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Spectroscopic investigation and molecular docking analysis of 5- (4- Chlorobenzylidene)-2-{3-(4-chlorophenyl)-5-[4-(propan-2-yl) phenyl]-4, 5-

dihydro-1H-pyrazol-1-yl}-1, 3-thiazole-4(5H)-one

J Jayasudhaa, V Balachandrana,*

aCentre for Research – Department of Physics, Arignar Anna Government Arts College, Musiri, (Affilated to Bharathidasan University), Tiruchirappalli, India 621 211

Abstract

The targeted molecular structure of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5-[4- (propan-2-yl)phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1,3-thiazole-4(5H)-one have been determined and analyses by DFT method employing CAM-B3LYP/6-31G(d,p) and B3LYP/6- 311G (d, p) level of theory. Theoretically calculated geometric parameters were compared with experimental (XRD) data. Based on local reactivity descriptor such as HOMO-LUMO energy gap, electrostatic potential were calculated and deliberated. On the basis of potential energy distribution (PED) by VEDA software, the scaled values of the calculated normal modes of vibration frequencies (FT-IR and FT-Raman) were assigned and compared with experimentally observed one. Natural bond orbital (NBO) analysis of the title molecule was studied. Docking analysis revealed that the title compound (Ligand) has strong binding affinity against protein for antibacterial, anti-cancer and anti-fungal activities. The ligand forms a stable complex with the proteins and recommended further analysis on present compound for their in-depth biological and pharmaceutical consequence.

Keyword: DFT, Molecular Docking, NBO, Anti-tumor 1. Introduction

In recent years, Pyrazole – thiazolee established a class of heterocyclic compound which contains oxygen, nitrogen and sulphur atoms. This organic molecule has exhibit imposing importance in medicinal and chemical applications. These heterocyclic compounds and their derivatives have good anti-cholinesterase, anti-cancer, anti-analgesic and anti-inflammatory activities [1-3]. The five-membered nitrogen linked heterocyclic compounds were widely applied as cosmetics, food additives, agrochemicals, bio-mimetic catalysts, optical brighteners, laser,

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fluorescent and dyes [4-6]. Various thiazolee based pharmaceutical drugs have been playing indispensable role for the diagnosis of different types of syndromes and generate potential to synthesis new thiazolee derivatives with biological influence were actively oppressed worldwide.

Due to the broad therapeutic properties of thiazolee derivatives, chemists have interest to synthesize a colossal number of novel chemotherapeutic agents in the medicinal field [7].

Recently I.Azad et al [8] reported pyrazole moity have anti-tumor behavior against hepato- cellular carcinoma (liver disease) which is only treated by non- surgical methods [9]. Some pyrazole-thiazolee derivatives have antibacterial, antiviral, insecticidal and fungicidal activities [10-15]. For drug design, computational studies make an essential role before experimental validation in laboratory and farther clinical trials leading to avoid loss of money and time. Now- a-days pyrazole - thiazoleidinone derivatives were very much useful to improve in drug design.

Influenced by the above mentioned applications, the present molecule 5-(4-chlorobenzylidene)- 2-[3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1, 3-thiazole- 4(5H)-one has chosen for the computational studies and evaluated spectroscopic features, structural properties, also focus on the potent of antibacterial, anticancer and antifungal agents using computational stimulated methodology. The binding affinity to the receptor of the molecule has predicted by docking to form a stable complex with least energy of binding. MEP analysis to affirm reactive sites and chemical reactivity parameter attained through molecular orbital analysis. Density functional theory has been widely used for various quantum chemical calculations to achieve above consequence. In the present study, theoretical calculations of spectral and structural parameters have been explore through DFT/B3LYP/6-31G (d,p) and 6- 311G (d,p) level of methods. Through the literature survey, there are no reported studies on the title compound using DFT method.

2. Experimental and computational procedures

The molecular structure of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5-[4-(propan-2- yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1,3-thiazole-4(5H)-one was synthesized as per the procedure reported in Salian et al.[16] with melting point 282284C. The experimental data of FT-IR and FT-Raman spectra were recorded in solid phase at room temperature. The FT-IR spectrum of the compound have been recorded in the range 4000-450 cm-1 using Perkin Elmer spectrometer with KBr pellet technique, while FT-Raman spectrum has recorded by Nd-YAG

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laser source having 1064nm wavelength in the range 4000-0 cm-1and these spectral data have been compiled at SAIF (Sophisticated Analytical Instruments Facility), IIT Chennai, India.

The quantum chemical calculations were performed by Gaussian 09W[17] and Gauss view software[18] at CAM-B3LYP/6-31G(d,p) and B3LYP/6-311G(d,p) basis set using DFT method.

With the Becke's three parameter hybrid functional (B3) [19,20] with Lee-Yang-Parr (LYP) correlation function [21] of DFT method was approved due to its cost efficiency and exemplary correctness in occurring observed value for geometrical parameter and vibrational frequencies.

The vibrational assignments were done according to their Potential Energy Distributions (PEDs) by VEDA (Vibrational Energy Distribution Analysis) program [22] and visualization from Gauss view [18]. The charge distribution of the title compound was summarized by molecular electrostatic potential and HOMO-LUMO to examine the neucleophilic and electrophilic regions for the compound in three dimensions with help of TD-DFT. The molecular docking study has also investigated by Auto Dock Tools [23] and the visual representations of protein–Ligand complex were obtained via PyMol interface and in Discovery Studio 4.1 [24].

3. Result and Discussion

3.1 Description of molecular structure

The optimized structure of the title compound is given along with atom labeling scheme as shown in Figure 1. The geometry parameters such as bond length and bond angle were computed by DFT method using B3LYP/6-311G (d, p). Table 1 displays the optimized geometry parameter of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5-[4-(propan-2-yl) phenyl]-4-5-dihydro-1H- pyrazol-1-yl]-1,3-thiazole-4(5H)-one molecule belongs to C1 point group symmetry. The experimental values are correlated well with theoretical value; however some of the calculated values of the compound have slightly varied from experimental values. The phenyl ring C-C bond length lies in the range of 1.40-1.38 Å for MPDIA, 1.49-1.39 Å for BPDIA [25]. In addition, for „chloro‟ substitution of PBA the C-C bond length observed in the range of 1.39 - 1.36 Å and calculated values were in the range 1.40-1.39 Å [26]. In this case the calculated bond length are C10-C11, C20-C21, C20-C28, C23-C25, C25-C26, C48-C49, C48-C50, C49-C51, C50-C53, C51-C55, C53-C55 ≈ 1.40 Å, C10-C18, C11-C13, C13-C15, C15-C16, C16-C18, C21-C23, C26-C28 ≈ Å. The substituted methyl groups of the carbon bond length of the title compound are C30-C32 and C30-C36 is 1.53 Å, which are slightly vary with experimental value

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as 1.51 Å. Due to the electron displacement by the external field and an induced dipole moment is produced which changes when the bond length changes during the molecular vibration. While the bond length of C4-C6 ≈1.55 Å, C4-C20, C6-C9 and C41-C42 ≈ 1.51 Å, C9-C10 ≈ 1.50 Å were elongated due to the transfer of a lone pair of electrons [27]. The halogen substituted carbons of Cl1-C15 and C55-Cl58 bond length is 1.74 Å and 1.76 Å [28]. The bond length of N-C single bond is N2-C4 ≈ 1.48 Å, N2-C40≈1.47 Å, and N3-C9≈1.28 Å which are well agree with experimental value [29-31].

Table 1: optimized Geometrical parameter of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5- [4-(propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1,3-thiazole-4(5H)-one: bond length (Å)

Label DFT

Value XRD Label DFT

Value XRD Label DFT

Value XRD Cl1-C15 1.7435 1.7402 C18-H19 0.9503 0.9310 C40-S43 1.7765 1.7521

N2-N3 1.3812 1.3861 C20-C21 1.3947 1.3797 C40-N44 1.2955 1.2971 N2-C4 1.4889 1.4845 C20-C28 1.3929 1.3756 C41-C42 1.5144 1.5168 N2-C40 1.4701 1.3571 C21-H22 0.9496 0.9306 C41-S43 1.7900 1.7890

Figure 1. Molecular structure of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5-[4- (propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1, 3-thiazole-4(5H)-one

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N3-C9 1.2823 1.2725 C21-C23 1.3842 1.3891 C41-C46 1.3500 1.3401 C4-H5 0.9997 0.9971 C23-H24 0.9505 0.9299 C42-N44 1.3593 1.3719 C4-C6 1.5461 1.5461 C23-C25 1.394 1.3603 C42-O45 1.2155 1.2156 C4-C20 1.5136 1.5079 C25-C26 1.3954 1.3828 C46-H47 0.9965 0.9300 C6-H7 0.9901 0.9699 C25-C30 1.5159 1.5156 C46-C48 1.4609 1.4601 C6-H8 0.9899 0.9701 C26-H27 0.9495 0.9305 C48-C49 1.4083 1.3904 C6-C9 1.5105 1.5099 C26-C28 1.3823 1.3927 C48-C50 1.4106 1.3936 C9-C10 1.4709 1.4582 C28-H29 0.9500 0.9300 C49-C51 1.3888 1.3800 C10-C11 1.4046 1.3923 C30-H31 1.0007 0.9803 C49-H52 0.9904 0.9300 C10-C18 1.3870 1.3837 C30-C32 1.531 1.4307 C50-C53 1.3868 1.3774 C11-H12 0.9499 0.9292 C30-C36 1.5245 1.4354 C50-H54 0.9987 0.9301 C11-C13 1.3862 1.3825 C32-H33 0.9796 0.9584 C51-C55 1.3913 1.3886 C13-H14 0.9497 0.9301 C32-H34 0.9795 0.9592 C51-H56 0.9897 0.9302 C13-C15 1.3833 1.3631 C32-H35 0.9801 0.9602 C53-C55 1.3910 1.3895 C15-C16 1.3753 1.3676 C36-H37 0.9806 0.9597 C53-H57 0.9908 0.9300 C16-H17 0.9504 0.9307 C36-H38 0.98 0.9606 C55-Cl58 1.7579 1.7440 C16-C18 1.389 1.3728 C36-H39 0.98 0.9605

3.2 Spectral analysis

The molecular structure of 5-(4-Chlorobenzylidene)-2-[3-(4-Chlorophenyl)-5-[4-(propan-2- yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1,3-thiazole-4(5H)-one has 58 atoms of 168 normal vibration modes. The FT-IR and FT-Raman vibrational assignments of the studied compound were performed on the basis set of harmonic force field calculations at CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G(d,p) level. Table 2 shows the comparison of experimental and theoretical frequency band assignments with potential energy distribution (PED) and the compared IT and Raman spectra were displayed in figure 2 and 3 respectively. From the result of computed vibration frequencies are slightly differ from experimentally observed one.

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Carbon-Hydrogen vibration

The C-H stretching vibrations in hetro aromatic structure exhibit in the range of 3100- 2900cm-1[32] and this occurrence clear identification of the structure. In this present work, the C- H stretching vibration observed at 3061cm-1 in IR spectrum and at 3065 cm-1 in FT-Raman spectrum. The calculated values of C-H stretching bands are 3071, 3063, 3058, 3054, 3049, 3046, 3039, 3027, 3019, 3008, 2999, 2992, 2976 cm-1 with CAM-B3LYP/6-31G(d,p) and at 3064, 3059, 3054, 3051, 3047, 3042, 3038, 3021, 3012, 3003, 2997, 2988, 2980, 2972 cm-1 with PED range from 96-98% by B3LYP/6-311G(d,p) method. For aromatic ring C-H in-plane- bending and out-of plane bending vibrations are appeared in the range 1500-700cm-1 through literature [33]. The C-H in-plane-bending mode has observed at 1327, 1087cm-1 in IR spectrum and at 1333, 1285, 1250, 1089 cm-1 in FT-Raman spectrum. Theoretically calculated values of C- H in-plane bending mode were obtained at 1465, 1452, 1441, 1355, 1343, 1332, 1323, 1309, 1294, 1287, 1265, 1260, 1251, 1165, 1153, 1107, 1098, 1091cm-1 with CAM-B3LYP/6-31G (d, p) level. By B3LYP/6-311G(d,p) level this vibration bands have been assigned at 1461, 1448, 1439, 1353, 1341, 1330, 1318, 1304, 1290, 1284, 1263, 1258, 1250, 1214, 1163, 1150, 1105, 1195, 1088 cm-1. Additionally C-H out-of-plane bending mode in aromatic ring have been determined at 952, 897, 747 cm-1 in FT-IR and at 950, 748 cm-1 in Raman spectrum. The computed C-H(out-of-plane) bending mode were obtained at 954, 945, 931, 919, 905, 899, 875, 835, 819-745, 296cm-1 and at 951, 941, 928, 917, 902, 895, 870, 832, 814-740, 292 cm-1 through CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G(d,p) methods correspondingly. These assignments were supported by the literature survey [34-36].

CH2 vibration

The asymmetric and symmetric CH2 stretching vibrations were determined in the region 3000-2900 cm-1 and 2900-2800 cm-1 and also it exist at lower frequencies [27]. The computed CH2 asymmetric and symmetric stretching vibration modes are assigned at 2957, 2953 cm-1 with

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PED 88% and at 2917, 2913cm-1 with PED 89% through CAM-B3LYP/6-31G (d,p) and

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B3LYP/6-311G(d,p) methods. But experimentally recorded spectra does not exist any peak in these vibration bands. The CH2 bending modes normally emerge in the region between 1450 and 875cm-1 [33]. The scissoring mode of CH2 vibration is recorded at 145555 cm-1 in FT-IR band [27]. In CH2 group, the computed scissoring mode found at 1364, 1362 cm-1 with PED contribution 71%. The CH2 rocking vibration is assigned at 1197 and 1195 cm-1 with PED 68%.

The recorded band at 1123 cm-1 in FT-Raman spectrum determine to the CH2 twist mode and the calculated wavenumber for this mode at 1125 and 1120 cm-1 with potential energy of 68%. CH2 wagging vibration mode observed at 461cm-1 in FT-IR spectrum and computed wavenumber assigned at 465 cm-1 and 460 cm-1 with energy contribution of 62% by CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G(d,p) methods.

Methyl group vibration

In general, CH3 group associated to electron donating substitution in aromatic system [27, 37] and these vibrations are arises in the range 3000-2840 cm-1. Asymmetric stretching vibration of methyl group assigned at 2968, 2946, 2934, 2925/2965, 2941, 2930, 2922 cm-1 by CAM- B3LYP/6-31G (d,p) and B3LYP/6-311G(d,p) levels. Similarly, the computed symmetric stretching of CH3 group is found at 2909, 2895/2904, 2893 cm-1. Normally, the symmetric and asymmetric bending vibration modes of methyl group emerging in the range 1355-1395 cm-1 and 1430-1470cm-1 [38]. The symmetric bending vibration have been observed at 1397 cm-1 in FT-IR and at 1401cm-1 in FT-Raman spectra and it has calculated at 1427, 1402, 1315, 1299/ 1422, 1400, 1311, 1297 cm-1. The computed asymmetric bending vibration mode of methyl group assigned at 1394, 1387/1391, 1384 cm-1 with PED 67, 68%. The rotating mode of rocking CH3

vibration mode is computed at 1056, 999/ 1054, 998cm-1 and the out-of-plane bending CH3 band assigned at 890, 844/ 888, 840cm-1. The CH3 torsion vibration mode has fall below 500cm-1 [27,39] and it has assigned at 199, 192/ 197, 189 cm-1 theoretically by CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G (d,p) methods. For the title compound the observed wavenumber were in agreement with computed ones.

Aromatic ring vibration

For the hetero aromatic molecular structure C-C and C=C stretching vibrations were assigned in the range of 1650-1430cm-1 and 1380-1280 cm-1 respectively [34,40]. In the aromatic ring vibration mode the form of substitution plays major role. FT-IR peaks of the title compound were observed at 1541, 1274, 1225, 1183, 1115cm-1 and FT-Raman bands at 1609, 1562,

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1182cm-1, which were attributed to C-C stretching vibration mode. Theoretically computed C-C stretching vibration mode have been found at 1611, 1578, 1567, 1562, 1543, 1526, 1488, 1278, 1272, 1235, 1228, 1207, 1189, 1183, 1174, 1118cm-1 by CAM-B3LYP/6-31G(d,p) and at 1610, 1575, 1566, 1560, 1540, 1522, 1486, 1275, 1269, 1234, 1225, 1202, 1188, 1180, 1171, 1114 cm-1 through B3LYP/6-311G (d,p) level. The observed and theoretically computed values of C-C stretching vibration were congruence with reported values. Slightly differ from the expected range of values due to the substitution along with interface cause by C-N which happens to fall lower range. The C-C in-plane and out-of-plane bending vibrations were obtained in the range of 600-250 cm-1 and 560-420cm-1 [34, 41]. In the present structure C-C in-plane bending mode has observed at 589cm-1 in FT-IR spectrum and computed values at 994, 989, 985, 978, 967, 592, 407, 398, 176, 78, 73 cm-1 through CAM-B3LYP/6-31G (d,p) and at 991,988, 982, 973, 963, 588, 403, 394, 170, 74, 71cm-1 through B3LYP/6-311G (d,p) methods. Out -of –plane C-C bending vibration has observed at 825 cm-1 and 823, 81 cm-1 in FT-IR and FT-Raman spectra and theoretically calculated value are 827, 362 ,308, 285, 278, 272, 235, 219, 208, 184, 86cm-1, at 825, 320, 304, 281, 275, 269, 230, 217, 203, 179, 80 cm-1 through same basis methods. The calculated CC torsion vibration mode has to be assigned at 69, 56, 47, 36, 31, 27, 24, 21, 19, 10cm-1 and 68, 50, 45, 31, 28, 25, 21, 20, 16, 8cm-1. Below 500cm-1 wavenumber have been found to ring in-plane (

ring) and ring out-of-plane (

ring) bending vibration modes [34, 41, 42].

The observed ring in-plane vibration is at 554cm-1 in FT-Raman spectrum and the computed values are 734, 726, 687, 579, 572, 567, 559, 426, 265, 97cm-1 and at 731, 720, 681, 575, 570, 563, 555, 422, 260, 91cm-1 by CAM-B3LYP/6-31G(d,p) and B3LYP/6-311G(d,p) methods. A band observed at 706cm-1 in FT-IR is assigned to

ring vibration and corresponding computed vibrations at 710, 672, 648, 624, 597, 541, 495, 448, 441, 371, 356, 335, 141, 117, 109cm-1 and at 705, 668, 643, 619, 594, 538, 491, 444, 439, 369, 353, 332, 137, 112, 103 cm-1 by both CAM- B3LYP/6-31G(d,p) and B3LYP/6-311G(d,p) methods and these values are congruence with the literature.

C=O vibration

The most characteristic vibration mode of the IR and FT-Raman spectra has been C=O (ketones) vibration mode for the subjected molecular structure, which occurs in the range of

65 1

1725 cm [43, 44]. The observed C=O stretching band at 1668 cm-1 in FT-IR spectrum for

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the title compound. Theoretically (CO)band were obtained at 1669 and 1667cm-1 with PED contribution of 85% for CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G (d,p) basis set and it has exemplary synchronize with the experimental wavenumber. The reported (CO)vibration band for the synthesized title compound observed at 1666 cm-1in FT-IR spectrum [16]. Murthy et al.[45] reported that at 1668cm-1 (IR), 1680cm-1(Ra), 1679, 1678cm-1 (DFT) and at 1689 cm-1(IR)of stretching mode in venil et al.[46]. An observed band at 711cm-1 in FT-Raman has corresponds to out-of-plane bending mode with PED 62%, while the vibration bending mode located at 719 and 712 cm-1 theoretically by both CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G (d,p) methods. The reported values of (CO)vibration mode were 679, 662 cm-1(IR), 658, 551cm-1 (Ra), 678, 667, 553 cm-1 (DFT) [45], 606, 569 cm-1 (DFT) [47], at 753cm-1 (IR), 755, 751, 748, 745cm-1 (DFT)[46].

C-Cl vibration

The C-Cl vibration modes are obtainable due to the lowering of molecular symmetry and heavy atoms being on the molecular structure. In general, the frequency range of 1129-480cm-1 assigned to the C-X group (X- Cl, F, Br, I) vibration [27, 35]. In the present work, the stretching vibration mode between chlorine and phenyl ring is observed at 1010 cm-1 in FT-IR, 1037, 1033, 1015, 1011 cm-1 with PED contribution of 68% theoretically by CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G (d,p) methods correspondingly. However the strong absorption vibration bands between chlorine and aromatic ring, there is a shift might be occurs as high as 840cm-1 [48]. The stretching C-Cl vibration band appears at 389, 386, 377, 375 cm-1 with PED 62% due to the long bond length the vibration mode fall into lower frequency. In –plane-bending vibration of C-Cl mode to be cited at 257, 253, 246, 241 cm-1 with 62% of potential energy distribution and for out-of-plane C-Cl bending mode assigned at 163, 159, 154, 148 cm-1 of 52% of PED contribution through CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G (d,p) methods. The observed reported value of CCl mode at 829cm-1 (IR) in v.v.salian et al.[16], at 673cm-1 (Ra), 671cm-1 (DFT) in Beegum et al.[49]. Viji et al.[14] reported that observed CClband at 414 cm-1 (IR), 416, 415 cm-1 (DFT) and at 311, 309 cm-1 of C-Cl in-plane-bending, at 155, 153 cm-1 (DFT) of C-Cl out-of-plane bending given by Sivakumar et al.[15].

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Table 2: Observed and calculated scaled vibration wavenumbers of 5-(4-Chlorobenzylidene)-2- [3-(4-chlorophenyl)-5-[4-(propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1,3-thiazole-

4(5H)-one : IR and FT-Raman bands and assignments

S. No

FTIR FT-Raman

Calculated wavenumbers (cm-1)

Vibrational Assignment (%PED)

Cam- B3LYP/6-

31G (d,p)

B3LYP/6- 311G (d,p)

1 3061 vw 3065 ms 3071 3064 νCH (98)

2 3063 3059 νCH (97)

3 3058 3054 νCH (98)

4 3054 3051 νCH (98)

5 3049 3047 νCH (97)

6 3046 3042 νCH (98)

7 3039 3038 νCH (98)

8 3027 3021 νCH (97)

9 3019 3012 νCH (98)

10 3008 3003 νCH (96)

11 2999 2997 νCH (96)

12 2992 2988 νCH (97)

13 2988 2980 νCH (99)

14 2976 2972 νCH (98)

15 2968 2965 νass CH3 (89)

16 2957 2953 νass CH2 (88)

17 2946 2941 νass CH3 (88)

18 2934 2930 νass CH3 (88)

19 2925 2922 νass CH3 (88)

20 2917 2913 νss CH2 (89)

21 2909 2904 νss CH3 (88)

22 2895 2893 νss CH3 (90)

23 2889 2888 νCH (95)

24 1668 m 1669 1667 νC=O (85)

25 1609 s 1611 1610 νCC (79), δCH (18)

26 1598 m 1596 vs 1599 1598 νCN (76), νCC (18)

27 1578 1575 νCC (72), δCH (27)

28 1567 1566 νCC (80), νCN (12)

29 1562 vs 1562 1560 νCC (81), δCH (13)

30 1541 s 1543 1540 νCC (68), δCH (22), δCC (10)

31 1526 1522 νCC (65), δCH (18)

32 1510 1507 νCN (89)

33 1489 s 1488 1486 νCC (71), δCH (22)

34 1465 1461 δCH (78)

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35 1452 1448 δCH (78)

36 1441 1439 δCH (75)

37 1427 1422 δipbCH3 (68)

38 1397 s 1401 s 1402 1400 δipbCH3 (66)

39 1394 1391 δopbCH3 (67)

40 1387 1384 δopbCH3 (68)

41 1364 1362 δsissCH2 (71)

42 1355 1353 δCH (70)

43 1343 1341 δCH (72)

44 1332 1330 δCH (75)

45 1323 1318 δCH (75)

46 1315 1311 δsym CH3 (72)

47 1327 s 1333 s 1309 1304 δCH (68)

48 1299 1297 δsym CH3 (74)

49 1294 1290 δCH (77)

50 1285 s 1287 1284 δCH (75)

51 1274 ms 1278 1275 νCC (63)

52 1272 1269 νCC (62), δCH (12)

53 1265 1263 δCH (70), νCC (13)

54 1260 1258 δCH (71), νCC (12)

55 1250 vs 1251 1250 δCH (71), νCC (10)

56 1235 1234 νCC (68), δCH (17)

57 1225 w 1228 1225 νCC (67), δCCl (12), νCC (10)

58 1219 1214 δCH (69)

59 1207 1202 νCC (70), δCC (17), δCH (10)

60 1197 1195 δrock CH2 (68), δCH (12)

61 1189 1188 νCC (68)

62 1183 ms 1182 s 1183 1180 νCC (68), δCH (12)

63 1174 1171 νCC (68), δCH (12)

64 1165 1163 δCH (66)

65 1153 1150 δCH (68)

66 1146 1141 νCN (63)

67 1132 1129 δCH (72)

68 1123 vs 1125 1120 τCH2 (68)

69 1115 w 1118 1114 νCC (67)

70 1107 1105 δCH (70)

71 1098 1095 δCH (71)

72 1087 m 1089 m 1091 1088 δCH (70)

73 1072 1069 νNN (55), νCN (28)

74 1056 1054 δiprCH3 (62)

75 1037 1033 νCCl (66), δCH (12)

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76 1010 m 1015 1011 νCCl (68), δCH (12)

77 999 998 δiprCH3 (60)

78 994 991 δCC (61)

79 989 988 δCC (60), δCH (13)

80 985 982 δCC (62), δCH (12)

81 978 973 δCC (62), δCH (12)

82 967 963 δCC (66), δCN (16)

83 952 w 950 m 954 951 γCH (59)

84 945 941 γCH (60)

85 939 934 νSC (70), δCH (16), νCC (10)

86 931 928 γCH (60)

87 919 917 γCH (61)

88 905 902 γCH (58)

89 897 m 899 895 γCH (58)

90 890 888 γoprCH3 (60)

91 875 870 γCH (58)

92 857 855 νCN (58), νCC (27)

93 844 840 γoprCH3 (58)

94 835 832 γCH (60)

95 825 s 823 w 827 825 νCC (68)

96 819 814 γCH (76)

97 810 809 γCH (68)

98 808 804 γCH (66)

99 797 795 γCH (68)

100 789 788 γCH (56)

101 769 767 γCH (65)

102 762 759 γCH (66)

103 747 m 748 w 753 750 γCH (65)

104 745 740 γCH (65)

105 734 731 δring (58)

106 726 720 δring (58)

107 711 w 719 712 γCO (62), γCH (12)

108 706 ms 710 705 γring (57)

109 687 681 δring (60)

110 672 668 γring (55)

111 648 643 γring (55)

112 624 619 γring (58)

113 597 594 γring (60)

114 589 w 592 588 δCC (62)

115 579 575 δring (66)

116 572 570 δring (66)

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117 567 563 δring (65)

118 554 w 559 555 δring (66)

119 541 538 γring (55)

120 495 491 γring (55)

121 501 w 478 475 νCS (62)

122 469 467 νCS (63), δCO (16)

123 461 w 465 460 σwagg CH2 (62)

124 448 444 γring (60)

125 441 439 γring (60)

126 436 vw 426 422 δring (61)

127 407 403 δCC (57)

128 398 394 δCC (58)

129 389 386 ν CCl (63)

130 377 375 ν CCl (62)

131 371 369 γring (58)

132 356 353 γring (55)

133 335 332 γring (54)

134 326 320 γCC (52)

135 308 304 γCC (50)

136 296 292 γCH (53)

137 285 281 γCC (52)

138 278 275 γCC (52)

139 272 269 γCC (52), γCCl (18)

140 265 260 δring (62)

141 257 253 δCCl (62)

142 246 241 δCCl (64)

143 235 230 γCC (52)

144 219 217 γCC (52)

145 208 203 γCC (52)

146 199 197 τCH3 (52)

147 192 189 τCH3 (52)

148 184 179 γCC (53)

149 176 170 δCC (60)

150 163 159 γCCl (53)

151 154 148 γCCl (50)

152 141 137 γring (48)

153 117 112 γring (50)

154 109 103 γring (52)

155 97 91 δring (56)

156 81 m 86 80 γCC (52)

157 78 74 δCC (55)

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158 73 71 δCC (56)

159 69 68 τCC (49)

160 56 50 τCC (50)

161 47 45 τCC (50)

162 36 31 τCC (48)

163 31 28 τCC (50)

164 27 25 τCC (48)

165 24 21 τCC (48)

166 21 20 τCC (48)

167 19 16 τCC (48)

168 10 8 τCC (50)

Abbreviations: ν: stretching, δ: in-plane bending, γ: out-of-plane bending, ass: asymmetric stretching, ss: symmetric stretching, τ: torsion, siss – scissoring, wag: wagging.

C-S vibration

The C-S stretching vibration mode can be found in an extensive range 1035-245 cm-1 in both aliphatic and aromatic sulfides, since it is absorbed as strong bands in Raman spectra are normally easy to identify [33,50]. In this study, non-polar covalent C-S stretching vibration assigned at 939, 934 cm-1 (70%) and at 501cm-1 observed in FT-Raman spectrum, 478, 475, 469, 467 cm-1 (62%) obtained theoretically by CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G (d,p) methods. The reported C-S stretching vibrations were assigned at 646, 639 cm-1 [51], 752 cm-1 [52] theoretically and at 820,658 cm-1(IR) [53]. Viji et al.[12] reported the C-S stretching vibration at 664 cm-1 in IR spectrum, 658 cm-1 in FT-Raman spectrum, 660, 662, 655, 654 cm-1 theoretically and at 854 cm-1 in IR spectra, theoretically computed at 860, 854, 786, 785 cm-1 given by venil et al.[46 ].

C-N, N-N vibrations

According to the survey of the C-N stretching vibration mode obtained in the range of 1600-1100 cm-1 of pyrazole ring at variable intensities. In general, these vibration modes were assigned in the range 1300-1100 cm-1 [27, 35], so these vibration modes are very difficult job to identify. The C=N stretching vibration mode was observed at 1600 cm-1 in FT-IR spectrum by V.V.Salian et al.[16]. P. Rajamani et al.[54] reported experimentally observed at 1588 cm-1 and 1571 cm-1 in FT-IR and Raman spectra respectively and at 1488, 1383, 1333, 998 cm-1 calculated by Y. Sert et al.[55]. The reported C-N stretching vibration modes were assigned at 1491, 1332 cm-1 in IR spectrum, 1530, 1493,1485,1336 cm-1 theoretically by venil et al.[46], at 1546

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cm-1(IR), 1549 cm-1 (Ra) and calculated bands obtained at 1625, 1551,1525, 1205, 1106, 1025 cm-1 for C-N stretching and at 963, 960 cm-1 assigned to C-N in-plane bending mode by Sivakumar et al.[15]. In the studied molecular structure, the C-N bands were accomplished at 1598 cm-1 and 1596 cm-1 in FT-IR and FT-Raman spectra refer to stretching vibration mode. The calculated values are found at 1599, 1510, 1146, 857 cm-1 and 1598, 1507, 1141, 857 cm-1 with PED contribution of 76, 89, 63, 58% by CAM-B3LYP/6-31G (d,p) and B3LYP/6-311G(d,p) methods. The band at 963 and 967 cm-1 are associated to C-N in-plane bending vibration of the title molecule. These assigned wavenumbers had a better correlation with those reported in literature survey.

The N-N stretching vibration mode of the pyrazole ring is expected in the range of 1100-950 cm-1 [39]. This vibration mode is assigned at 1072, 1069 cm-1 for studied molecular structure theoretically. For the similar pyrazole ring N-N vibration mode reported at 894 cm-1 for PHOXPY, 917cm-1 for STOXPY and at 926cm-1 for FUOXPY theoretically by A.S.El-Azab et al.[56]. M.Sathish et al.[39] reported at 1135cm-1 in FT-Raman spectrum and calculated at 1132cm-1 for N-N vibration mode belonging pyrazole ring. Al-Tamimi et al.[36] reported that computed values of N-N vibration has 944, 921, 895 cm-1 and these values are in good agreement with literature.

3.3 Molecular electrostatic potential

The molecular electrostatic potential for the title compound has been shown in Figure 4 in the range of -6.590e-2 a.u to 6.590e-2 a.u at B3LYP/6-311G (d,p) basis set. It provides various information about the molecular activities such as electrophilicity, nucleophilicity, hydrogen bonding, hydronation/dehydronation and distinct other desirable molecular interactions. Bright red colored surface describes the relative abundance of electrons that indicate negative potential surface of the molecule viz., C and O atom (V(r) < -6.590e-2 a.u).

Pyrazole ring N-atoms has comparatively less negative potential than that of O-atom. Since, its lone pair of electrons involved in an aromatic delocalization and S-atom seems to be concealed inside the highest possible positive potential surface of the studied compound.

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Figure 4. Molecular electrostatic potential of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5- [4-(propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1, 3-thiazole-4(5H)-one

3.4 Frontier molecular orbital

After geometric optimization the highest occupied molecular orbital (HOMO) and lowest unoccupied orbital (LUMO) criterions are very influential to find out quantum chemistry mechanism and chemical reactivity. Generally energy is related to ionization potential known as donor, although LUMO energy is related to electron activation as acceptor. And the energy differences between HOMO and LUMO called energy gap (

EE

LUMO

E

HOMO) plays crucial role to determined stability of the molecule. While the energy gap of the molecule have been small represents low kinetic stability. It results the significant degree of intermolecular charge transfer from HOMO to LUMO through π- conjugated path. The following parameters were computed from HOMO to LUMO energy values as; Ionization potential:

I   E

HOMO, Electron affinity:

A   E

LUMO, Chemical hardness:

2 ) (IA

,

Electron chemical potential: ( ) 2

1

HOMO LUMO E

E

 , Eleectrophilicity index:

  2

2 ,

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Figure 5. Frontier molecular orbital of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5-[4- (propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1, 3-thiazole-4(5H)-one

HOMO LUMO

HOMO-1

HOMO-2 LUMO+1

LUMO+2

Eg = -4.0754 eV Eg = -5.3143 eV Eg = -6.1788 eV

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Softness:

  2

 1 [57-59] tabulated in Table 3. Figure 5 shows the distribution of HOMO-

LUMO cloud stimulated from the optimized molecular geometry computed in gas phase at B3LYP/6-311G (d,p) level for the tested compound. In the present molecule

E

LUMO= - 1.9437 eV,

E

HOMO= -6.0191 eV, energy gap Eg= -4.0754 eV, global hardness η = 2.0377 eV, chemical potential μ= -3.9814 eV, and global electrophilicity =3.8895 eV. When the chemical potential of the investigated compound seems to be negative, it refers to higher kinetic stability of the studied compound.

Table 3: Calculated HOMO-LUMO energy gap and Global reactive descriptors of 5-(4- Chlorobenzylidene)-2-[3-(4-Chlorophenyl)-5-[4-(propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-

1-yl]-1,3-thiazole-4(5H)-one using B3LYP/6-311G(d,p) basis set State

Energy gap (a.u)

Energy gap (eV)

Hardness (eV)

Softness (eV)

Electrophilicity (eV)

Electronegativity (eV) HOMO

0.1497 -4.0754 2.0377 0.2454 3.8895 3.9814

LUMO HOMO-1

0.1953 -5.3143 2.6572 0.1882 2.6815 3.7750

LUMO+1 HOMO-2

0.2270 -6.1788 3.0894 0.1618 2.3118 3.7795

LUMO+2

3.5 Natural bond analysis

The knowledge of interactions between donor and acceptor of the molecular structure in the natural bond orbital analysis were elucidated with the help of second order perturbation theory [60, 61]. The highest possible electron density distribution of the molecule among the orbital were given by NBO analysis. The equation related for the stabilization energy E(2) were given by

j i

i

F

ij

E

q

2 )

2 (

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Where, the off-diagonal components are represented as

jand

i.

F

ij is the diagonal and

E

2

measured in kcal/mol by NBO Fock matrix elements. Also

q

ideliberates from the donor orbital occupancy. For the studied compound of natural bond analysis investigation is an impressive tool Table 4: Second order perturbation theory analysis corresponding to intra- molecular bands of 5- (4-Chlorobenzylidene)-2-[3-(4-Chlorophenyl)-5-[4-(propan-2-yl) phenyl]-4-5-dihydro-1H- pyrazol-1-yl]-1,3-thiazole-4(5H)-one by B3LYP/6-311G (d, p) basis set in NBO.

S.

No Type Donor (i) ED/e Typ

e Acceptor

(j) ED/e

E(2) kcal/mo

l

E(j)- E(i) a.u.

F(i,j) a.u.

1 σ N2 - N3 1.9807

5 σ* C9 - C10 0.0338

8 4.85 1.32 0.07

2 2 σ N3 - C9 1.9839

6 σ* N2 - C40 0.0639

3 4.69 1.2 0.06

8 3 π N3 - C9 1.9109

2 π* C10 - C18 0.3806

6 9.04 0.37 0.05

5

4 π C10 -

C18

1.6460

5 π* N3 - C9 0.2386

1 18.88 0.28 0.06

7

5 π C10 -

C18

1.6460

5 π* C11 - C13 0.2850

2 18.5 0.29 0.06

7

6 π C10 -

C18

1.6460

5 π* C15 - C16 0.3861

9 20.95 0.28 0.06

8

7 σ C11 -

C13

1.9663

4 σ* Cl 1 - C15 0.0346

7 5.6 0.84 0.06

1

8 π C11 -

C13

1.6793

2 π* C10 - C18 0.3806

6 19.2 0.29 0.06

7

9 π C11 -

C13

1.6793

2 π* C15 - C16 0.3861

9 22.06 0.27 0.07

1

10 π C15 -

C16

1.6871

7 π* C10 - C18 0.3806

6 18.17 0.3 0.06

7

11 π C15 -

C16

1.6871

7 π* C11 - C13 0.2850

2 18.6 0.31 0.06

8

12 σ C16 -

C18

1.9652

6 σ* Cl 1 - C15 0.0346

7 5.76 0.84 0.06

2

13 π C20 -

C28

1.6568

2 σ* N2 - C4 0.0637

9 5.8 0.55 0.05

4

14 π C20 -

C28

1.6568

2 π* C21 - C23 0.3269

2 20.99 0.28 0.06

9

15 π C20 -

C28

1.6568

2 π* C25 - C26 0.3383

8 19.35 0.29 0.06

7

16 π C21 -

C23

1.6741

4 π* C20 - C28 0.3567

6 19.97 0.29 0.06

8

17 π C21 - 1.6741 π* C25 - C26 0.3383 21.44 0.29 0.07

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C23 4 8 1

18 π C25 -

C26

1.6392

2 π* C20 - C28 0.3567

6 23.1 0.28 0.07

2

19 π C25 -

C26

1.6392

2 π* C21 - C23 0.3269

2 20.05 0.28 0.06

7 20 σ C40 - S43 1.9776

5 σ* C41 - C46 0.0356

6 7.29 1.21 0.08

4

21 σ C40 -

N44

1.9644

5 σ* C42 - O45 0.0695

3 6.09 1 0.07

22 σ C41 -

C42

1.9784

7 σ* C41 - C46 0.0356

6 4.52 1.02 0.06

1 23 σ C41 - S43 1.9796

3 σ* C41 - C46 0.0356

6 4.7 1.37 0.07

2

24 σ C49 -

C51

1.9681

0 σ* C46 - C48 0.0301

4 4.72 1.05 0.06

3

25 σ C50 -

H54

1.9730

7 σ* C48 - C49 0.0530

8 4.64 1.09 0.06

4

26 σ C51 -

H56

1.9710

3 σ* C53 - C55 0.0291

9 4.68 1.09 0.06

4

27 σ C53 -

H57

1.9763

8 σ* C51 - C55 0.0457

3 4.64 1.09 0.06

4 28 LP(2

) Cl 1 1.9700

9 σ* C13 - C15 0.0304

4 4.68 0.89 0.05

8 29 LP(2

) Cl 1 1.9700

9 σ* C15 - C16 0.0298

6 4.58 0.9 0.05

7 30 LP(3

) Cl 1 1.9245

1 π* C15 - C16 0.3861

9 13.2 0.33 0.06

4 31 LP(1

) N2 1.6904

0 π* N3 - C9 0.2386

1 26.31 0.28 0.07

9 32 LP(1

) N2 1.6904

0 σ* C40 - N44 0.1078

6 6.62 0.56 0.05

9 33 LP(1

) N3 1.9301

9 σ* N2 - C4 0.0637

9 8.1 0.72 0.06

8 34 LP(1

) N3 1.9301

9 σ* C6 - C9 0.0355

4 8.12 0.8 0.07

3 35 LP(1

) S43 1.9377

5 σ* C41 - C42 0.0705

9 8.94 0.94 0.08

3 36 LP(1

) S43 1.9377

5 σ* C42 - O45 0.0695

3 0.55 0.85 0.01

9 37 LP(1

) N44 1.9307

8 σ* C41 - C42 0.0705

9 6.55 0.8 0.06

5 38 LP(2

) O45 1.8615

3 σ* C41 - C42 0.0705

9 9.56 0.63 0.07

39 LP(2

) O45 1.8615

3 σ* C42 - N44 0.0168

4 11.74 0.69 0.08

1

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40 π* C15 -

C16

0.3861

9 π* C10 - C18 0.3806

6 294.94 0.01 0.08

4

41 π* C15 -

C16

0.3861

9 π* C11 - C13 0.2850

2 225.16 0.01 0.08

1 for expose intra and inter molecular bonding and also evaluate conjugative interactions in the molecular structure. The electron devoting shift from donors to acceptors in any molecular system may lended larger values of the

E

2. The summarized NBO data of the molecular structure were tabulated in Table 4. The immense stabilized energies of the strong  conjugative interactions were

(C11-C13)

(C15-C16),

(C21-C23)

(C25-C26),

(C10-C18)

(C15-C16),

(C20-C28)

(C21-C23) and

(C25-C26)

(C21- C23) with energy value of 22.06, 21.44, 20.95, 20.99 and 20.05 kcal/mol respectively. Also the minimum stabilization energy of the transition having

(N3-C9)

(C10-C18) contains 9.04kcal/mol.

Based on the weak donor (

)

() interactions due to transitions were studied for the title compound resulting in least stabilization energy values E(2).

(C40-S43)

(C41-C46) with E(2) value 7.29 kcal/mol showing higher value amongst all  transitions and

(C41-C42) (C41-C46) having 4.52 kcal/mol shows least energy value.

The interaction of electron delocalization of the compound occurs between (C15-C16)

(C10-C18) and (C15-C16)

(C11-C13) with large value of stabilization energy as 294.94 and 225.16 kcal/mol respectively which could be the impulse for bioactive behavior of the molecule [62]. The lone pair making anti bonding interaction with higher stabilization energies are LP3 (Cl1)

(C15-C16) and LP1(N2)

(N3-C9) having E(2) value 13.2 and 26.31 kcal/mol. While LP2(O45)

(C42-N44), LP2(O45)

(C41-C42), LP1(S43)

(C41-C42), LP1(N3)

(C6-C9), LP1(N3)

(N2-C4) and LP1(N2)

(C40-N44) produced 11.74, 9.56, 8.94, 8.12, 8.10 and 6.62 kcal/mol which shows least electron donating interaction energies in the studied molecular structure correspondingly.

3.6 Biological application: Docking studies

The molecular docking analysis of different protein in anti-tumor, antifungal and antibacterial activity of the title compound was carried out by using Auto Dock software and Discover studio visualizer 4.1 software [23, 24]. Docking of the subjected molecular compound

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into the binding site of a receptor and supposing the binding affinity is an influential part of the drug design process. A complete molecular view and a graphical support computationally offered by Auto Dock Tools for all steps required for run docking process. The X-ray crystal structures of the selected protein were downloaded from the RSCB protein data bank website (PDB ID: 1DLG, 1NQ3, 2KCN, 3A7I, 4OQS, 5W7M, 3BCI, 3T8R) [63]. The rigid docking process was carried out in the form of macromolecule active sites within grid box size of 60Åx60Åx60Å (spacing = 0.375Å) over the target protein binding pocket. About 100 genetic algorithm runs, the minimum binding affinity values were obtained to anti-tumor (PDB ID:

1DLG, 1NQ3/-8.90, -8.89 kcal/mol), antifungal (PDB ID: 2KCN, 3A7I, 4OQS, 5W7M/-7.05, - 9.58, -7.75, -8.53 kcal/mol) and antibacterial (PDB ID: 3BCI, 3T8R/-8.39, -6.30 kcal/mol)

Figure 6. Molecular docking of 5-(4-Chlorobenzylidene)-2-[3-(4-chlorophenyl)-5-[4- (propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1, 3-thiazole-4(5H)-one

4OQS

5W7M

3A71

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proteins might be beneficial for biological activity with title compound. The lowest value of inhibition constant was an essential parameter desired in molecular docking studies, which is obtained in Table 5. The binding distance of anti-tumor protein were obtained as 1.84Å (GLY A: 162), 3.56Å (Alkyl), 3.40Å (ILE A: 327) in 1DLG and the oxygen and nitrogen atoms bind with 1NQ3 protein of distance 3.03Å (ALA A: 24) and 3.05Å (TRY A:32), 2.17Å (SER A:22).

The ligand- protein interaction between antifungal protein shows carbon-hydrogen interaction with 2.82Å (ASP A: 32) in 2KCN and π-Lone pair interaction of 2.83Å (ALA A: 179), H-bond at 2.97Å (LEU A: 177; O), 3.22Å (LEU A: 177;N) in 3A7I protein. The distance for H-bond, carbon–hydrogen and π-donor hydrogen bond interactions were obtained as 2.60Å (SER A:

387; O), 2.70Å (GLU A: 385;N), 2.66Å (ARG A: 384;N) and 2.71Å (LEU A: 383) in 4OQS.

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The H-bond interaction of „N‟ atom is at 2.25Å (SER A: 131), sulfur-X interaction at 3.23Å (TRP A: 157) and alkyl interaction recorded at 3.64Å (ALA A: 54), 3.44Å (ALA A: 23) is formed with chlorophenyl ring of ligand in 5W7M. There are H-bond interactions of =O at 2.01Å (TYR A: 28), 3.01Å (CYS A: 26), 2.98Å (CYS A: 26; N), 3.0Å (THR A: 153) and π- lone pair interaction formed at 2.89Å (LYS: 151) of antibacterial protein in 3BCI. The π-donor hydrogen interaction formed at 2.47Å (ASN A: 35), π-sigma and H-bond were obtained at 2.85Å (ARG A: 8) and 2.15Å (ARG A: 8; N) in 3T8R protein. Figure 6 and 7 showed the details about the binding interaction of the receptor with the title compound.

Table 5: Molecular binding affinity for docking in 5-(4-Chlorobenzylidene)-2-[3-(4- chlorophenyl)-5-[4-(propan-2-yl) phenyl]-4-5-dihydro-1H-pyrazol-1-yl]-1,3-thiazole-4(5H)-one

Protein Name

Pub Chem

ID

Amino

acid Bond Interaction

Bond Length

(Å)

Binding Energy (kcal/mol)

Inhibition Constant

(molar)

E.Coli

Cancer 1DLG

GLY

A:164 Conventional Hydrogen 1.84

-8.90 299.82 nM SER

A:162 Carbon Hydrogen 3.40 ILE

A:327 Alkyl Interaction 3.56

Tumor 1NQ3

SER

A:22 Carbon Hydrogen 2.17

-8.89 305.36 nM SER

A:22 Conventional Hydrogen 2.40 SER

A:22 Conventional Hydrogen 2.79 ALA

A:24 Carbon Hydrogen 3.03 TRY

A:32 Conventional Hydrogen 3.05

S. Auraus 3BCI

TYR

A:28 Conventional Hydrogen 2.01

-8.39 711.70 nM LYS

A:151 Pi-Lone pair 2.89

CYS

A:26 Conventional Hydrogen 2.98 THR

A:153 Conventional Hydrogen 3.00

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CYS

A:26 Conventional Hydrogen 3.01

3T8R

ARG

A:8 Conventional Hydrogen 2.15

-6.30 23.97 μM ASN

A:35 Pi-Donor Hydrogen 2.47 ARG

A:8 Pi-Sigma 2.85

Penicillium

2KCN ASP

A:32 Carbon Hydrogen 2.82 -7.05 6.79 μM

3A71

ALA

A:179 Pi-Lone pair 2.83

-9.58 94.60 nM LEU

A:177 Conventional Hydrogen 2.97 LEU

A:177 Conventional Hydrogen 3.22

4OQS

SER

A:387 Conventional Hydrogen 2.60

-7.75 2.08 μM ARG

A:384 Carbon-Hydrogen 2.66 GLU

A:385 Conventional Hydrogen 2.70 LEU

A:383 Pi-Donor Hydrogen 2.71

5W7M

SER

A:131 Conventional Hydrogen 2.25

-8.53 557.42 nM TRP

A:157 Sulfur-x interaction 3.23 ALA

A:23 Alkyl 3.44

ALA

A:54 Alkyl 3.64

4. Conclusion

In present study, the optimized structure of studied molecule compared with X-ray crystallographic data of related molecule was found to be reliable agreement. The stimulated vibrational spectrums of present molecule have been obtained from density functional theory

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(DFT) method of different level exhibits good agreement with experimental one while compared in solid phase. The HOMO – LUMO energy gap has evident that there is a significant influence on bioactivity of the molecule. The reactive site of the molecule has been located by MEP study.

The ligand forms a stable complex with the proteins and gives good binding affinities and the preliminary docking results suggest that the title compound exhibits inhibitory activity against S.

aureus, E. coli-anti-cancer and Pencillium. This could be useful to develop a new drug.

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