Molecular Structure, Experimental and Theoretical Vibrational Spectroscopy, (HOMO-LUMO, NBO) Investigation, (RDG, AIM) Analysis, (MEP, NLO) Study and Molecular Docking of Ethyl-2-{[4-Ethyl-5-(Quinolin-8-yloxyMethyl)-4H-1,2,4-Triazol-3-yl] Sulfanyl} Acetate

Abstract The spectroscopic characterization of the new synthesized heterocyclic aromatic organic compound ethyl −2-{[4-ethyl −5-(quinolin- 8-yloxymethyl) -4H- 1,2,4-triazol −3-yl] sulfanyl} acetate (abbreviated by Q-tsa) was carried out using experimental FTIR, UV–Vis, 1H, and 13C NMR techniques. To support the analytical results, theoretical calculations were performed on Q-tsa using DFT method associated with B3LYP functional with 6-31G(d,p) and 6-311G(d,p) basis sets. Furthermore, the reactivity of the title compound was studied by the investigation of frontier molecular orbitals (FMO) analysis, HOMO-LUMO energies, density of state (DOS), molecular electrostatic potential (MEP), global and local chemical reactivity descriptors. Thermodynamic properties were separately computed and discussed. The attractive, repulsive and van der Waals strong and weak interactions in Q-tsa were performed via RDG analysis followed by the investigation of topological properties via AIM theory. Similarly, the NLO activity of the studied compound was highlighted by computing the first hyperpolarizability in different available solvents. Finally, through molecular docking, the biological activity of Q-tsa was studied and discussed.


Introduction
Quinoline-triazole derivatives are well recognized in many papers for their significant biological activities as agents against bacterial, fungal, 1,2 plasmodial, 3,4 and malarial 5 pathologies. Other researchers developed strategies for the application of these compounds in treatment of Alzheimer's disease. 6 In other works these derivates show antitebercular properties. 7 The SAR analyses indicate the substitution of these compounds with Fluor have potent antitumor activity 8 and newly synthesized hybrids possess a broad spectrum of chemotherapeutic properties. 9 In addition, the flexible substitution of various donor and acceptor groups at the opposite extremities of the quinoline-triazole derivates permits not only developing of new significant bioactive heterocyclic compounds but also generation of broad spectrum of compounds exhibited important physicochemical properties. Particularly, the charge transfer resulting due to the electron movement from donor to acceptor region through the conjugated molecular system gives the molecule relevant nonlinear optical features. The NLO behavior of the title compound can be measured by the investigation of the value of the molecular polarizability (a) and (b). Compounds with high hyperpolarizability can be considered as NLO materials, which have potential applications in semiconductors, data storage, optical switching, and photovoltaic. 10 Keeping in the view all of these observations and in continuing our research on the synthesis of quinoline-triazole derivatives, this article presents detailed results on the structural characterization of ethyl-2-f[4-ethyl-5-(quinolin-8-yloxymethyl)-4H-1,2,4-triazol-3yl]sulfanylgacetate (Q-tsa). 11 The experimental analytical techniques for identifying unknown organic molecules are NMR, FTIR, UV-Vis, X-ray, and/ other spectroscopic methods. Today, experimental techniques are no longer enough to completely characterize a complex molecular structure and the best way is to combine the experimental with theoretical methods. Computational methods can be an important tool to increase the accuracy of the characterization process and report some key physicochemical properties. In our work, all theoretical calculations were performed using density functional theory method associated with B3LYP functional by applying 6-31G(d,p), 6-311G(d,p), 6-311Gþþ(d,p) basis sets. Both experimental and molecular modeling are combined for studying the potential energy surface (PES), molecular structural description, spectroscopy analysis (FTIR, RMN, UV-Vis), reduced density gradient (RDG) isosurface and AIM analysis, frontier molecular orbital's, the local as well as the global reactivity descriptors, namely, hardness, softness, chemical potential, electrophilicity index, thermodynamic parameters, population charge distribution, molecular electrostatic potential, polarizability (a), and first-order hyperpolarizability (b) are also computed to describe and understand the reactive nature of the title compound. Finally, to determine the biological activity of Qtsa, tools such as molecular docking and prediction of activity spectra for substances (PASS) were used and the results were discussed.

Experimental details
The Q-tsa compound was synthesized according to the chemical pathways indicated in the published work. 11 FTIR characterizations were recorded on a JASCO FT/IR4200 Fourier transform infrared spectrometer as KBr pellets in the solid phase at room temperature in the range (4000-400 cm À1 ). ( 1 H, 13 C) NMR spectra were performed on a BRUKER Ac DPX-200 spectrometer (300 MHz) in deuterchloroform solution. All chemical shift values were recorded as d (ppm) relative to tetramethylsilane (TMS) as an internal standard. The ultraviolet absorption spectrum of Q-tsa was measured in CDCl 3 solution using a spectrophotometer in the range 200-800 nm. The melting point of synthesized yellow crystals with moderate yield 70% was determined on Kȏ fler heating banc apparatus. All chemicals were purchased from Aldrich and Fluka.

Computational details
The quantum chemical calculations for the title compound were conducted with employing Gaussian09W program package. 12 Computations were carried out by using DFT level and the Becke three-parameter exchange functional (B3), 13 combined with the correlation functional of Lee, Yang and Parr (LYP) 14 methods in conjunction with 6-31G(d,p), 6-311G(d,p), and 6-311Gþþ(d,p) basis set. The resulting chemical quantum data as molecular and optimized structure, UV-Vis and RMN spectra, theoretical FTIR frequencies and molecular electrostatic surfaces (MEP) were investigated and visualized with help GaussView program. 15 The calculated vibrational wavenumbers were interpreted using VEDA 4 program. 16 The Ultraviolet-Visible electronic transitions and density of states (DOS) of Q-tsa molecule were assigned and plotted by GausSum 3.0 program. 17 The natural bond orbitals (NBO) analysis were carried out with help NBO 3.1 program. 18 Reduced density grandient (RDG) and 3D density isosurface were computed and pictured by using Multiwfn and VMD program, respectively. 19,20 In relation topological analysis of the electron density were done and two maps were visualized by using MoPro and MopoViewer Program. 21 Finally, nonlinear optical (NLO) properties and dipole moment of title compound in different solvents were studied by employing Gaussian09W program using DFT/B3LYP 6-311G (d,p) basis set.

PES scan studies
To investigate the possible rotational isomerism of the title compound, the potential energy surface were scanned along the dihedral angle (O 1 ÀC 10 ÀC 11 ÀN 4 ) at the B3LYP/6-31G(d,p) level. All possible geometries of the conformers were obtained by changing the torsion angle at every 10 for 360 rotation around the bond. The PES curve was plotted and presented in Figure 1. The molecular geometry has three different conformers. The minimum calculated energy (A) at 58 is À1540.84931 Hartrees. The maximum energy (B) called the saddle point, occurs at 178 by À1540.835504 Hartrees. Finally, the local minimum energy (C) occurs at 308 in the potential energy curve by À1540.848336 Hartrees.
Other PES scans were computed as function of possible rotatable dihedral angles (N 3 ÀC 12 ÀS 1 ÀC 13 ) and (C 8 2O 1 2C 10 2C 11 ) and were reported in Supporting Information Figures S1 and S2, respectively. The minimum total energies were registered at the same angles as the optimized structure.
Both bond dihedral angels of triazole and quinoline moieties indicate the planarity of the two rings; however, the two plans inclined to one another. The dihedral angle O1─ C10─ C11─ N4 [63.40 (X-ray); 59.73 (theo.)] was found to be a key parameter for the stability of the title molecule. Besides, the torsion angle C11─ N4─ C17─ C18 [-97.06 (X-ray); 93.51 (theo.)] can be referred to effect of the weak C17 À H17BÁÁÁO1 hydrogen bonds and/or the intermolecular interactions. 24 Generally, in our study a good agreement between experimental and theoretical results was found and the deviation can be explained that the experimental results were observed in solid state, while the computed data were obtained for an isolated chemical system in gas phase. Spectroscopy analysis (IR, RMN, UV-Vis)

Vibrational analysis
The Q-tsa structure is expected to exhibit 132 normal modes of vibrations (3 N -6). The vibrational frequencies were calculated by using the Gaussian 09 W program and GaussView molecular visualization program with applying B3LYP method and following 6-31G(p,d), 6-311G(p,d) basis set. All calculated wave numbers were scaled by factor 0.96. The resulted modes and frequencies by the last basis set were then performed with help VEDA program based on potential energy distribution (PED) assignment. 16 The computed fundamental vibration modes, the corresponding FTIR experimental values, intensities and their assignments were collected in Supporting Information Table S2. The experimental FTIR and calculated IR spectra are visualized in Supporting Information Figure S3.
Carbon-Hydrogen vibrations. The aromatic C-H stretching vibrations are generally expected around 3000-3300 cm À1 . 25 The C-H symmetric and asymmetric stretching vibrations are usually located at lower wave numbers around 2900-2800 cm À1 and 3100-2900 cm À1 , 25,26 respectively. According to the calculation based on B3LYP method the wave numbers at range 3210-3138 cm À1 were assigned to ring quinoline CH-stretching and were observed at the range of 3228-3158 cm À1 in the FTIR spectrum. All these modes have very high percentage of potential energy distribution. However, frequencies in the range 3129-2991 cm À1 were assigned to symmetric and asymmetric stretching vibrations of CH 2 and CH 3 groups with corresponding FTIR values in the region 3154-3000 cm À1 .The calculated frequencies own high values of PED.
The C-H out of plane bending and the C-H in plane bending vibrations are expected in the range of 950-800 cm À1 and 1500-1000 cm À1 , respectively. 27 The Carbon-Oxygen vibration. The C ¼ O stretching frequency is generally observed in the region 1800-1600 cm À1 depending on the configuration and conformation of the compound. 28,29 The strong band at 1719 cm À1 in experimental spectrum is detected to C ¼ O stretching vibration which is calculated at 1803 cm À1 with 89% PED. Furthermore, strong bands appear at 1296, 1134, and 1015 cm À1 in the experimental data which are calculated at 1284, 1128, and 1007 cm À1 , respectively. These modes were assigned as stretching CO vibrations mixed with HCC quinoline Carbon-Carbon vibration. We expected the C-C aromatic stretching vibrations in the region of 1600-1400 cm 1 . 23,30,31 The C ¼ C stretching vibrations are observed in FTIR spectrum at frequencies 1667, 1653, 1620, and 1549 cm À1 which were calculated at 1653, 1639, 1605, and 1537 cm À1 , respectively. These vibrations are assigned to C ¼ C stretching modes within the quinoline ring.
The saturated C-C vibrations are expected at lower wavenumbers in the region 1300-1000 cm À1 . 32 These vibrations are located at 1495, 1330, 1191, and 1042 cm À1 and the experimental absorptions are, respectively, obtained at 1505, 1341, 1204, and 1053 cm À1 .
The second highest experimental vibration occur at 1108 cm À1 wavenumber in FTIR spectrum and was assigned as mixed symmetric and asymmetric CCC bending with CCN bending vibration mode within quinoline ring.
Some important torsion modes with high PED% were assigned to vibrations within quinoline ring. These were obtained at 1001, 976, and 837 cm À1 and detected in FTIR spectrum at 1002, 976, and 834 cm À1 , respectively.  Carbon-Nitrogen vibration. In the middle region of the FTIR spectrum appear the C-N stretching vibration mode 33,34 at frequencies 1575, 1488, 1426, 1407, 1237, 997, and 663 cm À1 , which were calculated at 1567, 1477, 1417, 1395, 1234, 999, and 662 cm À1 , respectively. These modes are assigned to C ¼ N and C-N stretching mode within the triazole ring.
The H-C-N bending modes were calculated at 1427, 1424, 1417, and 1270 cm À1 , which the last one is assigned to vibrations within quinoline ring and the others within triazole ring. These vibrations are observed in the FTIR spectrum at 1437, 1433, 1426, 1275 cm À1 , respectively.
The most important of C-C-N bending modes was calculated at lower frequencies at 818 cm À1 , which yield the highest signal in FTIR spectrum. This was assigned as mixed mode with symmetric and asymmetric CCC bending within quinolone ring. 35 Carbon-Sulfur vibration. The C-S stretching mode is normally observed in the region 745-720 cm À1 . 36 In the present work this vibration was calculated at 780 cm À1 assigned to CS stretching mode mixed with CCO bending mode and located in the FTIR spectrum with middle peak at 787 cm À1 .
Two HCS bending modes assigned to mixed vibrations with torsional modes were obtained at 1159 and 923 cm À1 and observed in the FTIR spectrum at 1162 and 924 cm À1 . However HCSC torsional modes were calculated with very high intensity at 1330 and 1191 cm À1 and located in FTIR spectrum at 1341 and 1204 cm À1 , respectively.
In the present study, several torsional modes in the middle and lower region of FTIR spectrum were detected, some of them are important and were assigned to vibrations within triazole and/or quinoline mixed with bending and stretching modes .These were calculated at 1427, 1417, 1378, 1157, 809, 801, and 712 cm À1 and observed in FTIR spectrum at 1437, 1426, 1386, 1155, 804, 802, and 711 cm À1 , respectively. Generally, a good agreement between experimental and simulated frequencies was found.

RMN characterization
NMR spectroscopy is an indispensable technique for the analysis of the molecular structure of organic products. The combined use of theoretical 1 H and 13 C nuclear magnetic resonance spectroscopy and experimental methods present the opportunity to obtain more accurate results. Theoretical 1 H and 13 C chemical shifts were calculated for the optimized geometry by B3LYP/6-31Gþþ (d. p) using the Gaussian09W program with the standard GIAO approach. All obtained shifts were listed in Tables 1 and 2, which were referred to the calculated isotropic chemical shifts (d) of TMS by the same method and basis set.
The Q-tsa 1 H NMR spectrum shows a triplet peaks of methyl protons attached to (O) at 1.12 ppm. The corresponding values were calculated at (1.17, 1.47, and 1.47) ppm for H18 H19 and H20, respectively. A second triplet gave a resonance at 1.27 ppm, which the theoretical chemical shifts were obtained at 1.05, 1.68, and 3.32 ppm for H11, H12, and H13, respectively. At 4 ppm appear a singlet peak of CH2 protons connected to sulfur atom for H14 and H15, which were computed at 4.56 and 4.50 ppm, respectively. More peaks for CH2 protons attached to Nitrogen and Oxygen were observed at 4.07, 4.16, and 5.50 ppm. These values have been also calculated at 3.86, 3.92, 4.19, 4.21, 5.00, and 5.40 ppm for H9, H10, H17, H16, H7, and H8, respectively. 23,[37][38][39][40] The experimental peaks for aromatic protons appear at higher region. The registered multiplet proton signals between 7.28 and 7.34 ppm were computed at 7.12, 7.50, 7.57, and 7.69 ppm for H6, H2, H4, and H5, respectively. Other both doublet signals at 7.03 and 8.81 ppm were calculated at 8.24 and 9.12 ppm for H3 and H1, respectively. The divergence in chemical shifts is due to the presence of the nitrogen atom with its electronegative characteristic in the quinoline ring. 41 In this work, the Q-tsa 13 C NMR spectrum shows below 100 ppm two regions for signals. Two peaks were registered in at 14 41 The carbonyl carbon gave resonance as expected at higher values of chemical shifts at 168.26 ppm and was calculated at 175.90 ppm. Finally, all 1 H and 13 C NMR signals were in good agreement with computed chemical shift and consistent with the literature. 42 The intermolecular interaction between the compound and solvent can be the cause of the small difference between theoretical and experimental chemical shifts values.

UV-Vis and DOS studies
The experimental UV-Vis spectrum was recorded in the range 200-400 nm. The TD-DFT calculations for the title compound were computed using B3LYP/6311Gþþ(d,p) functional with involving chloroform as solvent. The theoretical electronic transition energies, wavelengths (k) and oscillator strengths (f) were reported in Table 3 and the contributions were computed with help of GausSum 3.0 software. 17 The experimental observed peak in Supporting Information Figure S4 at wavelength k exp ¼ 322 nm, which was calculated at 313 nm with an oscillator strength (f ¼ 0.1146), has been assigned to HOMO!LUMO electronic transition with 96% contribution. The next observed peak experimentally at 282 nm was calculated at the same wavelength with an oscillator strength (f ¼ 0.0019), which described by excitation from H-3!LUMO with (91%) major contribution. One more transition was computed at 285 nm with an oscillator force (f ¼ 0.0002), has been originated to the mixed contribution of H-1!LUMO (93%) and H-3!LUMO (5%). All these computed electronic transition bands can be assigned to p!p Ã and n!p Ã transitions with significant intra-molecular charge transfer from donor to acceptor groups. These results confirmed the already demonstrated conclusion by Frontier Molecular Orbital analysis. For more analysis, the density of states DOS was convoluted from the molecular orbital contributions using GaussSum 3.0 and their pictorial representations were plotted in Figure 3. The red and green lines indicate the non-and occupied orbitals, respectively. Additionally, a partial density of states PDOS for the title compound was computed and the percent contributions of various groups to each molecular orbitals for electronic transitions were summarized in Supporting Information Table S3. Commonly, the highest contribution results to the electronic transitions p!p Ã with significant intra-molecular charge transfer from the quinoline ring to the triazole ring and the excitation of sulfur lone pairs electrons to exited state.

RDG and AIM analyses
The reduced density gradient (RDG) is used to develop an overview about the intra and inter nonbonded interactions in the studied chemical system. The RDG is given by the following equation. 43 RDG where q(r) is the electron density and r q(r) is the gradient of q(r) at the point r. The calculated RDG were then visualized by mapping the results in 2D scatter plot versus sign (k 2 ). The sign of k 2 is used to identify the nature of interactions. The case of sign (k 2 )> 0 indicates the region of repulsive nonbonded interactions, while negative values correspond to the zone of attractive bonded interactions. The region in between corresponds to van der Waals (VDW) weak interactions. In our work, the 2D scatter plot and 3D RDG isosurface were calculated by Multiwfn and VMD program 20,44 and results are showed in Supporting Information Figure S5.
The green colors indicate the zone of van der Waals intermediate interactions. Repulsive strong steric effects were observed in centers of quinoline and triazole rings, which were represented on the RDG plot as the red region. Mixed red and green color region around acetate group, (N3, C13) and (N1, O1) describing a weak repulsive region. van der Waals interactions intra molecular were seen between C17 À H18BO1 and/or C17 À H18BN4, which will be confirmed later by evaluating atom charges.
More details about the presence of weak or strong hydrogen bonds can be studied by using topological analysis of atoms in the molecule. This tool permits to calculate electron density (q) and Laplacian of the electron density (r2q) at line critical points (LCPs), cage critical points (CCP), and ring critical points (RCPs). The results were computed with help Multiwfn program and the BCP baths of the title molecule were visualized in Supporting Information Figure S6. The picture shows the existing of 46 NACPs (3,-3), 50 LCPs (3, -1), and 5 RCPs (3, þ1).
Based on quantum theory of atoms in molecule theory (QTAIM) and topological analysis of the electron density analysis 45 the chemical bonding characteristics were identified. The experimental electron density (ED) deformation maps were determined through multipole refinement using X-ray diffraction data by using the Mopro program. 21 The 2D maps describing the ED deformation for Q-tsa were visualized in Supporting Information Figure S7 with contour map of 0.05 e .Å À3 . The positive and negative EDs are represented by solid lines (blue) and (red), respectively. The Figure shows that, the ED distributions were well centered on the C-C and C-N chemical bonds confirming the covalent character of these bonds. The influence of the lone-pair charge concentration is clearly to recognize. Mopro program allows making a precise analysis of all covalent or noncovalent interactions trough tabulation all values of the topological quantities on the bond critical points (BCPs). This analyze allow us to locate the critical points of bonds where rq(r) ¼ 0.The results were collected in Supporting Information Table S4, which contains (q), (᭞ 2 q), d as the distance between two atoms, (r 1 ) and (r 2 ) are the distances from the CP to the atoms, the ratios (r 1 /d, r 2 /d) represent the symmetries of bonds, (k 1 , k 2 , k 3 ) are the principle curvatures (eigenvalues of Hessian matrix) and (e) is the ellipticity.
In general, a negative value of the Laplacian indicates a local concentration of electrons, while a positive value will indicate a local depletion of electrons. Besides, when the ED is large with a small Laplacian, the corresponding bond is considered strong. The ellipticity (e) of a bond represents the deviation from the cylindrical symmetry and calculated as (k 1 /k 2 ) À 1. The collected bond critical points with signature (3,-1) in Supporting Information Table S4 are characterized with three nonzero eigenvalues, two of them being negative and one positive. The large ED  The next parameters identifying the symmetry along the bonds were the ratios between the curvatures of the electron density (k 1 /k 2 ), which were by critical points (3,-1) always greater than unity (1) and yield an average of ellipticity (e) of (0.16 ± 0.03).The lowest value was registered by N2-N3 at (0.0135), which indicate a cylindrical symmetry of the bond. The highest deviation from this property was found by C12-S1 bond at value of 0.2998.
The More (3,-1) CPs associated with a lower q (r) density and a positive (r2q(r)) Laplacian were found. According to AIM theory positive Laplacian indicates that G(r) is greater than V(r), where G(r) and V(r) are Lagrangian kinetic energy and potential energy densities at critical points, respectively. The total ED at the bond critical point is given by the expression.
This useful criterion referred to a depletion of along the bond path and indicates the existence of closed shell interaction like hydrogen bonding. 46,47 In our study, MoPro program compute two more (3, À1) bond critical points with low ED (q) and positive (r 2 q) Laplacian values. From BCP analysis in Table 4 the calculated bond N1 H18B density at the critical point was equal to (0.04150 e/Å 3) and the Laplacian (0.475 e/Å 5 ) and for O1H18B the density at the critical point was equal to 0.05991e/Å 3 and the Laplacian 0.749 e/Å5, respectively.
In our study, we remarked that the values of k 3 by hydrogen bonds were very smaller than that found in Supporting Information Table S4 for non-hydrogen bonds. This confirm the proposed classification of Espinosa et al., of hydrogen bond on curvature k 3.

48
The total ED H CP and the hydrogen bond interaction energy E HB characterize the strength of the HB. The strength of hydrogen bond can be classified as strong for (r2q CP <0; H CP < 0; E HB > 24.0 kCal/mol), medium for (r 2 q CP > 0; H CP < 0; 12.0< E HB < 24.0 kCal/mol) and weak for (r 2 q CP > 0; H CP > 0; E HB < 12.0 kCal/mol). [49][50][51] The hydrogen bond interaction energy E HB is From the results in Table 5, for N1H18B the hydrogen bond interaction energy E HB was equal (-0.88 kCal/mol), ᭢ 2 q >0 and H CP > 0. For O1H18B E HB was equal (-1.50 kCal/mol), ᭢ 2 q >0 and H CP >0. These results let us to consider that both N1H18B and O1H18B E HB as weak hydrogen bonds. With the same expression the H-bond energy was calculated based on the summarized results in Table 5 with help of Multiwfn program.
Newly Emamian et al. 54 propose a model to estimate the hydrogen bond interaction energy E HB as function of q (r) density at the critical point: The calculation gives a value of (-0.75 kCal/mol) for N1H18B and (-0.73 kCal/mol) for O1H18B, respectively. Both HBs are classified by the last proposed model as very weak interaction with E HB < 2.50 kCal/mol and are mainly dominated by both dispersion and electrostatic interactions.
The type of the hydrogen bonding can be classified by using the ratio of │V CP │/G CP as follows, 55 Tables 4 and 5 indicate that the nature of hydrogen bonding of Q-tsa can be considered as closed-shell interaction.

to covalent interaction, intermediate and closed-shell interaction. The results in
More bond critical points as (3, þ1) called ring critical points were well identified in Supporting Information Figure S8. The ring CPs were located at the center of the quinoline and triazole ring and characterized with negative k 1 and two positive k 2 and k 3 . Cage critical points with signature (3,-3) within quinoline ring were computed with high density q CP equal to (858.0 e/Å 3 ) and highly negative r 2 q CP Laplacian (-2.753 Â 10 7 e/Å 5 ) and ellipticity equal to zero.

Frontier molecular orbital's
The highest occupied molecular orbital (HOMO) energies, the lowest unoccupied molecular orbital (LUMO) energies and the energy gap (DE) between both energy levels for the title compound were computed by several methods. The results by applying DFT/B3LYP with 631G(d,p), 6311G(d,p), and 6311Gþþ(d,p) basis sets were listed in Table 6. HOMO level characterizes the ability to donate an electron; however LUMO level presents the electron acceptance ability. The energy gap is helpful to determine the molecular electrical transport properties. According to the calculated molecule energy level, showed in Table 6 and the value of dipole moment, which is a significant issue for the structural molecule stability, stands the title compound more stable by applying the B3LYP/6311Gþþ (d,p). The experimental dipole moment of the Q-tsa amounts 3.27 Debye, which is close to the value by B3LYP/6311Gþþ (d,p). As result, the energy gap of our molecule is more accurate at B3LYP/6311Gþþ (d,p) and equal 4.40 eV.
The distribution of frontier molecular orbits and energy levels showed in Supporting Information Figure S9(a). The highest HOMO is localized over the donor triazole ring and Sulfur atom. The LUMO spreads over the acceptor quinoline ring. The energy gap explains that the electron density transfer taking place from the triazole ring and sulfur atom to the quinoline ring and the electronic transitions are mainly derived from the p!p Ã . The contour plots of the LUMO-HOMO electron density (Dq) for Q-tsa are shown in Supporting Information Figure S9(b). The purple color indicates an increase of electron density, while the blue color the decrease of electron density, respectively.

Mulliken population analysis
Atomic charge has important application in the field of quantum chemistry, molecular modeling, and chemical information, such as calculating electrostatic, dipole moment and a lot of properties of molecular systems. 56 In our study, we used the density functional theory (DFT) in its B3LYP with 6-31G (d,p), 6-311G(d,p), and 6-311G(d,p)þþ basis sets in gas-phase. The computed results by both levels were summarized in Supporting Information Table S5. The calculated Mulliken atomic charges depend strong on the kind of the applied basis set. The atomic charges of Nitrogen and oxygen atoms have higher negative charges by all mixed methods except for diffuse basis set than carbon atoms. The charges of carbon atoms within quinoline ring attached to nitrogen showed positive values, while other carbon atoms were negative or positive depending on the charge of the neighbor atom. In the case of triazole ring, the carbon atoms connected to nitrogen atoms C11, C12 were as expected positive. The expected negative charge of atom S1 was found positive excepting by 6-311Gþþ(d,p) basis set, which can be attributed to effect, that the sulfur atom is attached to triazole ring and acetate group. The most positive charges were registered by C10, C11, and C14 for carbon atoms connected to triazole ring and/or oxygen atoms. All the hydrogen atoms have a net positive charge. By applying 6-311Gþþ(d,p) basis set, the hydrogen atom H18B shows the highest positive charge (0.379929) in comparison with other hydrogen atoms. This behavior can be the result of intramolecular C17-H18BO1 and/or C17-H18BN4.

Natural bonding orbital analysis
The NBO approach provides insights into the interaction between a filled orbital and vacant orbital. 57 The donor (bonding)-acceptor (anti bonding) energetic analysis was estimated via second-order perturbation theory analysis of the Fock matrix, and establishes the strength of that interaction. The Lewis-type NBOs determine the localized Natural Lewis Structure (NLS) representation of the wave function, while the remaining "non-Lewis"-type NBOs complete the span of the basis. 58,59 The stabilization energy E ð2Þ arises from delocalization between donor (i) and acceptor (j), for this purpose the hyper-conjugative interaction can be treated by E ð2Þ where q i is the donor orbital occupancy, F(i,j) is the Fock matrix elements between the NBO i and j, and e i and e j are the orbital energies. The last equation is used to examine all possible interactions between filled Lewis-type NBOs (donor orbitals) and weakly occupied non-Lewistype NBOs (acceptor orbitals) and evaluate their relevance. These donor-acceptor interactions are responsible for the loss of occupancy in filled NBOs and measure the deviation from the idealized Lewis structure. 60 The second-order perturbation theory analysis of Fock-matrix in NBO basis yields different types of donor-acceptor interactions and their stabilization energy, which is a measure of hyper-conjugation and electrons density transference. The NBO calculations has been implemented on Q-tsa compound using DFT at B3LYP level using 6-31G(d,p) basis set as performed in the Gaussian09W package using NBO 3.1 program. 18 The computed results were summarized in Supporting Information Table S6.

Global and local reactivity descriptors
In this work, the global chemical reactivity descriptors (GCRD) for the title compound were calculated using energies of the frontier molecular orbital by combination of several methods and basis set. 61 The ionization potential (IA), electro affinity (AE), band gap energy (DE g ) and electronegativity (v) were calculated using Koopmann's theorem. 62 Parr and Pearson provided definitions of the absolute hardness (î), global softness (r), global electrophilicity index (x), chemical potential (l) and the maximum number of electrons transferred (N max ). 63 All these parameters provided the global reactivity and stability of a compound and were summarized in Table 6. The donor-acceptor occurring within the molecule can be predicted with help of absolute and global hardness, which are determined from energy gap value between HOMO and LUMO energies. Soft hardness is the reciprocal of absolute hardness. A soft molecule has a small energy gap, while a hard molecule has a great energy gap. Therefore, hard molecules may be less polarizable than soft molecules. In the other hand, molecules with higher chemical potential are less stable and more likely to lose their electrons. Further parameter is the global electrophilicity index (x). Molecules with higher value of x demonstrate stronger electrophilic nature, whereas molecules with lower value of x display higher nucleophilic nature. According to results by FMO analysis, the GCRD parameters seem to be more accurate by using B3LYP/6-311Gþþ(d,p). The Ionization potential (I) and the electron affinity (EA) of the title compound were 6.2476 and 1.8465 eV, respectively. The molecule tends easily to attract an electro than to lose an electron. The value of the global hardness (î) is the indicator for the charge transfer within the molecule, whereas the obtained global softness (r) (0.2272 eV À1 ), which can be considered as low amount. As result, the Q-tsa chemical system can be designated as compound with harder properties than softer. The molecular stability of Q-tsa can be explained by negative amount of chemical potential of À4.0471 eV. The theoretical global electrophilicity index (x) was 3.7216 eV and the maximum number of electrons transferred (N max ) was 1.8391.
To understand the site-specific electrophilic, nucleophic or radical character in reactivity of the target molecule and to predict diverse aspects of possible reaction mechanism or chemical bonding, we need to add the local quantities such as Fukui functions. The condensed FF for an atom k in a molecule proposed by Yang and Mortier 64 are expressed as: where q k is the atomic charge at the kth atom in the neutral(N), anionic(N þ 1), and cationic(N -1) chemical system. AlRabiah et al. 65 introduced atomic descriptors (sf) k called local softness in order to solve the negative Fukui function problem. Similarly, Padmanabhan et al. 66 proposed the concept of generalized philicity (x a k ) and local softness (s a k ) to describe the local reactivity within a molecule, where a ¼ þ/-/0 refer to nucleophilic, electrophilic and radical attacks, respectively. Both local quantities of an atom within the chemical system are resulting by multiplying (f a k ) by global softness (s) and global electrophilicity index (x), respectively.
Morell and S anchez-M arquez [67][68][69][70][71][72] introduced new dual descriptors Df based on molecular orbital densities for describing both reactive behaviors and they define this index as the difference between nucleophilic and electrophilic Fukui functions. They propose Df as the difference of LUMO and HOMO densities and is given by the expression: This parameter Dq ¼ q LUMOq HOMO will be used in the calculation of local reactivity descriptors as a new proposed index of selectivity toward nucleophilic and electrophilic attack. 67 If Df > 0, then, the site is favorable for a nucleophilic attack, whereas if Df < 0, then, the site is favorable for an electrophilic attack.
Other authors use the ratio (f þ k /fk ) and (fk /f þ k ) as relative nuecleophilicity and relative electrophilicity, respectively. The highest value of f þ k /fk represent the most probable site of nucleophilic attack and the site with the highest value of fk /f þ k should be the most to be attacked by an electrophile.
Based on good consensus in researches, 73 we used Hirshfield charges, Mulliken and MBS Mulliken charges for evaluating condensed Fukui functions by using DFT/6-31G(d,p) level of Table 7. Corresponding fitting equations of standard thermodynamic properties with temperature of Q-tsa.
In our study, the sulfur atom S1 had by all several charges the most electrophilicity, whereas the nitrogen atom N1 within the quinoline ring displays higher nucleophilic amounts. These results were confirmed by evaluating relative nucleo-order electrophilicity. Other atoms as C14, O3 of acetate group show by compute using MBS Mulliken and Hirshfeld charges high relative nucleophilic values.

Molecular electrostatic potential
To predict how the molecule interacts with another, we need to study the molecular electrostatic potential (MEP), which is related to electron density. This tool is used to identify the zones responsible for hydrogen bonding interactions as well as potential nucleophilic and electrophilic sites in the molecule. The resulted MEP surfaces represent the electrostatic potential V(r) created in the space at each point r around a molecule, is given by the following equation 74 : where Z A is the charge on nucleus A located at R A and (r') is the electron density function of the molecule. For this purpose, the electrostatic potentials V(r) of optimized molecules were computed at the B3LYP/6-31G (d,p) level, using the Gaussian programs. The electrostatic potential can then be mapped onto the electron density by using color graduation to represent the value of the potential. The color degradation from bleu to red, as shown in Figure 4, displays the different values of electrostatic potential, which increases in the order red < yellow < blue. The blue surfaces represent the most positive electrostatic potential region of the molecule and indicate the electrophilic site. Against this, the mapped surface with red color represent the most negative electrostatic potential region of the molecule and identified as nucleophilic site. In the majority of the MEPs, while the maximum negative region which preferred site for electrophilic attack indications as red color, the maximum positive region which preferred site for nucleophilic attack symptoms as blue color. In our study, the negative region (red region) was localized on the nitrogen atoms of the triazole ring. In addition, a less negative potential region was observed around the oxygen atoms. The maximum positive regions (blue region) are localized on the hydrogen atoms; this indicates possible sites for nucleophilic attack.

Thermodynamic properties
The theoretical calculation of thermodynamic properties of the title compound at 298.15 K and 1 atmosphere pressure in gas phase is evaluated from the computed harmonic frequencies. We expect an elevation of enthalpy (H), entropy (S), and heat capacities (C) with increase of temperature. This can be explained by the effect of increasing temperature on translational, vibrational, rotational and electronic energies. The values of the thermodynamic parameters were computed by applying DFT method in ground state and were registered in Supporting Information Table S8. The summarized data indicate a lowest amount of zero-point correction and lowest energy values by applying DFT/B3LYP 6-311Gþþ(d,p) basis set. The correlation of heat capacity C p with temperature was collected in Figure 5 and displays, that the correlation was independent from applied functional using several basis set. Same remarks were registered by the Supporting Information Figures S10 and S11. The elevation of DH ¼ H (T) -H (298) and per consequence the entropy in the range of temperature 300-800 K due to the increasing of enhancement of molecular vibration and escalation of disorder. The equations of correlation between enthalpy H, entropy S, heat capacity C p and the temperature in the range 298-800 K were fitted by quadratic formulas and were expressed in Table 7.
The fitting factors R 2 were 0.9999 for the enthalpy, entropy, and the heat capacity.

NLO activity
In order to exanimate the nonlinear optical (NLO) properties of the title compound, parameters such as dipole moment (l), molecular polarizability (a), and first order hyperpolarizability (b) were computed and the results in the Table 8 summarized. 75,76 In our study, the calculations were performed by applying DFT method with B3LYP/6-31G(p,d), 6-311G(p,d) and 6-311Gþþ(p,d) bases sets in the gas phase. The calculated a and b parameters with help of GaussView program in atomic unit were converted into electrostatic esu (for a 1 a.u. ¼ 0.1482 Â 10 À24 esu; for b 1 a.u. ¼ 8.6393 Â 10 À33 esu). By applying DFT/B3LYP/6-311Gþþ(d,p) functional, the dipole moment increases and moves more and more toward experimental X-ray value. The calculated (a) and (b) by the last level theory were 41.54 Â 10 À24 esu and 9.09 Â 10 À30 esu (39 times of urea), 77 respectively. Therefore, these results predict that Q-tsa can be considered as NLO material.
To explore the solvent effects on the non linear optical properties of the title compound, DFT calculation were performed by applying the DFT/B3LYP 6-311G(d,p) and BPV86 level of theory and using several solvents such as (CCl 4 , diethylether, chloroform, acetone, ethanol, acetonitrile, DMSO, and water). 42, 78 The parameters were collected and reported in Table 9. From this Table, it can be concluded, that the effect of solvent polarity on polarizability (a) and hyperpolarizability (b) of the title compound are considerable. Other studies confirm the existence of these conclusions. 10

Molecular docking
The molecular docking is considered as an essential and preliminary method for the design of new drugs. 79,80 In recent years, this method has been widely used to study several newly synthesized organic structures, especially molecular structures containing the quinoline and the triazole ring. 81,82 The molecular docking predicts the intermolecular interactions between proteins and Table 9. Dipole moment (D), molecular polarizability (10 À24 esu), and hyperpolarizability (10 À30 esu) calculated values in different solvents for Q-tsa using DFT (B3LYP, BPV86)/6-311G(d,p). the investigated ligand. Conversely, the target protein is selected on the basis of binding energy value. The ligand has a better docking ability to protein when its binding energy has more negative value. 83 In the present work, molecular docking study was carried out with the ligand including quinoline and triazole moieties. The title molecule is selected as inhibitor for the C-Met protein which is available in the Protein Data Bank (PDB) under the code 5EOB. 84 The 5EOB protein has been selected due to its investigation in several research works using molecular docking to design new inhibitors. [85][86][87][88] Furthermore, molecules containing quinoline and triazole moieties have been found to be a powerful antitumor agent by inhibiting the activity of the C-Met kinase (PDB ID: 5EOB) enzyme. 89 The molecular docking was performed using AutoDock Vina tools. 90 The C-Met protein was considered as receptor and Q-tsa optimized structure as ligand.

Solvents
The docking results for Q-tsa with the target protein were visualized to highlight binding modes of the ligand on the active site of C-met enzyme (PDB ID: 5EOB) using Accelrys Discovery Studio version 4.1. 91 The binding affinities and their root-mean-square deviation (RMSD) values for different poses in 5EOB inhibitor are reported in Table 10. The best docking poses along with 2D intermolecular interactions of Q-tsa with the target protein C-met (PDB ID: 5EOB) are visualized in Supporting Information Figure S12. From Table 10, the C-Met enzyme active site with the grid box size of 40 Â 46 Â 40 Å 3 for x, y, and z, respectively, and the grid center at position À0.3, 10.852, 31.013 for x, y, and z, respectively, constitute a grid box in which the ligand can interact with the target protein. 88 According to this grid box position, nine affinity modes of molecular confirmation were obtained. These modes are classified according to their binding affinity and RMSD values. As found in literature, the molecular docking best pose corresponds to the lowest binding affinity and RMSD not exceeding 2 Å. 92,93 From Table 10, the binding energy system (ligand-protein) of À7.2 Kcal/Mol is the best value. This value is lower compared to the binding energy of previous works, using the same target protein C-met (PDB ID: 5EOB) and the same active site. 88 This low value of energy can be explained by the decrease in the gap energy of the molecule which promotes a stronger interaction between the title ligand and the C-met protein. However, Q-tsa is considered as a potential candidate for C-met protein inhibition. Furthermore, interactions protein-ligand are closely related to the decrease of gap energy value which affects generally the binding energy as reported by numerous molecular docking studies. [94][95][96][97][98][99] Conversely, the inhibition constant K i is an important parameter to describe the inhibition activity which can be obtained by using the following equation: where DG, R, and T are the docking energy, gas constant (1.9872036 Â 10 À3 kcal/Mol) and room temperature (298.15 K), respectively. For Q-tsa ligand, the inhibition constant value (5.27669 lM) indicates that this ligand can be used to inhibit the C-Met (PDB ID: 5EOB) enzyme. According to molecular docking analysis, and considering the active site of the C-met protein (PDB ID: 5EOB), the investigated ligand can interacts with the following seven residues: TYR1230, ALA1226, ALA1108, MET1160, GLY1085, MET1211, and ALA1221 as displayed in Figure 6. These intermolecular interactions are established by hydrogen and hydrophobic bonds. GLY1085, TYR1230, and ALA1108 residues interact with N2 atom of triazole ring (3.78 Å), quinoline ring (3.50 Å), and ethyl group of triazole moiety (3.79 Å), respectively. In addition, sulfur interaction has been observed between MET1211 sulfur atom and quinoline group with distance of 3.38 Å. Molecular docking results show that the two moieties, triazole and quinoline, are the most important active sites in the investigated ligand. Intermolecular interaction details between the ligand and the target protein are summarized in Table 11. The corresponding 3D interactions along with the binding modes of Q-tsa -protein Cmet (PDB ID: 5EOB) are displayed in Figure 6. Finally, the obtained results demonstrate that Qtsa ligand can be used as inhibitor for the protein C-met (PDB ID: 5EOB), and for the design of a new antitumor drug.

Conclusion
In the current work, we reported and compared a detailed investigations of quinoline-triazole derivate named ethyl 2-f[4-ethyl-5-(quinolin-8-yloxymethyl)-4H-1,2,4-triazol-3yl]sulfanylg acetate (Q-tsa) using theoretical calculations with DFT/B3LYP method at different basis sets. Q-tsa compound has been also characterized by different spectroscopic analyses such as FTIR, NMR, and UV-Vis. According to this study, good linearity between theoretical and experimental structural parameters as well as spectroscopic results were established. The UV-Visible characterization of Q-tsa in solvent was carried out in which experimental and TD-DFT spectra reveal that absorption bands are related to n!p Ã and p!p Ã electronic transitions. Donor and acceptor groups effect on the electron delocalization was highlighted by using the DOS diagram. Similarly, the analysis of intramolecular interactions especially hydrogen bonding by quantum of atoms in molecule theory and reduced density gradient approaches demonstrate good agreement. By describing both probable reactive behaviors of the title compound, dual descriptors based on molecular orbital densities using different charges have shown a good consensus, which were confirmed by plotting the MEP surface. The MEP drawing showed that the negative regions were localized on the nitrogen atoms of the triazole ring and the maximum positive regions are Table 11. Distances, types, and location of intermolecular interactions formed from the residues of the protein C-met (PDB ID: 5EOB) and the title molecule.

Protein
Residues Compound localized on the hydrogen atoms which indicates a possible sites for nucleophilic attack. Furthermore, global chemical reactivity parameters were calculated and discussed to describe the stability of the molecular system. The Q-tsa molecule shows moderate nonlinear optical properties by comparing its polarizabilty and first order hyperpolarizability to urea. In addition, the decrease in the HOMO-LUMO energy gap and the increase in solvent polarity were accompanied by an increase in the hyperpolarizability values. Finally, the obtained molecular docking results demonstrate that Q-tsa ligand can be used as inhibitor for the protein C-met (PDB ID: 5EOB), and for the design of a new antitumor drug.

Disclosure statement
No potential conflict of interest was reported by the authors.