View of Molecular Docking, Vibrational, Structural and Electronic Studies of 5-(4-Butoxybenzylidene)-2-[3-(4-Chlorophenyl)-5[4-(Propan-2-Yl)-4,5-Dihydro-1H-Pyrazol-1-Yl]-1,3-Thiazol-4(5H)-One

Molecular Docking, Vibrational, Structural and Electronic Studies of 5- (4-Butoxybenzylidene)-2-[3-(4-Chlorophenyl)-5[4-(Propan-2-Yl)-4,5-

Dihydro-1H-Pyrazol-1-Yl]-1,3-Thiazol-4(5H)-One

K.Venil^a, A.Lakshmi^a , V. Balachandran^b

a Department of Physics, Government Arts College (Affiliated to Bharathidasan University), Trichy 621 222, TN, India.

bCentre for Research, Department of Physics, Arignar Anna Government Arts College, Musiri ,621 211, TN, India

Abstract

Spectroscopic and structural investigations of 5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4- (propan-2-yl)-4, 5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one are presented by using experimental (FT-IR and FT-Raman) spectra and theoretical (Density functional theory) calculations.

The optimized geometrical assignments were made on the basis of potential energy distribution. The molecular electrostatic potential map was used to detect the electrophilic and nucleophilic sites in the molecule. The directly calculated ionization potential (I), electron affinity (A), electronegativity (), electrophilic index (), hardness () and chemical potential (µ) are all correlated from HOMO- LUMO energies with their molecular properties. The reduced density gradient of the title molecule was investigated by the interaction of molecule. Molecular docking studies were also described.

Keywords:DFT, Thiazole, Reduced Density Gradient and Docking.

1. Introduction

Thiazoleis a heterocyclic compound that contains both sulphur and nitrogen and a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and they have extensive applications in agriculture and medicinal chemistry [1, 2]. Varieties of biologically active molecules accommodate the thiazole and its derivatives, aminothiazoles [3]. They are used as important fragments in different drugs related to anti-tuberculosis, anti-inflammatory, [4, 5, 6], anti-allergic [7], anti-hypertensive [8], schizophrenia [9], anti-bacterial, HIV infections [4, 10] and human

lymphatic filarial parasites [11]. Various thiazole derivatives are used as fungicides and herbicides and have numerous applications in agricultural field [12]. Hydantoin derivatives, in particular phenytoin, are important antiepileptic drugs.

In the present work, optimized molecular structure of the title compound is investigated. The vibrational spectroscopic investigations combined with DFT (Density functional theory)calculations are employed to provide comprehensive vibrational spectral assignments of the title compound. The molecular properties like dipole moment, polarizability, hyper polarizability and molecular electrostatic potential surface have been calculated to get a better understanding the properties of the title molecule.The non-covalent interactions like hydrogen bonding and Van der Waals interaction were identified from the molecular geometry and electron localization function. These interactions in molecules have been studied by using reduced density gradient (RDG) and graphed by Multiwfn.Molecular docking is a computer-assisted drug design (CADD) method used to predict the favourable orientation of a ligand (viz. drug) to a target (viz. receptor) when bound to each other to form a stable complex.

2. Experimental details

5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4-(propan-2-yl)-4, 5-dihydro-1H-pyrazol-1-yl]- 1,3-thiazol-4(5H)-one was synthesized as per the reported procedure [13-15]. The Fourier Transform infrared (FT-IR) spectrum of the title compound was recorded using Perkin Elmer Spectrometer fitted with a KBr beam splitter around 4000-450 cm^-1. The Bruker RFS 27 FT-Raman spectrometer in the region 4000-0 cm^-1 using a 1064 nm Nd:YAG laser source was used to reported the FT- Raman spectrum. Both the spectral measurements were performed at the Sophisticated Analytical Instrumentation Facility (SAIF), IIT, Madras, India.

3. Computational details

All calculations of the title compound were carried out using Gaussian 09 program [16] was performed with Becke’s three-parameter hybrid model and therefore the Lee-Yang-Parr correlation was a useful functional (B3LYP) in DFT [17, 18] technique. The electronic structure of the molecule has to be proven with the density functional theory. The visual representations for fundamental modes are also checked by the Gauss view program [19]. Electron density map and reduced density

gradient (RDG) were calculated with the use of Multiwfn program [20] and plotted by visual molecule dynamics program (VMD) [21]. The reactivity descriptors, such as electrophilicity (ω), global hardness (η), the chemical potential (µ), ionization potential (I) and electron affinity (A) were determined from the energies of frontier molecular orbitals. The molecular docking calculation was performed by the AutoDock 4.0.1 software [22], which was also applied to detect the docking input files and analyze the docking result. Using Discovery studio visualize software, one of the best active site was visualized for ligand-protein interaction.

4.0 Results and discussions

4.1 Optimized molecular geometrical parameters

The geometrical structure and parameters of 5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4- (propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one are depicted in Figure 1 and Table 1 by using B3LYP/6-31G and B3LYP/6-31G (d,p) methods.

Figure 1: Optimized molecular structure of 5-(4-Propan-2-yl)benzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)phenyl-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

Table 1: Optimized structural parameters of 5-(4-Butoxybenzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

obtained by B3LYP/6-31G and B3LYP/6-31G (d,p) basis sets.

Parameters

Bond length (Å)

Parameters

Bond angle(°)

Parameters

Dihedral angle(°) B3LYP/6-

31G

B3LYP/6- 31G(D,P)

B3LYP/6- 31G

B3LYP/6- 31G(d,p)

B3LYP/6- 31G

B3LYP/6- 31G(D,P)

C1-C4 1.4604 1.4628 C4-C1-N24 121.7147 121.788

N24-C1-C4-

C5 179.171 178.663

C1-N24 1.3062 1.294 C4-C1-C26 125.171 125.091

N24-C1-C4-

C6 -0.574 -1.023

C1-C26 1.5223 1.5184

N24-C1-

C26 113.104 113.11

C26-C1-C4-

C5 0.425 -0.056

C1-C14 1.5184 1.5174

C14-C2-

N25 112.3446 112.421

C26-C1-C4-

C6 -179.319 -179.743

C2-N25 1.5078 1.4931

C14-C2-

C26 115.1468 114.938

C4-C1-N24-

N25 -179.833 179.898

C2-C26 1.5576 1.5519

C14-C2-

N25 109.2771 109.088

C26-C1-

N24-N25 -0.948 -1.241

C2-H55 1.0919 1.0919

N25-C2-

C26 100.1893 100.201

C4-C1-N26-

C2 -174.604 -174.939

H3-C26 1.0937 1.0932

N25-C2-

H55 107.2673 107.668

C4-C1-C26-

H3 -54.509 -54.804

C4-C5 1.4082 1.4042

C26-C2-

H55 121.7147 121.788

C4-C1-C26-

H28 65.533 65.160

C4-C6 1.4121 1.4083 C1-C4-C5 125.171 125.091

N24-C1-

C26-C2 6.557 6.245

C5-C7 1.3979 1.3933 C1-C4-C6 113.104 113.11

N24-C1-

C26-H3 126.652 126.379

C5-C8 1.0844 1.0852 C5-C4-C6 112.3446 112.421

N24-C1-

C26-H28 -113.306 -113.657

C6-C9 1.3932 1.3882 C4-C5-C7 115.1468 114.9386

N25-C2-

C14-C15 68.304 64.354

C6-H10 1.0835 1.0843 C4-C5-H8 109.2771 109.088

N25-C2-

C14-C16 -111.460 -115.788

C7-C11 1.392 1.3929 C7-C5-H8 100.1893 100.201

C26-C2-

C14-C15 -45.540 -49.422

C7-H12 1.0829 1.084 C4-C6-C9 107.2673 107.668

C26-C2-

C14-C16 134.697 130.437

C9-C11 1.3963 1.3978 C4-C6-H10 121.7147 121.788

H55-C2-

C14-C15 -172.766 -176.292

C9-H13 1.083 1.0842 C9-C6-H10 125.171 125.091

H55-C2-

C14-C16 7.471 3.566

C11-Cl27 1.8237 1.7554 C5-C7-C11 113.104 113.11

C14-C2-

N25-N24 -113.650 -114.317

C14-C15 1.4058 1.4019 C5-C7-H12 112.3446 112.421

C14-C2-

N25-C42 69.525 71.318

C14-C16 1.4006 1.3959

C11-C7-

H12 115.1468 114.938

C26-C2-

N25-N24 9.079 8.210

C15-C17 1.3957 1.3917 C6-C9-C11 109.2771 109.088

C26-C2-

N25-C42 -167.745 -166.155

C15-H18 1.0867 1.0872 C6-C9-H13 100.1893 100.201

H55-C2-

N25-N24 126.247 125.504

C16-C19 1.3982 1.3951

C11-C9-

H13 107.2673 107.668

H55-C2-

N25-C42 -50.578 -48.861

C16-H20 1.0849 1.0859 C7-C11-C9 121.7147 121.788

C14-C2-

C26-C1 112.154 112.861

C17-C21 1.4076 1.4037

C7-C11-

Cl27 125.171 125.091

C14-C2-

C26-C3 -8.727 -7.907

C17-C22 1.086 1.0865

C9-C11-

Cl27 113.104 113.11

C14-C2-

C26-H28 -128.840 -128.348

C19-C21 1.4035 1.399

C2-C14-

C15 112.3446 112.421

N25-C2-

C26-C1 -8.582 -7.874

C19-H23 1.0862 1.087

C2-C14-

C16 115.1468 114.939

N25-C2-

C26-C3 -129.463 -128.642

C21-C29 1.5261 1.5226

C15-C14-

C16 109.2771 109.088

N25-C2-

C26-H28 110.424 110.917

N24-N25 1.3915 1.37

C14-C15-

C17 100.1893 100.201

H55-C2-

C26-C1 -122.075 -121.822

N25-C42 1.3483 1.3513

C14-C15-

H18 107.2673 107.668

H55-C2-

C26-C3 117.044 117.409

C26-H28 1.0969 1.096

C17-C15-

H18 121.7147 121.788

H55-C2-

C26-H28 -3.069 -3.032

C29-C30 1.5465 1.5402

C14-C16-

C19 125.171 125.091

C1-C4-C5-

C7 -179.695 -179.612

C29-C30 1.546 1.5402

C14-C16-

H20 113.104 113.11

C1-C4-C5-

H8 0.260 0.318

C29-H38 1.0993 1.0978

C19-C16-

H20 112.3446 112.421

C6-C4-C5-

C7 0.054 0.082

C30-H32 1.0965 1.0953

C15-C17-

C21 115.1468 114.938

C6-C4-C5-

C8 -179.991 -179.988

C30-H33 1.0953 1.094

C15-C17-

H22 109.2771 109.088

C1-C4-C6-

C9 179.712 179.627

C30-H34 1.0968 1.0955

C21-C17-

H22 100.1893 100.201

C1-C4-C6-

H10 -0.241 -0.339

C31-H35 1.0956 1.0944

C16-C19-

C21 107.2673 107.668

C5-C4-C6-

C9 -0.037 -0.066

C31-H36 1.0966 1.0954

C16-C19-

H23 121.7147 121.788

C5-C4-C6-

H10 -179.990 179.968

C31-H37 1.0968 1.0956

C21-C19-

H23 125.171 125.091

C4-C5-C7-

C11 -0.039 -0.047

C39-C40 1.493 1.5081

C17-C21-

C19 113.104 113.11

C4-C5-C7-

H12 179.976 179.971

C39-S41 1.8656 1.794

C17-C21-

C29 112.3446 112.421

H8-C5-C7-

C11 -179.994 -179.978

C39-C45 1.3602 1.3596

C19-C21-

C29 115.1468 114.939

H8-C5-C7-

H12 0.020 0.040

C40-N43 1.4066 1.3966

C1-N24-

N25 109.2771 109.088

C4-C6-C9-

C11 0.006 0.015

C40-O44 1.2485 1.2232

C2-N25-

N24 100.1893 100.201

C4-C6-C9-

H13 -179.979 -179.983

S41-C42 1.8391 1.776

C2-N25-

C42 107.2673 107.668

H10-C6-C9-

C11 179.958 179.981

C42-N43 1.3043 1.2987

N24-N25-

C42 121.7147 121.788

H10-C6-C9-

H13 -0.027 -0.018

C45-C46 1.4585 1.4571 C1-C26-C2 125.171 125.091

C5-C7-C11-

C9 0.006 -0.006

C45-C56 1.0902 1.0904 C1-C26-H3 113.104 113.11

C5-C7-C11-

Cl27 -179.973 -179.967

C46-C47 1.416 1.4105

C1-C26-

H28 112.3446 112.421

H12-C7-

C11-C9 179.992 179.977

C46-C48 1.4198 1.4156 C2-C26-H3 115.1468 114.939

H12-C7-

C11-Cl27 0.013 0.016

C47-C49 1.3931 1.3906

C2-C26-

H28 109.2771 109.088

C6-C9-C11-

C7 0.010 0.021

C47-H50 1.0867 1.0872

H3-C26-

H28 100.1893 100.201

C6-C9-C11-

Cl27 179.989 179.982

C48-C51 1.3882 1.3839

C21-C29-

C30 107.2673 107.668

H13-C9-

C11-C7 179.995 -179.980

C48-H52 1.0817 1.082

C21-C29-

C31 121.7147 121.788

H13-C9-

C11-Cl27 -0.026 -0.019

C49-C53 1.4036 1.4017

C21-C29-

H38 125.171 125.091

C2-C14-

C15-C17 179.751 179.385

C49-H57 1.0828 1.0831

C30-C29-

C31 113.104 113.11

C2-C14-

C15-H18 -0.979 -1.326

C51-C53 1.4054 1.4049

C30-C29-

H38 112.3446 112.421

C16-C14-

C15-C17 -0.483 -0.476

C51-H54 1.0837 1.0851

C31-C29-

H38 115.1468 114.939

C16-C14-

C15-H18 178.787 178.813

C53-O58 1.3842 1.3595

C29-C30-

H32 109.2771 109.088

C2-C14-

C15-C19 -179.424 -179.063

O58-C59 1.4618 1.4285

C29-C30-

H33 100.1893 100.201

C2-C14-

C16-H20 2.293 2.184

C59-H60 1.0988 1.0996

C29-C30-

H34 107.267 107.668

C15-C14-

C16-C19 0.806 0.799

C59-H61 1.0988 1.0996

C40-C39-

C45 113.104 113.11

C15-C14-

C16-H20 -177.477 -177.954

C59-C62 1.5233 1.5217

S41-C39-

C45 118.135 118.670

C14-C15-

C17-C21 -0.126 -0.137

C62-H63 1.0976 1.0969

C39-C40-

N43 113.471 112.705

C14-C15-

C17-H22 179.731 179.737

C62-H64 1.0976 1.0969

C39-C40-

O44 124.813 124.954

H18-C15-

C17-C21 -179.403 -179.432

C62-C65 1.5402 1.5336

N43-C40-

O44 121.716 122.339

H18-C15-

C17-H22 0.454 0.442

C65-H66 1.1 1.0984

C39-S41-

C42 86.313 87.757

C14-C16-

C19-C21 -0.532 -0.522

C65-H67 1.1 1.0984

N25-C42-

S41 119.688 119.294

C14-C16-

C19-H23 -179.815 -179.889

C65-C68 1.5369 1.5315

N25-C42-

N43 122.861 122.033

H20-C16-

C19-C21 177.745 178.228

C68-H69 1.0969 1.0956

S41-C42-

N43 117.447 118.672

H20-C16-

C19-H23 -1.538 -1.139

C68-H70 1.0958 1.0945

C40-N43-

C42 113.818 112.104

C15-C17-

C21-C19 0.407 0.421

C68-H71 1.0969 1.0956

S41-C39-

C45 118.135 118.670

C15-C17-

C21-C29 179.921 -179.872

For the title compound, the C-C bond length for pyrazole ring of C1-C26, C2-C26 are 1.5223/1.5184, 1.5576/1.5519 Ǻ, for thiazole ring for C39-C40 is 1.493/1.5081 Ǻ for the B3LYP/6-31G and B3LYP/6-31G (d,p) methods and these values are in between the single and double bond (1.54 Ǻ and 1.33 Ǻ) [23]. In the present work, the C-O bond length are observed at

C40-O44=1.2485/1.2232 Å, C53-O58 = 1.3842 / 1.3595Å, O58-C59=1.4618/1.4285Å which are in good agreement with the reported values for a similar derivatives (1.3871 Ǻ and 1.3653 Ǻ) [24].

The C-N bond length for the title compound are C1-N24, C2-N25, N25-C42, C40-N43, C42-N43 are 1.3062/1.294 Å, 1.5078/1.4931 Å, 1.3483/1.3513 Å, 1.4066/1.3966 Å, 1.3043/1.2987 Å which are in agreement with the literature [25]. The C-S bond length for the title compoundare 1.8656/1.794 Å for C39-S41 and for S41-C42 is 1.8656/1.794 Å, 1.8391 /1.776 Å and is similar toKuruvilla et.al [26] observed the C-S value at C5-S9= 1.748 Å and C8-S9=1.733 Å theoretically and experimentally at 1.8642, 1.862 Å. In the case of C-H bond lengths, (DFT/XRD) it is observed that aromatic C-H bonds measure 1.10/1.09 Å, which is equal to the experimental value. For the title compound, the bond lengths for C2-H55, C6-H10, C9-H13,C31-H35, C47-H50, C65-H66, C68-H70, C68-H71 are 1.0919/1.0919, 1.0835/1.0843, 1.083/1.0842, 1.0956/1.0944, 1.0867/1.0872, 1.1/1.0984, 1.0958/1.0945 and 1.0969/1.0956 Å observed. It was also very confined to experimental value [27]. The N-N bond lengths (DFT/XRD) are reported in the range 1.3409-1.3886Ǻ [28] and in the present case (BPT1), the N-N bond length is found at 1.3915/1.37 Ǻ for N24-N25. The thiazole ring is tilted from the phenyl ring as is evident from the torsion angles C45-C39-C40-N43=179.99/179.97˚, S41-C39-C40-H43 = -0.1457/-0.2921˚, C40-C39-S41- C42= 0.3713/ 0.414˚ and C45-C39-S41-C42= -179.74/-179.81˚.

For the title compound, the interactions between the thiazole and pyrazole groups are C40-C39- C45 = 132.917/132.571, S41-C39-C45 = 118.135/118.669, C39-C40-N43 = 113.471 /112.705, C39-C40-O44 = 124.813 / 124.954, N43-C40-O44 = 121.716/ 122.339, C39-S41-C42 = 86.313/87.757, N25-C42-S41= 119.688/119.294, N25-C42-N43 = 122.861 / 122.033, S41-C42- N43 = 117.447/118.672, C40-N43-C42 = 113.818 / 112.104 respectively.

4.2 Vibrational assignments

The title compound is consist of 71 atoms and has 207 fundamental modes of vibrations. The observed and simulated FT-IR and FT-Raman spectra of 5-(4-Butoxybenzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one at B3LYP level using 6-31G and 6-31G(d,p) basis sets are shown in Figures 2 and 3. The elaborated vibrational assignments of the title compound along with the calculated IR and Raman frequencies and normal mode descriptions are given in Table 2.

Figure 2:Observed FT-IR and simulated spectra of 5-(4-Butoxybenzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

Figure 3:Observed FT-Raman and simulated spectra of 5-(4-Butoxybenzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

Table 2:Vibrational assignments of 5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4- (propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one one by B3LYP/6-31G

and B3LYP/6-31G (d,p) basis sets.

Modes

Observed

wavenumbers (cm^-1)

Calculated

wavenumbers(cm^-1)

Vibrational assignments FT-IR FT-Raman B3LYP/6-

31G

B3LYP/6- 31G(d,p)

1 3150 3156 3152 CH(98)

2 3125 3123 CH(98)

3 3110 3107 CH(98)

4 3099 3095 CH(98)

5 3094 3088 CH(98)

6 3075 3078 3074 CH(98)

7 3058 3055 CH(98)

8 3045 3043 CH(98)

9 3038 3034 CH(98)

10 3033 3029 CH(98)

11 3026 3021 CH(98)

12 3016 3011 CH(98)

13 3002 3010 3003 CH(98)

14 3001 2995 assCH3(96)

15 2986 2983 assCH3(97)

16 2976 2971 assCH3(97)

17 2970 2966 assCH₂(95)

18 2964 2959 assCH3(96)

19 2950 2947 assCH₃(97)

20 2936 2935 CH(98)

21 2922 2930 2926 assCH3(98)

22 2922 2919 assCH2(96)

23 2910 2915 2912 ssCH₂ (96)

24 2910 2906 assCH2 (97)

25 2896 2893 ssCH₂ (96)

26 2888 2884 ssCH3(97)

27 2882 2878 ssCH3 (96)

28 2872 2869 assCH2 (97)

29 2856 2860 2854 ssCH₃ (96)

30 2846 2843 CH(98)

31 2841 2835 ssCH2 (96)

32 2830 2822 ssCH₂ (96)

33 1679 1680 1683 1680 CO(72), CC(20)

34 1644 1641 CC(70), CH(18)

35 1625 1623 CC(71), CH(20)

36 1613 1604 CC(70), CH(22)

37 1591

1596 1590 CC(68), CN(12),

CH(10) 38

1579 1572 CN(65), CC(14),

CH(10)

39 1563 1559 CC(64), CH(14), CC(11)

40

1538 1533 CC(60), CCl(18),

CN(10) 41 1541

1533 1529 CN(65), CC(15),

CH(12)

42

1525 1517 CN(65), CC(16),

CH(12)

43 1506 1510 1512 1508 CH(64), CC(18)

44 1499 1493 CH(64), CC(20) 45 1485 1485 1490 1486 CH(65), CC(18)

46 1481 1475 _opb CH3 (72)

47 1477 1470 opb CH3(75)

48 1472 1466 _opb CH3(73)

49 1455 1451 ipb CH3(73)

50 1442 1436 ipb CH3(72)

51 1437 1430 ipb CH3(72)

52 1429 1422 _sci CH2(80)

53 1415 1423 1415 sci CH2(80)

54 1420 1408 CH(65), CC(21)

55 1414 1403 CH(66), CC(22)

56 1400 1408 1399 sci CH2(80) 57 1394 1402 1395 sci CH2(81)

58 1388 1383 sb CH₃(75)

59 1385 1379 sb CH3(75)

60 1376 1370 sb CH3(74)

61 1370 1362 CN(64)

62 1350 1356 1351 CN(65), CH(14)

63 1346 1342 CO(67)

64 1329 1335 1330 CH(67)

65 1327 1323 CH(68)

66 1310 1318 1312 CH(66), CC(14)

67 1308 1302 CH(66), CC(15)

68 1295 1301 1297 CO(66), CH(12)

69 1280 1285 1281 CH(66), CC(12)

70

1278 1275 CH(66), CC(12),

CN(10)

71

1266 1263 CH(64), CN(18),

CC(10) 72 1254 1250

1260 1254 CO(65), CH(17),

Ccl(10)

73

1248 1244 CH(66), CC(12),

CN(10) 74 1230

1236 1231 CC(63), CH(16),

CN(12)

75 1215 1221 1217 CC(65), CH(18)

76 1214 1207 rockCH2(70), CH(12)

77 1200 1210 1200 rockCH₂(70), CH(12)

78 1195 1191 CC(65), CH(14)

79 1186 1182 CC(66), CH(15)

80 1173 1179 1175 rockCH₂(70)

81 1165 1163 rockCH2(69)

82 1162 1158 CC(68)

83 1145 1143 CC(68)

84 1140 1136 CC(68)

85 1131 1127 CC(66)

86 1118 1125 1120 CC(66)

87 1118 1113 CH2(75)

88 1110 1105 CH2(75)

89 1102 1097 CH(60)

90 1093 1088 CH(60)

91 1080 1075 CC(65), CH(13)

92 1056 1051 CH₂(75)

93 1044 1040 CH2(74)

94 1032 1028 opr CH3(62), CC(10) 95 1021 1017 opr CH₃(63), CC(10)

96 1013 1009 CC(74), CO(16)

97 1002 1003 1000 opr CH₃(64)

98 992 989 CC(66), CH(15)

99 984 980 CO(66), CH(14)

100 965 963 CO(65), CH(12)

101 960 956 CH(58), _ring(26)

102 948 950 953 948 CH(58), ring(26)

103 935 933 CH(58), ring(25)

104 932 929 CH(58), _ring(21)

105

925 921 CC(72), CO(15),

CH(10)

106 924 916 CC(63), CH(18)

107 909 910 914 910 CC(64), CH(20)

108 889 885 CH(58), ring(18)

109 883 879 NN(65), CH(18)

110 867 865 CH(55), CC(18)

111 845 842 CC(18), wagg CH2(12)

112 840 834 CH(62), ring(18)

113 827 833 829 CH(58), CC(21)

114 823 820 CH(58), CC(20)

115 817 812 wagg CH2(58), CC(20) 116 800 805 802 _wagg CH2(58), CC(21)

117 800 795 CH(56), CC(18)

118 796 790 CH(55), CC(17)

119 792 786 CC(63), CH(18)

120 785 780 _wagg CH2(57)

121 779 773 CH(58), ring(18)

122 775 769 _wagg CH2(58), CC(20)

123 768 765 ipr CH3(68)

124 760 756 ipr CH3(68)

125 747 741 748 ipr CH3(68)

126 738 731 CS(74), CH(20)

127 720 726 720 CN(64), CC(16)

128 715 711 CCipr CH3(19)

129 706 700 CH(58), _ring(16)

130 697 694 CS(75), CH(20)

131 690 688 CC(60), ipr(17)

132 685 679 CO(58)

133 670 666 CC(68)

134 664 659 CC(68)

135 658 655 CC(68)

136 653 648 ring(56)

137 646 643 ring(56)

138 640 638 _ring(56)

139 635 631 CC(66)

140 630 626 CO(51), ring(17)

141 625 620 CO(50), _ring(17)

142 616 612 CC(58)

143 608 603 CC(59)

144 597 602 598 CCl(68), ring(25)

145 590 586 CC(58)

146 588 580 _ring(52)

147 575 573 CC(58)

148 565 561 CC(58)

149 551 553 550 ring(52)

150 545 541 ring(53)

151 539 535 CC(59)

152 531 523 _ring(52)

153 522 518 ring(50)

154 510 506 CC(58)

155 503 502 503 500 CC(58)

156 487 481 ring(54)

157 477 472 CC(59)

158 480 466 CC(59)

159 457 463 460 ring(55)

160 438 445 440 CCl(60), ring(15)

161 427 422 _ring(52)

162 411 417 410 ring(54)

163 407 401 ring(50)

164 392 389 _ring(52)

165 381 375 _ring(52)

166 371 366 CC(53)

167 360 354 CC(54)

168 345 349 345 CC(54)

169 337 332 CC(54)

170 330 325 CC(55)

171 319 314 CC(54)

172 303 299 CC(53)

173 296 293 CC(55)

174 291 286 CC(54)

175 280 275 CCl(55)

176 273 268 CC(50)

177 262 259 CC(54)

178 246 242 CC(50)

179 230 221 CH3(55)

180 218 212 CH3(54)

181 210 206 CH₃(54)

182 197 191 CC(55)

183 189 185 CC(55)

184 176 173 CC(55)

185 166 162 ring(58)

186 150 158 151 CC(55)

187 146 142 _ring(55)

188 135 141 136 CC(56)

189 135 128 ring(56)

190 120 126 120 CC(56)

191 112 102 _ring(53)

192 92 95 89 ring(54)

193 86 79 _ring(53)

194 80 74 _ring(54)

195 75 69 ring(53)

196 66 57 ring(51)

197 60 49 ring(58)

198 52 46 _ring(58)

199 48 43 ring(58)

200 35 41 35 _ring(54)

201 37 30 ring(53)

202 30 24 ring(54)

203 25 22 ring(54)

204 23 20 _ring(53)

205 17 16 ring(54)

206 12 10 ring(54)

207 7 6 _ring(54)

-stretching, νsym-sym stretching, νasym-asym stretching, δ-in-plane bending, γ-out-of-plane bending, -scissoring, -wagging, -rocking, τ-twisting.

4.2.1 C-H vibrations

The substituted aromatic structures show the presence of C-H stretching vibration in the region 3100- 3000 cm^-1 which is the characteristic region for the identification of C-H stretching vibrational modes [29-31].

Soleymani et al [32] observed the C-H vibrations at 3112, 3113 3071, 2978 cm^-1 theoretically and 3050, 3128 cm^-1 experimentally. Saruadevi et al [33] reported the C-H stretching modes are observed at 3096 cm^-1 in the IR spectrum and at 3097, 3063, 3038 cm^-1 in the Raman spectrum experimentally and at 3098, 3075, 3072, 3066, 3055, 3044 cm^-1 theoretically. Renjith et al [34] reported the C-H stretching vibrations at 3097, 3086, 3081, 3057, 3055 cm^-1 in the IR spectrum and 3077, 3064 cm^-1 in the Raman spectrum. C-H stretching are found at 3090, 3062, 2964, 2940 cm^-1 in FT-Raman and at 2934, 2771 cm^-1 in FT-IR by Kuruvilla et.al. [26]. Kuruvilla et.al. [27] observed the C-H vibrations experimentally at 3050, 2900 cm^-1 in FT-IR spectrum and 3042, 2976, 2891, 2850 cm^-1 in FT- Raman

spectrum. For our title molecule, the C-H stretching vibrations observed at 3150, 3075, 3002 cm^-1 for FT-Raman spectrum, 3156,3125, 3110, 3099, 3094, 3078, 3058, 3045, 3038, 3033, 3026, 3016, 3010, 2936, 2846 cm^-1 and 3152, 3123, 3107, 3095, 3088, 3074, 3055, 3043, 3034, 3029, 3021, 3011, 3003, 2935,2843 cm^-1 are calculated by B3LYP method with 6-31G and 6-31G(d,p) basis sets.

Jeyasheela et al [35] observed the C-H in-plane bending vibrations at 1179, 1059 cm^-1 in Raman spectrum and at 1167, 1086, 1046 cm^-1 in IR spectrum and computed bands appeared at 1318, 1170, 1094, 1059 cm^-1.Tamilelakkiya et al [36] observed the C-H stretching mode at 1543, 1440 cm^-1 in IR spectrumand 1540, 1477 cm^-1 in Raman spectrum and was calculated in the range of 1511-1445 cm^-1. Saraudevi et al [33] reported the C-H bands theoretically at 1277, 1248, 1170, 1140, 1108, 1102, 1042 cm^-1 and experimentally observed at 1250, 1114, 1044 cm^-1 in IR spectrum and 1279, 1246, 1168, 1038 cm^-1 in Raman spectrum. In our title molecule, the C-H in-plane bending vibrations occurs at 1506, 1485, 1329 and 1510, 1485, 1310, 1280 cm^-1observed in FT-IR and FT-Raman spectrum and calculated theoretically at 1512, 1499, 1490, 1420, 1414, 1335, 1327, 1308,1285, 1278, 1266, 1248 and 1508, 1493, 1486, 1475, 1408, 1403, 1330, 1323, 1302, 1281, 1275, 1263, 1244 cm^-1 for the same basis set.

Saraudevi et al [33] observed the CH out-of-plane bending vibrations theoretically at 930, 897, 895, 858, 818, 811, 731 cm^-1 and experimentally at 931, 896, 855, 816 for IR, 788, 729 cm^-1 for Raman spectrum. In the present work, the C-H out-of-plane bending vibrations occurs at 948, 827and 950 for FT-IR and FT-Raman spectrum and calculated theoretically at 960, 953, 935, 932, 889, 840,833, 823,796, 779, 706 and 956, 948, 933, 929, 885, 865, 834, 829, 820, 795, 790, 773,700 by B3LYP/6- 31G and B3LYP/6-31G(d,p) respectively.

4.2.2 CH3 vibrations

The CH₃ modes are occurs in the region 2900-3050 cm^-1 [37]. Asymmetric and symmetric stretching modes of a methyl group attached to the benzene ring are usually downshifted because of electronic effects and are expected near 2925 and 2865 cm^-1 for asymmetric and symmetric stretching vibrations[38].

The asymmetric stretching modes of the methyl group are calculated at 3047, 3039, 3022, 3003 cm^-1 by Paniker et al [39]. For the title compound, asymmetric stretching vibrations observed at 2922 cm^-1

for IR spectrum, theoretically observed at 3001, 2986, 2976, 2964, 2950, 2930 cm^-1 and 2995, 2983, 2971, 2959, 2947, 2926 cm^-1by B3LYP/6-31G and B3LYP/6-31G(d,p) respectively.

The symmetric modes are observed at 3038, 2946 cm^-1 in the IR spectrum and theoretically observed at 2948, 2943 cm^-1 by Paniker et al [39]. Saraudevi et al [33] reported the CH₃ stretching mode at 3027, 2970, 2908 cm^-1 and experimentally observed at 3002, 2972, 2970 cm^-1. Parveen et.al [24]

observed the CH₃ stretching modes are assigned at 3002, 2980, 2958, 2914 cm^-1 in the IR spectrum, 2960, 2938 cm^-1 in the Raman spectrum and theoretically occurs in the range 3032-2906 cm^-

1.Murugavel et al [40] theoretically the C-H stretching modes of methyl group at 3056, 3022, 2984, 2964, 2944, 2917 and 2911 cm^-1 is the experimental values 3024 and 2943 cm^-1. Alphonsa et al [41]

reported CH3 stretching mode for FT-IR spectrum at 2983, 2924 cm^-1 and for FT-Raman at 2983, 2944, 2923 cm^-1 and asymmetric and symmetric stretching vibrations observed at 3059, 3053 cm^-1 for FT-IR, Raman spectrum and theoretically at 3012 cm^-1.For the title compound, symmetric stretching vibrations observed at 2856 cm^-1 for IR spectrum, theoretically observed at 2888, 2882, 2860 cm^-1 and 2884, 2878, 2854 cm^-1by B3LYP/6-31G and B3LYP/6-31G(d,p) respectively.

In this work, the CH3 in-plane bending vibrations theoretically observed at opb = 1481, 1477, 1472 cm^-1, _ipb= 1455, 1442, 1437 cm^-1, _sb = 1388, 1385, 1376 cm^-1, _ipr = 768, 760, 741 cm^-1, CH₃ =230, 218, 210 cm^-1 by B3LYP/6-31G method and opb = 1475, 1470, 1466 cm^-1, ipb= 1436, 1430, 1422 cm^-

1, sb =1383, 1379, 1370 cm^-1, ipb= 765, 756, 748 cm^-1, CH3 = 221, 212, 206 cm^-1 by B3LYP/6- 31G(d,p) method. For the title compound, the out-of-plane bending vibration occurs at 1002 cm^-1for FT-IR spectrum. The theoretically predicted values by B3LYP/6-31G opr =1032, 1021, 1003 cm^-1 by B3LYP/6-31G and 1028, 1017, 1000 cm^-1 by B3LYP/6-31G (d,p) methods.

4.2.3 CH2 group

The stretching vibrations of the CH₂ group and deformation modes of CH₂ group (scissoring, wagging, twisting and rocking modes) appears in the regions 3000 ± 20, 2900 ± 25, 1450 ± 30, 1330 ± 35, 1245 ± 45, 780 ± 55 cm^-1 respectively [37, 42,30].

Parveen et.al [24] observed the CH2 stretching modes at 2923 cm^-1 in the Raman spectrum and at 2926, 2966 cm^-1 theoretically. The deformation modes of CH2 are assigned at 1439, 1295, 1220, 1148 cm^-1 in the IR spectrum, 1146 cm^-1 in the Raman spectrum. Murugavel et al [40] the CH2 stretching

vibrations are calculated at 2991 cm^-1 (asymmetric) and 2944 cm^-1 (symmetric). Asymmetric bending of is found at 1275 cm^-1 which is consistent with the DFT value of 1274 cm^-1. Minithra et al [43]

observed CH₂ asymmetric and symmetric stretching at 2982, 2932 cm^-1 and 2905, 2893 cm^-1 and assigned at 2978, 2930, 2885 cm^-1 in the IR spectrum and at 2971, 2935, 2898 cm^-1 in the Raman spectrum. For the title compound, the asymmetric CH₂ stretching calculated at 2970, 2922, 2910, 2872 by B3LYP/6-31G method and 2933, 2919, 2906, 2869 by B3LYP/6-31G(d,p) method. The symmetric CH₂ stretching observed at 2910 in FT-Raman spectrum and the computed values are 2915, 2896, 2841, 2830 by B3LYP/6-31G method and 2912, 2893, 2835, 2822 by B3LYP/6-31G(d,p) method. For the title compound, CH2 scissoring band observed at 1394, rocking at 1173 in the IR spectrum and scissoring at 1415, 1400, rocking at 1200, wagging at 800 in the Raman spectrum. For the title compound, the CH2 stretching modes are observed at sci = 1429, 1423, 1408, 1402 cm^-1, rock = 1214, 1210, 1179, 1165 cm^-1, = 1118, 1110, 1056, 1044 cm^-1, wagg. = 817, 805, 785, 775 cm^-1 by B3LYP/6- 31G, sci = 1422, 1415, 1399, 1395 cm^-1, rock = 1207, 1200, 1175, 1163 cm^-1, = 1113, 1105, 1051, 1040 cm^-1, _wagg. = 812, 802, 780, 769 cm^-1 by B3LYP/6-31G (d,p) methods respectively.

4.2.4 C-O vibrations

The C-O stretching vibrations [44, 37] are expected in the region 1715-1600 cm^-1. The in-plane deformation of C-O found in the region 625 ± 70 cm^-1and out-of-plane bending is in the range 540 ± 80 cm^-1[37].

Lucose et al [45] observedC-O stretching vibrations at 1632 cm^-1 in IR spectrum and theoretically at 1636 cm^-1 (DFT). In-plane bending at 569 cm^-1 in IR and 555 cm^-1 in DFT is assigned as this mode and out-of-plane bending at 673, 676 cm^-1 in the IR spectrum.

The C=O stretching vibration appears both in the FT-IR and FT-Raman spectra due to intra molecular charge transfer from donor atom to acceptor atom through  and  bonds conjugated path, which can induce large variation in dipole and molecular polarizability of the molecule and hence high activity in both spectra [37]. Renjith etal [34] observed the C-O modes at 1625 at IR and 1614, 1626 cm^-1 at Ramanspectrum. The C-O stretching modes are reported at 1786, 1603, 1027 cm^-1 and at 1726, 1629 cm^-1 in the FT-IR, Raman spectrum and 1184, 1083, 1010, 974, 696 cm^-1 assigned theoretically by Sakthivel et al [46]. Benzon et al [47] reported the C-O stretching mode at 1212 cm^-1

(IR), 1228 cm^-1 (Raman) and at 1229 cm^-1 theoretically. For the title molecule, C-O stretching vibrations observed at 1679, 1254 cm^-1 in IR spectrum and 1680, 1295 cm^-1 in Raman spectrum. The reported values for C-O = 1683, 1301, 1260 cm^-1, CO = 1346, 984, 965 cm^-1, CO= 685, 630, 620 cm^-1 by B3LYP/6-31G method, C-O = 1680, 1297, 1254 cm^-1, CO = 1342, 980, 963 cm^-1, CO=

679, 626, 620 cm^-1 by B3LYP/6-31G (d,p) methods respectively.

4.2.5 C-C vibrations

C-C stretching vibrations occur in the range of 1625-1465 cm^-1 [48]. The in-plane and out-of plane bending modes of C-C were reported at 725± 95 and 595 ± 120 cm^-1 [49].

The C-C band observed by Kuruvilla et al [26] at 1579, 1531, 1439, 1380, 1123 for FT-Raman and for FT-IR bands at 1428, 1235, 1002 cm^-1.Soleymani et.al [32] observed C-C band at 1625, 1590, 1575, 1540, 1470, 1465, 1430, 1380, 1280 cm^-1. Tamil elakkiya et al [36] observed the C-C band at 1313, 1039 cm^-1 and calculated at 1600, 1625, 1319, 1054 cm^-1. In the present work, the C-C vibrations observed at 1591, 1230, 1118, 909 in IR spectrum, 1215, 910 in Raman spectrum. The reported values at 1644, 1625, 1613, 1596, 1538, 1236, 1221, 1195, 1186, 1162, 1145, 1140, 1131, 1125, 1080, 1013, 992, 925,924, 914, 845 cm^-1 by B3LYP/6-31G method, 1641, 1623, 1604, 1590, 1533, 1231, 1217, 1191, 1182, 1158, 1143, 1136, 1127, 1120, 1075, 1009, 989, 921, 916, 910, 842 cm^-1 by B3LYP/6- 31G (d,p) methods respectively. The C-C in-plane bending observed at 503 and 502, 345 in IR and Raman spectrum and the reported values are 792, 715, 690, 616, 608, 590, 575, 565, 539, 510, 503, 477, 480, 360, 349 cm^-1 by B3LYP/6-31G method,786, 711, 688, 612, 603, 586, 573, 561, 535, 506, 500, 472, 466, 354, 345 cm^-1 by B3LYP/6-31G (d,p) methods. The C-C out-of-plane bending vibration assigned at 150, 135, 120 in Raman spectrum and the calculated values are at 330, 319, 303, 296, 291, 273, 262, 246, 197, 189, 176, 158, 141, 126 cm^-1 by B3LYP/6-31G method, 325, 314, 299, 293, 286, 275, 268, 242, 191, 185, 173, 151,136, 120 cm^-1 by B3LYP/6-31G (d,p) methods.

4.2.6 C-N vibrations

The CN stretching modes are expected in the region 1400-1200 cm^-1

Sandhyarani et al [50] reported the C-N stretching mode at 1319 cm^-1. Benzon et al [47] reported at 1247, 129, 938 cm^-1 theoretically, 1268, 11135, 926 cm^-1 in the Raman spectrum and 924 cm^-1 in the IR spectrum. The C-N stretching modes were reported at 1268, 1220, 1151cm^-1 theoretically by Malek

et.al [51]. Al-Alshaikh et.al.[52] observed C-N stretching mode at 1329, 1092, 997 cm^-1 in the IR spectrum, 1328 cm^-1 in the Raman spectrum and theoretically at 1479, 1472, 1331, 1097, 998 cm^-1 . Bhagyasree et al [53] reported C-N stretching modes at 1247 and 1236 cm^-1 and Mary et al [14]

reported the C-N stretching modes at 1233, 1209 cm^-1 by theoretically and 1238 cm^-1 by Raman spectrum. shanaparveen et al [28] assigned the C-N stretching mode at 1579 cm^-1 and IR spectrum at 1553 cm^-1 . In the present work, C-N stretching vibrations observed at 1541 and 1350, 720 in IR and Raman spectrum. The predicted values at 1579, 1533, 1525, 1370, 1356, 726 and 1572, 1529, 1517, 1362, 1351, 720 cm^-1 by B3LYP/6-31G and 6-31G(d,p) methods.

4.2.7 N-N vibrations

N-N stretching mode occurs at 1417-1372 cm^-1[54].The υN-N has been reported at 1151 cm^-1 by Crane et al [55], 1121 cm^-1by Bezerra et al [56] and 1130 cm^-1 El-behery and El-Twigry [57] and 1083 cm^-1 theoretically by Sundaragensan et al [58]. Binil et al [59] reported the N-N stretching mode at 1138 cm^-1 in IR, 1139 cm^-1 in Raman and 1136 cm^-1 theoretically. For Murugavel et al [40], N-N stretching vibrations allocated at 1083, 1119 cm^-1 by DFT technique and experimentslly at 1082 cm^-1 in FTIR spectrum. For the title molecule, N-N stretching mode is calculated at 883 and 879 cm^-1 by B3LYP/6-31G and 6-31G(d,p) methods respectively.

4.2.8 C-S vibrations

This vibration cannot be identified easily as it results in weak infrared bands, which is susceptible to coupling effects and is also of variable intensity. In general, the C-S stretching vibration was reported in 750-600 cm^-1 [60].

Benzon et al [27] reported value this mode at 1515 cm^-1 in the IR spectrum, 1520 cm^-1 in the Raman spectrum, 1517 cm^-1 theoretically. The C-S stretching mode observed for Sarau et al [23] are assigned at 759, 660 cm^-1 theoretically and experimentally observed at 756, 665 cm^-1 and 756, 658 cm^-1in the IR and Raman spectrum. Kuruvilla etal [33] observed these vibrations at 822,608 cm^-1 and theoretically at 714 cm^-1. The C-S stretching modes were observed by Coates [53] in the range 710- 687cm^-1 while Kwiastkowski et al [61] reported the vibration at 839 and 608 cm^-1. The C-S stretching vibrations are reported at 783, 632 cm^-1 and 633 cm^-1 IR, Raman spectrum and 785, 635 cm^-1 theoretically found by El-Azab et al [62]. The C-S stretching vibrations are reported at 770 cm^-1 in the

IR spectrum, and at 770, 636 cm^-1 theoretically assigned by ShaheenFatma et al [48]. In the present work, C-S vibrations calculated at 738, 697 and 731, 694 cm^-1 by B3LYP/6-31G and 6-31G(d,p) methods respectively.

4.2.9 C-Cl vibrations

The vibrations belong to C-Cl absorption is obtained in the region between 850-550 cm^-1 [63].

Kuruvilla1 et al [26] observed theoretically at C-Cl vibration at 694 and 415 cm^-1 and experimentally at 710-505 cm^-1. Jayasheela et al [35] reported this band at 725 and 720 cm^-1 4- chlorophenyl ({[(1E)-3-(1Himidazol-1-yl)-1-phenylpropylidene]amino}oxy) methanone for theoretically and experimentally. For the title compound, the vibrations occurs at for C-Cl= 597,  C- Cl=438 in FT-IR spectrum and theoretically at C-Cl=602 and 598 cm^-1,  C-Cl=473 and 440 cm^-1,  C-Cl=280 and 275 cm^-1 by B3LYP/6-31G and 6-31G(d,p) methods respectively.

4.2.10 Ring vibration

The thiazole ring in-plane bending vibrations are observed at 551, 457, 411 by FT-IR spectrum and theoretically at 588, 553, 545,531, 522, 487, 463, 427, 417, 407, 392,381, 166, 146, 112, 52, 48 cm^-1 by B3LYP/6-31G method and 580, 550, 541, 523, 518, 481, 460, 422, 410, 401, 389, 375, 162, 142, 102, 49, 46, 43 cm^-1 by B3LYP/6-31G(d,p) method. The ring out-of-plane bending observed at 35 in FT-Raman spectrum, theoretically at 135, 95, 86, 80, 75, 66, 41, 37,30, 25, 23, 17, 12, 7 cm^-1 by B3LYP/6-31G method and 128, 89, 79, 74, 69, 57, 35, 30, 24, 22, 20, 16, 10, 6 cm^-1 by B3LYP/6- 31G(d,p) method.

4.3 Molecular electrostatic potential (MEP) surface analysis

Molecular electrostatic potential at a point in space around a molecule gives information about the net electrostatic effect produced at that point by total charge distribution (electron + proton) of the molecule and correlates with dipole moments, electro-negativity, partial charges and chemical reactivity of the molecules. It provides a visual method to understand the relative polarity of the molecule [64, 65]. An electron density iso-surface mapped with electrostatic potential surface depicts the size, shape, charge density and site of chemical reactivity of the molecules. Figure 4 illustrates the charge distributions of the molecule two dimensionally. As it can be seen from the figure, the different

values of the electrostatic potential at the surface are represented by different colours; red represents region of most electronegative electrostatic potential, blue represents region of the most positive electrostatic potential and green represents region of zero potential. Potential increases in the order red

< orange < yellow < green < blue. Blue indicates the strongest attraction and red indicates the strongest repulsion. Region of negative potential are usually associated with the lone pair of electronegative atoms. As can be seen from the MEP map of the title molecule, more reactive sited are close to C=O (C40-O44) groups, the region having the most negative potential over oxygen atom O44 and O58, then all the hydrogen atoms have positive potential.The negative potential which is represented by red colour corresponds to an interaction of a proton by aggregate the electron density of the molecule represented by red yellow shade and blue region is positive which corresponds to the repulsion of the proton represented by blue shades.

Figure 4: Molecular electrostatic potential surfaces of 5-(4-Butoxybenzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

The strong negative region spread over the phenyl rings, nitrogen atom and oxygen atom of the hydroxyl group and these are possible sites of electrophilic sites. The positive electrostatic potential regions are fully covered all the hydrogen atoms and it represents the possible site of the nucleophilic sites in the MEP plot.

4.4Frontier molecular orbital (FMO) study

DFT method with 6/31G(d,p) basis set is applied to compute the energy of HOMO and LUMO levels and the energies are shown in Table 3. The Frontier molecular orbitals (FMO) play a significant function in the electric and quantum chemistry [66]. The pictorial demonstration of these different FMOs is shown in Figure 5. The HOMO is the donor and LUMO is acceptor orbital and the energy difference between HOMO and LUMO have been used to investigate the global reactivity descriptors.

The electrophilic index (), hardness () and chemical potential (µ) are known reactivity parameters.

These parameters are considered as highly successful descriptors for biological activity.Moreover, electronegativity (),electron affinity (A), ionization potential (I) are also determined using the energies of frontier molecular orbitals and these reactivity parameters used in understanding the site selectivity and the reactivity. The compounds that possess positive electron affinity are known as electron acceptors and might participate in charge transfer reactions. The electron donation strength for any donor compound can be measured using ionisation potential is the energy which need to take off an electron from the HOMO. Electronegativity is known as one for the most important chemical properties which defined as power of species to attract electrons towards itself. The large E_HOMO- E_LUMO differences define a hard species, which means compound is more stable and less reactive.

While, small E_HOMO- E_LUMO gap defines a soft species is less stable and more reactive. The calculated energy of HOMO is -5.3304 eV and LUMO is -1.9783 eV and the energy gap for the title compound is 3.3521 eV and is a hard one. Ionization potential (I) =5.3304 eV, Electron affinity (A) = 1.9783 eV, Global hardness () = 1.6761 eV, Softness () = 0.5966 eV, Chemical potential () = -3.6544 eV, Electrophilicity index () = 3.9838 eV. The values for chemical potential and electrophilicity index are small that indicates the reactive nature of the title compound which confirms the bioactivity of the title molecule by the positive value of chemical softness.

ELUMO= -5.3304 eV ELUMO1 = - 5.9862 eV ELUMO2= -6.4777eV

E=3.3557eV E = 4.5911eV E = 5.8023eV

EHOMO = -1.9783 eV EHOMO1 = -1.3951 eV EHOMO2 = -0.6754 eV

Figure 5:Patterns of the principle highest occupied and lowest unoccupied molecular orbital 5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4-(propan-2-yl)-4,5-dihydro-1H-pyrazol-1-

yl]-1,3-thiazol-4(5H)-one

Table 3 HOMO-LUMO energies for 5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4- (propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one by B3LYP/6-31G (d,p)

basis set Molecu

lar properti

es Energ y (eV)

Energ y gap

(eV)

Ionisati on potentia

l(I)

Electron affinity

(A)

Global hardness

n ()

Global softness

()

Chemica l potensia

l ( )

Global Electroplici

ty()

EHOMO

- 5.3304

3.3521 5.3304 1.9783 1.6761 0.5966 -3.6544 3.9838 ELUMO

- 1.9783

EHOMO-1

- 5.9862

4.5911 5.9862 1.3951 2.2955 0.4356 -3.6907 2.9669 ELUMO-1

- 1.3951

EHOMO-2

- 6.4777

5.8023 6.4777 0.6754 2.9012 0.3447 -3.5765 2.2045 ELUMO-2

- 0.6754

4.5 Reduced density gradient

RDG is a pictorial visualization of various kinds of non-covalent interactions directly in the real space using Multiwfn and plotted by visual molecular dynamics (VMD) program [20,21].

Noncovalent interactions are very weak when compared with covalent bonds and hence play a vital role in nature. To understand the nature of inter molecular interaction of the title compound, RDG analyses were carried out and the resultant graphs are shown in Figure 6.

According to this graph, the green regions represent weak attractive interactions (λ2≈0) such as Van der Waals interaction; strong attractions like H-bond, C-Cl bonds are represented by blue colour. The red colour represents steric repulsion appears in the inside of phenyl rings, pyrazole, and 4- Butoxybenzylidene while van der waals interactions took place near 4(propan-2-yl) and over hydrogen atoms. The negative values of λ(2)ρ indicates strong attractive interactions, while the positive values mean the repulsive interactions.

Figure 6:Plots of the RDG versus λ(2)ρ of 5-(4-Propan-2-yl)benzylidene)-2-[3-(4- chlorophenyl)-5[4-(propan-2-yl)phenyl-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

4.6 Molecular docking

Molecular docking is a computer-assisted drug design (CADD) method used to predict the favourable orientation of a ligand (drug) to a target (receptor) when bound to each other to form a

stable complex. By understanding the favoured orientation can be used to find out the strength of binding affinity between ligand and target site, e.g. by docking score [67]. Moreover, docking study can be used to find out type of interactions between ligand and receptor like hydrogen bonding and hydrophobic interactions. Hence, molecular docking can be considered as first-line technique for a pharmaceutical lead discovery [68].Molecular docking studies were carried out to understand the binding profile of thiazole derivatives and to support the in vitro anticancerous activity. Automated docking was used to determine the orientation of inhibitors bound in the active site of Tubulin(PDB ID=4YJ2), which the protein has anti-cacerous activity. Protein 4YZJ has antiviral and 1OQE, 4YJE has anti tumer activity. A Lamarckian genetic algorithm method, implemented in the program AutoDockVina software was employed. The ligand used for docking was the optimized structure at B3LYP/6-31G (d, P). The files were prepared in a pdb format. The protein structure file (PDB ID:

4YZJ) taken from RCSB Protein Data Bank (PDB) was prepared for docking by removal of water molecules, adding polar hydrogens and Kollman charges to the structure file. In silico prediction of amino acids involved in the active site of protein responsible for binding with the ligands are obtained from the co-crystallized endogenous ligand from the PDB file. The ligand was docked in the functional sites of the selected protein and minimum docking energy value was examined. Docked conformation which had the lowest binding energy was chosen to scrutinize the molecule mode of binding. The molecular docking binding energies and inhibition constants were also obtained and listed in Table 4 The title compound taken as the ligand interactions with proteins are shown in Figure 7.

Figure 7:Ligand - 5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4-(propan-2-yl)-4,5- dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one, Proteins – 1JH5,1OQE, 4YJ2 and 4JZJ

Table 4:Binding affinity for docking in5-(4-Butoxybenzylidene)-2-[3-(4-chlorophenyl)-5[4- (propan-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]-1,3-thiazol-4(5H)-one

Drug Protei n

Type of activity

Bindi ng affinit y(kcal /mol)

Etimated inhibition

constant Ki(µM)

Bonded

residues Nature of bond

Bond distanc e (Å)

RMS D

In 5-(4- Butoxybenzylidene)-2- [3-(4-chlorophenyl)- 5[4-(propan-2-yl)-4,5- dihydro- -1H-pyrazol-1-yl]- 1,3-thiazol-4(5H)-one

-4.7 360.43 ASN A-42

Conventional

hydrogen bond 3.31

87.20 6

-4.33 667.85 PRO A-15 Alkyl 4.1

71.63 5

1OQ E

Antitumer

-4.19 845.86 ILE A-15 Alkyl 4.17

78.41 4

-3.97 1.23(mM) GLU A-41

Conventional

hydrogen bond 4.32

81.10 6

-3.8 1.64 (mM) ASN A-42

Conventional

hydrogen bond 4.55

82.08 3

4YJ2 Anticance r

-4.7 358.4 LEU A-397 Alkyl 3.72

80.98 3

-4.6 426.72

PRO A-

175 Alkyl 3.82

121.0 29

-4.21 817.23

PRO A-

173 -alkyl 4.24

111.2 28

-4.57 447.01

PRO A-

184 -alkyl 4.39

87.28 3

-4.53 482.07 GLN A-176

Carbon hydrogen

bond 4.55

94.62 7

4YJE Antitumer

-5.42 106.41

MET A- 438

Conventional

hydrogen bond 3.64

49.94 4

-5.42 106.79

MET A- 438

Conventional

hydrogen bond 3.8

47.99 5

-5.32 126.67 TYR A-486

carbon hydrogen

bond 3.89

48.81 2

-5.2 155.59

MET A- 438

Conventional

hydrogen bond 4.02

33.73 2

-4.95 234.91

MET A- 438

Conventional

hydrogen bond 4.17

25.06 4

4JZJ Antiviral

-5.17 163.56

PHE A:

107 van der waals 3.85

36.10 6

-4.95 236.07 TRP A: 47 van der waals 4.65

36.42 7 -4.49 514.73

PHE A: van der waals 4.94

30.37

107 4

-4.23 790.86

TRP A:

106 - Stacked 5.05

38.12 3

-4.2 838.87 LEU A: 45 - Stacked 5.08

32.47 1

4.6.1 Anti-tumer activity

Interaction of antitumor protein 1OQE shows the existence of many conventional bonds such as three conventional hydrogen bonds and two alkyl bond interaction with amino acid (ASN A:

42, GLU A: 41, ASN A: 42, PRO A: 15, ILE A: 15) with different binding energies (-4.7, -3.97, - 3.8, -4.33, -4.19)kcal/mol, inhibition constants (360.43, 1.23 (mM), 1.54 (mM), 667.85, 845.86)ki(µM) RMSD values are (87.206, 81.106, 82.083, 71.635, 78.414)Å. Interaction of antitumor protein 4YJE shows the existence of many conventional bonds such as five conventional hydrogen bond interaction with amino acid (MET A: 438, MET A: 438, TYR A: 486, MET A: 438, MET A: 438) with different binding energies (-5.42, -5.32, -5.2, -4.95, -4.45)kcal/mol, inhibition constants (106.41, 126.67, 155.59, 234.91, 544.29)ki(µM) RMSD values are (49.944, 48.812, 33.732, 25.064, 25.158)Å.

4.6.2 Anticancer activity

Interaction of anticancerous protein 4YJ2 shows the existence of many conventional bonds such as one Alkyl bonds, two -alkyl bond and one carbon hydrogen bond interaction with amino acid (LEU A: 397, PRO A: 175, PRO A: 173, PRO A: 184, GLN A: 176) with different binding energies (-4.7, -4.6, -4.21, -4.57, -4.53)kcal/mol, inhibition constants (358.4, 426.72, 817.23, 447.01, 482.07)ki(µM) RMSD values are (80.983, 121.029, 111.228, 87.283, 94.627)Å.

4.6.3 Antiviral activity

Interaction of antiviral protein 4JZJ shows the existence of many conventional bonds such as three van der waals bonds and two - stackedbond interaction with amino acid (PHE A: 107, TRP A: 47, PHE A: 107, TRP A: 105, LEU A: 45) with different binding energies (-5.17, -4.95, -4.49, -4.23, -

4.2)kcal/mol, inhibition constants (163.56, 236.07, 514.73, 790.86, 838.87)ki(µM) RMSD values are (36.106, 36.427, 30.374, 38.123, 32.471)Å.

5. Conclusion

Structures of the title compounds were investigated using high-level quantum chemistry calculation. The optimized geometrical parameters and vibrational frequency assignment of the fundamental modes of title compounds have been obtained from DFT/B3LYP/6-31G and DFT/B3LYP/6-31G(d, p) level of calculation. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule and the calculated HOMO and LUMO energies show the chemical activity of the molecule. The energy gap of the title molecule is E= 3.3557eV.

From the molecular electrostatic potential plot, it is evident that the negative charge covers the carbonyl group and the positive region is over the remaining groups and the more electronegativity in the carbonyl group makes it the most reactive part of the molecule. Weak interaction profile shows that the presence of Van der Waals interactions and steric effect are present in the molecule.

Molecular docking analysis reveals that the title molecule can act as a good inhibitor against the proteins 1JH5, 1OQE, 4YJ2 and 4JZJ.

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