the supporting information (Table S1), where all geometrical 5

ACCEPTED MANUSCRIPT parameters are within the normal ranges [42] and comparable with the previously reported structure of substituted chalcones [43, 44]. The molecular structure of the compound is shown in Fig.1(a) with displacement ellipsoids plotted at 50% probability level. The compound exists in E configuration with respect to the C8=C9 double bond with bond distance of 1.330 (2) Å (Table S1). The molecular structure is slightly twisted at 4-

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bromobenzaldehyde moiety (Br1/O1/C1–C7) indicated by the C6–C7–C8–C9 torsion angle of 162.19 (15)˚. In addition, the trifluoromethyl-substituted benzene ring (C10–C15) forms dihedral angle of 48.16(7)˚ with the bromo-substituted benzene ring (C1–C6), showing the molecule is slightly deviated from its planarity. The twisted compound is shown in Fig.1(b).

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In the crystal packing, the intermolecular C5–H5A···Cg1 [symmetry code: x,1/2y,1/2+z; Cg1 is the centroid of C1–C6 benzene ring] and C12–H12A···Cg2 [symmetry code: x,1/2-y,-1/2+z; Cg2 is the centroid of C10–C15 benzene ring] interactions (Table 2) link the

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molecules into infinite one dimensional chain along the c-axis as shown in Fig.2. The crystal structure are further stabilized by the short halogen···halogen interactions (Table 3) between the bromine and fluorine atoms of C3–Br1···F3 [Br···F = 3.1574(11) Å; symmetry code: 1+x,y,z], C16–F1···F1 [F···F = 2.8389(17) Å; symmetry code: -1-x,1-y,-1-z] and C16– F3···Br1 [F···Br = 3.1574(11) Å; symmetry code: -1+x,y,z] contacts where the short contact

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distances are found to be shorter than the sum of Van der Walls radii for fluorine (1.47 Å) and bromine (1.86 Å) atoms [45]. These short halogen···halogen contacts bridge the chains into a two-dimensional plane as shown in Fig.3. 4.2.

Hirshfeld Surface Analysis

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The Hirshfeld surface provides a three-dimensional picture of intermolecular interactions. This analysis approaches a graphical tool for visualization and understanding of

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intermolecular interactions. The Hirshfeld surface and the related 2-D fingerprint plots for the title compound were performed utilizing Crystal Explorer 3.1 [46]. The distance from the Hirshfeld surface to the nearest atoms outside and inside the surface are represented as di and de, respectively. For the distance from the surface to the nearest atom interior to the surface is known as di, while de represents the distance from the surface to the nearest atom exterior to the surface [47, 48]. The blue colour refers to the low frequency of occurrence of (di, de) pair and the grey colour is the outline of the full fingerprint [49]. The dnorm values are mapped onto the Hirshfeld surface by using a red-blue-white colour scheme, where a red spot represent shorter contacts, blue shows longer contacts and white is for contacts around the Van der Walls separation.

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ACCEPTED MANUSCRIPT In this work, Hirshfeld surface analysis of the title compound was performed to visualize the presence of halogen-halogen interactions. The short halogen···halogen interactions are visualized as bright-red spots on the Hirshfeld surface mapped over dnorm with neighbouring molecules connected by C3–Br1···F3, C16–F1···F1 and C16–F3···Br1 as shown in Fig.4. The overall 2-D fingerprint plots from the Hirshfeld surface analysis have

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been calculated to gain the quantitative data on the percentage contributions of intermolecular and halogen contacts on the molecules. The significant of intermolecular and halogen interaction patterns are delineated into H···H, C···H/H···C, Br···F/F···Br and F···F contacts as illustrated in Fig.5. The 17.8% contribution from the H···H contacts to the Hirshfeld

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surface of the title chalcone compound is shown in Fig.5(a). The presence of halogenhalogen interactions are shown by the 9.7% and 6.4% contribution to the Hirshfeld surface representing Br···F/F···Br and F···F, respectively (Fig.5b and Fig.5c). The presence of

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Br···F/F···Br interactions are indicated by two symmetrical narrow pointed spikes with di + de ~ 3.1 Å (Fig.5b), while the existence of F···F interactions are shown by the sharp distinct point at di + de ~ 2.8 Å (Fig.5c). The pair of characteristics wings with the edge at de + di ~ 3.2 Å (Fig.5d) in the fingerprint plot delineated by C···H/H···C contacts is due to the contribution of C–H···π interactions and clearly make the most significant contribution

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(30.4%). The presence of these interactions are also indicated through the pale-orange spots present on the Hirshfeld surface mapped over de, shown within the pink circle in Fig.6(a), and the bright-red spots over the front side of the shape-indexed surface identified with arrows in Fig.6(b). The reciprocal of these C–H···π contacts, π···H–C contacts are seen as

4.3.

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blue spots near the ring identified with blue arrow in Fig.6(b). IR spectrum

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FT-IR spectra of the title compound are presented in Fig.7. Observed and calculated vibrational modes with their tentative assignments are summarized in Table 4. In the following discussion the para-substituted phenyl rings are designated as PhI (C1–C2–C3–C4– C5–C6) and PhII (C10–C11–C12–C13–C14–C15). The vibrations involving both aromatic and aliphatic C–H stretching give rise to bands above 3000 cm-1, in the IR spectrum. In the present case, two C–H stretching modes of the vinylene group were calculated at 3096 cm-1 and 3050 cm-1. According to Panicker et al. [50], the bands at 3086 cm-1 (IR) and at 3089, 3050 cm-1 (DFT) was due to the stretching modes of the vinylene group. For the title compound, in-plane and out-of-plane CH bendings were calculated at 1311, 1194 cm-1 and 990, 729 cm-1, respectively and the wagging vibrations of vinylene CH group were observed

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ACCEPTED MANUSCRIPT at 991, 725 cm-1 in the IR spectrum. In the present case, bands calculated at 1269, 1071, 1048, 997 cm-1 were assigned to the non-cyclic C–C stretching modes and these vibrations were observed at 1266, 1069 cm-1 in the IR spectrum. The carbonyl moiety in substituted chalcones absorbs IR strongly in the 1750–1600 cm-1 region [51]. Clothup et al. [52] found that substituted chalcones absorb infrared

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radiation strongly around 1650 cm-1, because of the C=O stretching vibrations. The C=O stretching occur at lower frequencies when conjugated to C=C. In the present case, the C=O stretching vibration was observed at 1662 cm-1 in the IR spectrum and assigned at 1666 cm-1, theoretically, which are in well agreement with the reported values for substituted chalcones [43, 53]. For the majority of condensed-phase organic samples, C=C stretching band is

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observed around 1600 cm-1 due to the conjugation with the adjacent carbonyl group [54]. Recently, Praveen et al. [55] has examined C=C bands in substituted chalcones that are seen

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at 1578 cm-1 (IR) and 1588 cm-1 (DFT). The C=C stretching frequency of the title compound is estimated to be at 1591 cm-1, which is only 4 cm-1 higher than the experimental value of 1587 cm-1.

In the present discussion of IR spectrum, the assignments of the substituted phenyl ring vibrations were made by referring the case of benzene derivatives with 1,4-disubstitution by Roeges [51]. As per the reference [51], CH stretching modes in the para-substituted

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benzenes can give rise to IR bands in the range 3105–3000 cm-1. For the title compound, phenyl C–H stretching modes are assigned to bands in the range 3106–3081 cm-1 for PhI and 3102–3076 cm-1 for PhII and observed at 3086 cm-1 in the IR spectrum. The four in-plane CH

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bending modes of 1,4-disubstituted benzene ring usually give rise to bands in the 1315–1015 cm-1 region, while IR bands correspond to out-of-plane C–H stretching modes are located in a lower region, at 995–720 cm-1 [51]. In the present case, in-plane bendings of phenyl C–H

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were assigned at 1277, 1188, 1097, 1004 cm-1 for PhI and 1280, 1171, 1084, 1042 cm-1 for PhII and observed at 1182, 1081, 1038, 1006 cm-1 in the IR spectrum. In disubstituted benzenes, the C–H out-of-plane deformations are usually observed between 995 and 720 cm1

[51] and for the title compound these vibrations were assigned to bands in the range 967–

805 cm-1 for PhI and 960–817 cm-1 for PhII. In the IR spectrum these vibrations were observed at 948, 837, 818 and 807 cm-1. General IR and Raman regions for para-substituted benzenes include 1630–1280 cm-1 (ring stretching) and 810–680 cm-1 (ring breathing) [51]. For the title compound, these ring stretching vibrations are assigned to bands in the range 1568–1299 cm-1 for PhI and 1602–1317 cm-1 for PhII and observed at 1599, 1564, 1492, 1398, 1375, 1315 cm-1 in the IR spectrum. The ring breathing modes of the phenyl rings of 8

ACCEPTED MANUSCRIPT the title compound were calculated to be 739 and 793 cm-1, and the experimental value was found to be 774 cm-1 for PhII. The ring breathing mode of 1,4 di-substituted benzene was found in the IR spectrum at 785 cm-1 [56]. Kaur et al. [57], investigated the vibrational spectra of 4-methylbiphenyl-2-carbonitrile and parasubstituted phenyl ring stretching vibrations were assigned to the bands at 1614, 1560, 1504, 1379 cm-1, while the ring

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breathing mode was found at 820 cm-1 in the IR spectrum. In general, it has been found that no pure C–X stretching vibration band is observed for aromatic halogen compounds [58]. It has been reported that the C–X (X is a halogen atom like chlorine, bromine or iodine) stretching vibrations tend to interact with the phenyl ring

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vibrations, when a halogen atom is directly attached to a benzene ring [59]. The characteristic frequencies of C–Br stretching vibrations of 1,4-disubstituted benzene falls in the range 650– 395 cm-1 in the IR spectrum [60]. The C–Br stretching was reported to be at 621 cm-1

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theoretically [61]. Smith [62] suggested that the IR band in the region of 650–500 cm-1 is due to the C–Br stretching vibration. Xiao et al. [63] designated the band at 526 cm-1 to the C–Br stretching mode. In the present case, C–Br stretching vibration was assigned to the band at 630 cm-1 theoretically.

Roeges [51] suggested that the CF3 moiety absorbs IR strongly in the 1340–1155 cm-1 region, due to C–F stretching vibrations. In the present case, the asymmetric and symmetric

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CF3 stretching vibrations were assigned to bands calculated at 1278, 1163 and 1127 cm-1, respectively. Joseph et al. [64] reported that the IR absorption of a pyrazine derivative at 1140 and 1026 cm-1 were due to vibrations involving CF3 stretching mode. In the present

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case, stretching modes of CF3 were observed at 1274 and 1129 cm-1 in the IR spectrum. Symmetric and asymmetric deformation modes for CF3 group fall in the region of 720‒645 cm-1 and 610–440 cm-1, respectively. In the low frequency region, there are two characteristic

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IR bands in 470–260 cm-1 range, where these frequencies were assigned to CF3 rocking deformations [51]. In the IR spectrum of the title compound, the band at 482 cm-1 is attributed to the CF3 deformation mode and corresponding bands were calculated at 604, 554 and 488 cm-1. For the title molecule, rocking deformations of the trifluoromethyl group in title molecule were assigned to the bands at 389 and 368 cm-1, theoretically. The vibrational analysis of 3-Hydroxy Benzylidyne Trifluoride has been studied by Arivazhagan and Kamala [65] and found that the skeletal stretching vibration of CF3 occur at 1197 cm-1 in the IR spectrum. Al-Omary et al. [66] investigated the vibrational spectra of a pyrimidine derivative and CF3 stretching vibrations were assigned to bands at 1110, 1064 and 1048 cm-1, while the deformation bands were found in the region of 638–316 cm-1. 9

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ALIE surface, Fukui functions and non-covalent interactions Among many quantum-molecular descriptors ALIE is particularly useful for the

determination of molecule sites prone to electrophilic attacks because it indicates molecule areas where electrons are least tightly bound and most easily removed. ALIE was introduced by Sjoberg et al. [67, 68] and it is defined as a sum of orbital energies weighted by the orbital densities:

ρ (r )ε r I (r ) = ∑ i r i , where ρi (r ) represents the electronic density of the i-th molecular orbital ρ (r ) i r r at the point r , ε i represents the orbital energy and ρ(r ) is the total electronic density

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r

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function. ALIE values can be presented separately for each atom or they can be mapped to the electron density surface, which is the case in this work (Fig.8).

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In general it is better to employ the analysis of ALIE surfaces rather than MEP, when it comes to the determination of molecule sites that are prone to electrophilic attacks. Chalcone derivatives have been computationally investigated within DFT approach in other studies, for example [69, 70]. According to the presented ALIE surface in Fig.8, it can be seen that locations with the highest possibility for electrophilic attacks are bromine atom Br1 and, to much smaller extent, carbon atom C8. These molecular locations are characterized by

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the ALIE values somewhat lower than 200 kcal/mol. Near vicinity of the oxygen atom is also marked by yellow colour that indicates relatively lower ALIE values and sensitivity towards the electrophilic attacks. On the other side, results indicate that the electrons are the most tightly bonded within the trifluoromethyl group, characterized by the maximal ALIE values

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of 395 kcal/mol. In Fig.8, intramolecular noncovalent interactions are also visualized, and it can be seen that two of such interactions occur in the case of title molecule, in its central part,

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favouring planar molecular shape.

Other important quantum-molecular descriptors used to investigate local reactivity

properties of a molecule are the Fukui functions, which indicate locations where electron density increases or decreases when the charge is added or removed. In Jaguar Fukui functions are calculated in the finite difference approximation by the following equations:

f+ =

(ρ (r ) − ρ (r )) ,

f−=

(ρ (r ) − ρ (r )) ,

N +δ

N

δ

N −δ

N

δ

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ACCEPTED MANUSCRIPT where N represents the number of electrons in reference state of the molecule, while δ is fraction of electron which default value is set to be 0.01 [71]. Regarding visualization, Fukui functions can be presented either in the form of isosurfaces or their values can be mapped to the electron density surface, which is the method chosen in this work (Fig.9). In the case of Fukui function f+ presented in Fig.9(a), purple colour indicates location where electron

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density increased after the addition of charge. It can be seen in Fig.9(a) that purple colour is located in two locations, carbon atoms C7 and C9, designating them as locations where electron density increase when molecule acts as electrophile. On the other side it can be seen in Fig.9(b) that red colour is located in very low amount in the near vicinity of

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trifluoromethyl group, designating it as the location where electron density decreases when molecule acts as a nucleophile. 4.5.

Reactive properties based on autoxidation and hydrolysis

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Taking into account that this class of the compounds is developed to be highly stable, we decided to further investigate its reactivity in order to be able to draw conclusions regarding its degradation properties. In the case of highly stable organic molecules usual water purification methods are not appropriate and the advanced oxidation processes are seen as the efficient alternative for their removal. In order to develop new methods for the removal

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of highly stable molecule forced degradation experiments are being undertaken, but they are tedious and expensive procedures [72, 73]. However, these experiments could be rationalized via DFT calculations and MD simulations. Namely, calculations of BDEs for hydrogen abstraction could be used for the anticipation of the molecule sites where autoxidation

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process could start, while BDEs of the remaining single acyclic bonds could be used to locate the weakest bonds [18]. Related to autoxidation process formation of a radical of

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pharmaceutical substance happens with the formation of peroxy radical [74] and the autoxidation process can continuously conduct if the formed peroxy radical can abstract hydrogen from another pharmaceutical molecule. Molecule locations where hydrogen can be abstracted are indicated by the BDE of hydrogen abstraction of proper value. Initial assessment can be made according to the fact that BDE values of all peroxy radicals are similar and are in the interval of 87–92 kcal/mol, practically independent of chemical surroundings [74, 75]. However, the study of Wright et al. [76] indicates that BDE for hydrogen abstraction in the interval of 75–85 kcal/mol mean very high sensitivity of a molecule towards autoxidation. Taking all of this into account we have calculated BDE values of all single acyclic bonds of title molecule and the obtained results are presented in Fig.10. In Fig.10, red colour presents BDE values for hydrogen abstraction, while blue colour 11

ACCEPTED MANUSCRIPT presents BDE values of the remaining single acyclic bonds. Obtained results concerning the BDE values for the hydrogen abstraction show that title molecule is highly stable in the open air or in the presence of oxygen. All BDE values for hydrogen abstraction are high above the 92 kcal/mol and therefore it can be concluded that autoxidation mechanism is unlikely to happen in the case of this molecule. On the other side the weakest bond was determined to be

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the one denoted with number 7, indicating that degradation mechanism could start with the detaching of bromine atom. Nevertheless, all other BDE values for the rest of the single acyclic bonds are high; indicating that degradation of title chalcone molecule could be difficult. In the same time the reactivity of the bromine atom is in the accordance with the

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results obtained by ALIE surface.

The influence of water in degradation of title molecule has also been investigated, by calculation of RDFs after MD simulations. RDF, g(r), is the quantity that gives the

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probability of finding a particle in the distance r from another particle [77]. RDFs of the atoms with the relatively pronounced interactions with water molecules are presented and given in the supporting information (Fig.S2). Results concerning the RDFs also indicate high stability of the investigated chalcone molecule. Namely, all significant RDFs are having peak distance higher than 3.5 Å. The most important RDF was obtained for the bromine atom Br1,

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for which g(r) has the value of around 1.45, while peak distance is located at around 3.5 Å. Besides Br1, only carbon atom C11 has peak distance located at less than 4 Å, while its maximal g(r) value is around 1.0. Other atoms with representative RDFs include carbon atoms C3, C10, C13 and C16. Of these the most important is carbon atom C16, which has the

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g(r) value of around 1.4 and peak distance located at around 4 Å. Carbon atoms C3 and C13

Å. 4.6.

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also have significantly high maximal g(r) values located at peak distances between 4.5 and 5

NMR Spectra

GIAO 1H and

13

C chemical shift values with respect to trimethylsilane (TMS) were

calculated using the DFT/B3LYP method with 6-311++g(d,p) basis set and compared to the corresponding experimental values. The 1H NMR and

13

C NMR spectra are presented in

Fig.S3 and Fig.S4. For the title compound, 1H NMR chemical shift values were observed in the range 8.12–7.78 ppm, while the DFT values were calculated at 8.12–7.86 ppm. Two doublets observed at 8.12 and 7.76 ppm in the 1H NMR spectrum was assigned to vinylene group hydrogens and corresponding values were calculated at 8.36 and 8.20 ppm. In the 1H NMR spectrum, doublets and multiplets observed at 8.10, and 7.81–7.78 ppm, were assigned to aromatic CH groups, where as the corresponding theoretical values are in the range 8.17– 12

ACCEPTED MANUSCRIPT 7.78 ppm. Signal observed at 188.1 ppm in the 13C NMR spectrum was assigned to C7 atom of the carbonyl group and this was calculated at 192.9 ppm. The signals observed at 142.4 and 122.9 ppm were assigned to vinylene carbon atoms and these were calculated at 151.6, 125.5 ppm. The signal at 124.2 ppm is attributed to the carbon atom in the trifluoromethyl group, which is supported by the calculated value 135.6 ppm. 13C NMR spectrum of the title

the phenyl rings.

13

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compound show signals in the range 138.5–125.0 ppm corresponds to aromatic carbons of C NMR chemical shift values corresponding to aromatic carbons were

calculated in the range 154.8–131.6 ppm. The

13

C and 1H NMR chemical shifts values are

summarized in a table and given in the supporting information (TableS2 & Table S3). Molecular Docking Study

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4.7.

Monoamine oxidases (MAO), one of the most essential enzymes belong to the protein family of flavin-containing amine, catalyzes the deamination of monoamines to the

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corresponding aldehyde and ammonia using oxygen as an electron acceptor [78]. The catalyzing mechanism of MAO is mainly due to the presence of covalently bound redox cofactor flavin adenine dinucleotide (FAD) and hence these enzymes are known as flavoproteins. Based on which substrate they execute their catalytic activity, two isoform of MAO have been identified: MAO-A and MAO-B [79]. MAO-B dysfunction has been linked

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to a number of neurological and psychological disorders including Parkinson’s disease [80] and Alzheimer’s disease [81]. A series of fluorinated methoxylated chalcones were synthesized and evaluated as potential inhibitors of MAO-B isoform by Mathew et al. [82]. In this work they have studied the effect and orientation of fluorine and the trifluoromethyl

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group in methoxylated chalcones using molecular docking studies. The hMAO-B binding site consists of a substrate cavity, which extends from FAD to the entrance cavity. In addition to

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the substrate cavity, defined by Leu171, Tyr126, Phe168, Ile198 and Ile199, there exists an aromatic cage characterized by the tyrosine residues Tyr 186, 189, 398, 435 and Phe 343, together with the FAD [79, 82]. Residues Ile 199 and Tyr 326 form a bottle neck along the whole binding site, by separating the active pockets. In order to understand how the title molecule inhibits and hence increases the catalytic

efficiency of MOA-B enzyme, molecular docking study was performed to fit the title compound into the binding site of MOA-B enzyme. High resolution crystal structure of MOA-B (PDB ID: 2BYB) was used as the receptor enzyme and AutoDock4 software was used to perform all molecular docking simulations. For the calculations, water molecules were removed and polar hydrogen atoms were added to the receptor molecule. The active centre around the binding site of the receptor was defined by incorporating all amino acid 13

ACCEPTED MANUSCRIPT residues within a radius of sphere 7 Å centred on the co-crystallized inhibitor FAD. In order to model the interaction pattern between receptor and ligand, Lamarckian Genetic Algorithm (LGA) available in Autodock was employed. Out of ten docked confirmations obtained, one which has lowest binding energy (-7.98 kcal/mol) was selected and analyzed for detailed interactions using Discovery Studio Visualizer4.0 software. The predicted binding mode of

hydrophobic interactions with the ligand were labelled in Fig.11.

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the title compound showing significant inhibition and the amino acid residues which form

In the present case, the docking studies of the title compound revealed that the trifluoromethyl group in the phenyl ring-B of the title molecule is positioned between the

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benzene rings of tyrosine residues Tyr435 and Tyr398 and anchoring from the reface of FAD with an average distance of 5.00 Å from the aromatic cage of FAD unit. From the Fig.11., it can be seen that these interactions are highly stabilized by the hydrophobic interactions like

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π-π stacking and π-π-T shaped interactions and halogen interactions between the trifluoromethyl group and A-ring of the title compound with the FAD cofactor and tyrosine residues Tyr398 and Tyr435. Trifluoromethyl group forms strong halogen interactions in the aromatic cage site with the amino acid residues Tyr398, Gly434, Gly435 and anchoring from the FAD unit with a distance of 2.86 Å. The phenyl ring-A of the title compound was found

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to be located within the entrance cavity of the binding site defined by Ile199 and form a πalkyl bond with Ile199. Another two amino acids Leu171 and Tyr 326 located in the substrate cavity of the enzyme interacts with the phenyl ring-B of the title compound which was stabilized by π-sigma and π-π-T shaped interactions, respectively. From the docking study, it

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can be concluded that the substitution with the groups like trifluoromethyl group and bromine, reduces the electron density of the chalcone system and hence expected to enhance

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the interactions of the inhibitor within binding site of MOA-B and also with the FAD cofactor, via hydrophobic and halogen interactions. The results from molecular docking study demonstrate that the title compound is a selective inhibitor of MAO-B enzyme with a competitive mode of inhibition. 5.

Conclusion

A

novel

chalcone

derivative,

(E)-1-(4-bromophenyl)-3-(4-

(trifluoromethyl)phenyl)prop-2-en-1-one, was synthesized and characterized by X-ray diffraction, FT-IR and 1H and

13

C NMR spectra. The compound crystallizes in monoclinic

crystal system in P21/c space group, unit cell parameters a = 16.7629 (12) Å, b = 13.9681 (10) Å, c = 5.8740 (4) Å, β = 96.3860 (12)˚ and Z = 4. Hirshfeld surface was generated and analysed in order to establish a quantitative insight into the intermolecular interactions. The 14

ACCEPTED MANUSCRIPT recorded FT-IR spectrum was interpreted in details with the aid of Density Functional Theory (DFT) calculations and Potential Energy Distribution (PED) analysis. According to the ALIE surfaces bromine atom was recognized to be important reactive centre and prone to the electrophilic attacks. In the same time Fukui functions have indicated carbon atoms C7, C9 and trifluoromethyl group as possibly important reactive centres when the molecule’s charge

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is changed. BDE values for hydrogen abstraction indicate that it is very hard to expect that the title molecule is prone to autoxidation mechanism, while BDEs of the rest of the single acyclic bonds indicate that degradation could start by detaching of bromine atom. MD results and calculated RDFs indicate that all atoms with relatively pronounced interactions with

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water have their peak distances located at around 3.5 Å and more, implying that this molecule is stable in water. The results from molecular docking study demonstrate that the title compound is a selective inhibitor of MAO-B enzyme with a competitive mode of inhibition.

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Acknowledgements

The authors thank the Malaysian Government and Universiti Sains Malaysia (USM) for the research facilities and the Research University grant No. 1001/PFIZIK/811238 to conduct this work. NCK thanks the Malaysian Government for MyBrain15 scholarship. Part of this study was conducted within the projects supported by the Ministry of Education,

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Science and Technological Development of Serbia, grant numbers ON171039, TR34019. SA and SJA thanks the Schrödinger Inc. for the support received. References

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Figure Captions

Fig.1. (a) The molecular structure of the compound with 50% ellipsoids probability with atomic numbering scheme (b) The twisted structure of the compound. Fig.2. The molecules connected into columns by intermolecular C-H···π interactions.

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Fig.3. Halogen‒halogen intermolecular interactions (Br···F and F···F contacts). Fig.4 Hirshfeld surface of the title compound mapped over dnorm function. Fig.5. Fingerprint plots of (a) H···H; (b) Br···F/F···Br; (c) F···F; (d) C···H/H···C interactions, listing the percentage of contacts contributed to the total Hirshfeld

gray.

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surface area of the title molecule. The outline of the full fingerprint plot is shown in

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Fig.6. View of the Hirshfeld Surfaces for the title compound, showing (a) mapped over de with the pale-orange spot within the pink circle showing the involvement of the C— H···π interactions and (b) mapped over the shape index with the bright-red spot indicating the C—H···π interaction and the blue spots indicating complementary

π···H—C interactions.

Fig.7. FT-IR spectra of the title compound. Whole IR spectra is divided into three regions (a) 4000-2750 cm-1 (b) 1750-1000 cm-1 (c) 1000-400 cm-1. Fig.8. ALIE surface of the title compound. Fig.9. Fukui functions of the title compound: a) Fukui f + and b) Fukui f – function. Fig.10. BDEs of all single acyclic bonds of title molecule – red colour presents BDE values 20

ACCEPTED MANUSCRIPT Fig.11. Ligand-Enzyme interactions, Halogen, π-π-T shaped and alkyl-π interactions are represented by light blue, violet and pink dotted lines, respectively. Fig.S1. Single Crystals of the title compound Fig.S2. Significant RDFs of the title molecule. Fig.S3. 1H NMR spectrum of the title compound.

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Fig.S4. 13C NMR spectrum of the title compound.

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Table 1. Crystal data and structure refinement. Refinement Parameters CCDC deposition numbers 1013208 Molecular formula C16H10BrF3O Molecular weight 355.15 Crystal system Monoclinic Space group P21/c a/Å 16.7629 (12) b/Å 13.9681 (10) c/Å 5.8740 (4) α /° 90.00 β/° 96.3860 (12) γ/° 90.00 V/ Å3 1366.84 (17) Z 4 1.726 Dcalc (g cm−3) Crystal Dimensions (mm) 0.54×0.14×0.05 µ/mm−1 3.04 0.71073 Radiation λ (Å) F(000) 704 Tmin/Tmax 0.292/0.853 Reflections measured 28118 Ranges/indices (h, k, l) h = −23→23 k = −19→19 l = −8→8 θ limit (°) 1.9-30.2 Unique reflections 4017 3319 Observed reflections (I > 2σ(I)) Parameters 190 R1[a], wR2 [b][I ≥ 2σ(I)] 0.029/0.070 Goodness of fit [c] on F2 1.04 Rint 0.037 Largest diff. peak and hole, 0.43 and −0.59 -3 e/Å 2 2 w = 1/[σ (Fo ) + (0.0301P)2 + 0.7730P], where P = (Fo2 + 2Fc2)/3; [a] R = Σ||Fo| – |Fc||/Σ|Fo|, [b] Rw = {wΣ(|Fo| – |Fc|)2/Σw|Fo|2}}1/2, [c] GOF = {Σw(|Fo| – |Fc|)2/(n–p)}1/2, where n is the number of reflections and p the total number of parameters refined.

ACCEPTED MANUSCRIPT Table 2. Hydrogen Bond interactions of the compound Bond length, (Å) Angle Bond D—H···A, (°) D—H···A D—H H···A D···A (i) 0.93 2.85 3.4668(17) 124 C5—H5A···Cg1 0.93 2.80 3.4881(17) 132 C12—H12A···Cg2 (ii)

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Symmetry code: (i) x,1/2-y,1/2+z; (ii) x,1/2-y,-1/2+z. Cg1= Centroid of C1-C6 benzene ring and Cg2 = Centroid of C10-C15 benzene ring.

ACCEPTED MANUSCRIPT Table 3. Halogen…Halogen [I…J = F or Br] Interactions. X—I···J Bond length, I—J, (Å) Angle, X—I···J, (°) 3.1574(11)

159.85(6)

(iv)

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C16—F3···Br1 (v)

3.1574(11)

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C16—F1···F1

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Symmetry code: (iii) 1+x,y,z; (iv) -1-x,1-y,-1-z; (v) -1+x,y,z. Van de Waals radii (Å) : F=1.47 ; Br=1.86.

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C3—Br1···F3 (iii)

ACCEPTED MANUSCRIPT Table 4. Vibrational Frequency Assignments of the title compound with experimental and DFT methods. Assignments

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υCHI(100) υCHI(100) υCHII(95) υCHII(78), υCHI(15) υCH(62), υCHI(24), υCHII(11) υCHI(98) υCHII(59), υCHI(40) υCHII(23), υCH(21), υCHI(54) υCHII(98) υCH(98) υC=O(54), υC=C(18), δCH(13) υPhII(57), υC=C(15), δCHII(12) υC=C(66), υC=O(12), υCC(14) υPhI(65), δCHI(16) υPhII(85) υPhI(79), δCHI(12) υPhI(79), δCHI(12) δCHI(29), υPhI(61) υPhII(60), δCHII(29) υPhI(52), δCHI(31), υCC(11) δCH(22), υPhII(63), υCC(12) δCH(59), υCC(13), δCHII(20) δCHII(29), υPhI(56) υPhI(18), δCHII(79) υCC(17), υCF3(62), υPhI(12) δCHI(66), υPhI(16) υCC(45), υPhII(27), δCH(18) δCH(48), υPhII(28), δCHII(17) υCC(13), δCH(12), δCHI(62) δCHII(63), υPhII(26) υCF3(58), υPhI(14) υCF3(68), δCHII(14), υCC(15) δCHI(57), υPhI(29) υCF3(13), δCHII(62), υPhII(14) υCF3(24), υCC(71) υPhI(33), υCC(56) δCF3(18), δCHII(59) υCC(22), δCHI(52), δC=O(15)

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Experimental IR υ (cm-1) 3086 1662 1599 1587 1564 1492 1398 1375 1315 1274 1266 1182 1129 1081 1069 1038 1006

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Theoretical DFT (6-311+g(d,p) υ (cm-1) IRI 3106 3.13 3104 5.83 3102 1.21 3099 3.98 3096 3.44 3092 0.50 3085 6.52 3081 0.24 3076 3.25 3050 0.34 1666 158.33 1602 135.69 1591 258.15 1568 124.71 1554 33.87 1546 14.41 1496 0.53 1465 11.41 1397 27.42 1377 30.65 1317 142.71 1311 4.99 1299 3.24 1280 32.75 1278 248.53 1277 0.08 1269 484.47 1194 9.42 1188 169.80 1171 10.39 1163 77.71 1127 92.74 1097 11.89 1084 134.17 1071 273.92 1048 51.85 1042 165.08 1004 83.47

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υCC(58), υPhII(19) γCH(42), τCC(27), δPhI(10) δPhI(58), υCC(10), γCH(7) γCHI(83), τPhI(11) γCHII(91), τPhII(8) γCHII(77), τPhII(18) γCHI(75), τPhI(14) γCH(15), δCC(33), υPhII(18), δC=O(11) γCH(17), δC=O(20), δCC(59) γCHI(78), γCHII(12), τPhII(5) γCHII(75), γCHI(12) γCHII(64), γCHI(32) γCHI(82) υCC(11), δC=O(12), υPhII(74) τPhII(11), υPhI(76), γC=O(12) δCF3(15), γCH(42), υCF3(17) τPhI(34), τPhII(29), γCC(12) δPhI(26), δC=O(52), υC-Br(10) τPhI(21), γC=O(13), υC-Br(17) δPhII(30), υC-Br(47) δPhI(85) δPhII(31), δCF3(50), δC=O(10) τPhII(19), γC=O(63) δCF3(17) δCF3(63), δCC(19) δCC(46), δC=C(16) τPhII(25), δCF3(37), δCHII(18) τPhI(23), δCC(36), υC-Br(17) τPhI(36), γC-Br(23), υCC(25), δC=O(7) τPhII(45), τPhI(22) τPhI(64), τPhII(18) δCF3(52), δCC(36) τPhII(47), δCF3(12), δCC(21), γCC(7) υCC(20), δCF3(50), υC-Br(10), δCC(13) δCC(57), δC-Br(12), δPhII(15) δC-Br(23), δCC(33), δPhII(36) τPhII(30), δCC(26), γCC(12), τCC(16) γCC(34), γC-Br(21), τPhII(18), δCC(12) δCC(31), γCC(23), γC-Br(12) δCC(65), δC-Br(19) δPhII(13), δPhI(10), δCC(36), δC-Br(13) γCC(21), τCC(12), δCC(20), δC-Br(5) γCC(21), τC=O(20), τCC(11), δCC(15) τCC(37), τPhI(14), δCC(23) τCC(38), τPhI(14), γCC(11)

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51.94 43.17 215.10 0.16 0.47 6.89 1.05 5.24 1.40 7.35 2.47 57.08 41.75 32.32 13.36 18.73 0.78 11.74 3.67 0.26 2.41 1.96 15.46 0.56 6.31 8.85 9.08 14.27 0.58 0.63 3.78 1.42 1.48 24.67 0.66 2.06 0.33 0.71 1.07 0.29 1.25 0.69 0.65 3.49

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46 0.67 τPhII(22), δCC(18), τCC(18) 31 0.22 τCC(31), δCC(23), γCC(15) 25 0.12 τCC(43), δCC(28), δC=C(12) 21 0.16 τCF3(50), δCC(13), τCC(12) τCF3(30), τCC(26), δCC(15) 14 0.02 υ-stretching; δ-in-plane deformation; γ-out-of-plane deformation; τ-twisting; Ph-phenyl ring; as-asymmetric; s-symmetric; IRI-IR intensity; PED contribution is given in bracket in the assignment column.

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Highlights A novel chalcone derivative is synthesized and characterized using XRD, FT-IR 1

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H and 13C NMR.

Hirshfeld surface analysis was carried out in order to establish a quantitative insight into the intermolecular interactions.

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The recorded FT-IR spectrum was interpreted in details with the aid of DFT and PED analysis.

Local reactivity properties are investigated by ALIE surfaces and Fukui functions.

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Bond dissociation energies using MD approach are calculated in order to predict

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the open air stability and possible degradation properties.

In order to understand how the title molecule inhibits and hence increases the

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catalytic efficiency of MOA-B enzyme, molecular docking study was performed to fit the title compound into the binding site of MOA-B enzyme.

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.