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Density Functional Theory and Molecular Modeling of the Compound 2-[2-(4-Methylphenylamino)-4-phenylthiazol-5-yl]benzofuran

Written By

Yardily Amose, Fathima Shahana and Abbs Fen Reji

Submitted: July 7th, 2021 Reviewed: July 20th, 2021 Published: May 11th, 2022

DOI: 10.5772/intechopen.99577

From the Edited Volume

Furan Derivatives

Edited by Anish Khan, Mohammed Muzibur Rahman, M. Ramesh, Salman Ahmad Khan and Abdullah Mohammed Ahmed Asiri

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The compound 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran was prepared from 1-(4-methylphenyl)-3-(N-phenylbenzimidoyl)thiourea and 2-(2-bromoacetyl) benzofuran in the presence of triethylamine and characterized by FTIR, NMR, and mass spectra. Density functional theory (DFT) computations were adopted for the geometry optimization of this compound, to evaluate their Mulliken atomic charge distribution, HOMO-LUMO energy gap, and vibrational analysis. The titled compound induced G1 cell cycle arrest, which is regulated by CDK2 in cancer cells. Therefore, we used molecular modeling to study in-silico for the possible inhibitory effect as a mechanism of this compound as anticancer agents (PDB code: 2KW6, 6DL7, 6VJO, 6WMW, and 7LAE). The molecular docking study revealed that the compound was the most effective in inhibiting CDk2 cancer cells.


  • benzofuran
  • DFT
  • vibrational analysis
  • molecular docking
  • anticancer agent

1. Introduction

Natural products have the potential to provide medicine with a source of novel structures. Nature is capable of producing complex molecules with numerous chiral centers that are planned to interact with biological systems. The marine environment is a rich source of biologically active natural products, many of which have not been originated in terrestrial sources [1, 2]. Marine natural products have fascinated the attention of biologists and chemists all over the world. As a consequence of the potential for new drug discovery, marine natural products have attracted scientists from different disciplines such as organic chemistry, bioorganic chemistry, pharmacology, biology, and ecology. From the studies 2,4-diaminothiazoloylbenzofuran and 2-aminothiazoloylbenzofuran analogs of dendrodoine have good docking characteristics, antimicrobial activities, we further planned to synthesize and evaluate the biological properties of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran (Figure 1) as further analogs of dendrodoine. These observations show that synthesis of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran with a view to studying their biological activity, they exhibit a variety of bioactivity such as antibiotics, anticancer, anti-inflammatory, antitumor, antiviral, antibacterial, and antifungal activities. Hence, in this work the computational DFT calculation, particularly those based on hybrid functional method evolved to a powerful quantum chemical tool for the determination of the electronic structure of the molecule. Besides, molecular docking studies were carried out and the mechanisms of action of this compound on CDK2 cancer cell lines were studied.

Figure 1.

Structure of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.


2. Experimental

2.1 Material and methods

All chemicals were purchased from Sigma-Aldrich and were used without purification. It includes benzonitrile, aniline, anhydrous aluminum chloride, sodium hydroxide, triethylamine, p-tolyl isothiocyanate, and 2-bromoacetylbenzofuran. The organic solvents (spectroscopic grade) were used as received. The spectra had been documented on Bruker Avance400 FTNMR spectrometer (400 MHz for 1H and 13C NMR spectra), mass spectrometer on Agilent 6520(QTOF) positive mode ESI-MS, and Nicolet 400 FTIR spectrometer. The melting point was examined using digital melting point apparatus and uncorrected.

The density functional theory (DFT) was performed with Guassian-03 B3LYP/6-31G(d,p) basis set. Docking studies were carried out using the Hex 8.0 dock software with a grid dimension of 0.6. Discovery studio 3.5 visualizer was used to analyze the docking results.

2.2 General procedure for the synthesis of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran

To a solution of 1-aryl-3-(N-phenylbenzimidoyl)thiourea (1 mmol) in 5 ml N,N-dimethylformamide (1 mmol) was added. The mixture was stirred well and kept at room temperature for 5 hours. Triethylamine (2 mmol) was then added and the mixture was heated carefully at 55°C for 1 hour with occasional stirring afforded yellow precipitate. It was subsequently purified by crystallization from ethanol–water [3, 4].

2.3 Synthesis of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran

The orange yellow precipitate obtained was recrystallized using 2:1 ethanol–water solution. Yield 65.5%, m.p. 244–247, Analysis found: C, 73.63: H, 4.39: N, 7.02%: Calc. for C25H18N2O2S (410.49): C, 73.15: H, 4.42: N, 6.82%: IR (KBr)cm-1: 3584, 3577, 3561, 3493, 3425, 3407, 3286, 3224, 3130, 3062, 3037, 3010, 2924, 2372, 1566, 1552, 1533, 1514, 1447, 1427, 1251, 1118, 1045, 1020, 746, 661. 1H NMR: (400 MHz, DMSO-d6) 2.37(s, 3H, CH3), 6.87 (d, 8.4 Hz, 2H, 2ArH), 7.18–7.39 (m, 7H H-5, H-6, 5ArH), 7.49–7.65(m, 4H, H-3, H-4, 2ArH), 7.87(d, 7.6 Hz, H-7), and 10.98(s, 1H, NH).


3. Results and discussion

3.1 Computational chemistry

3.1.1 Molecular geometry

The quantum chemical calculation is performed by DFT method with Becke’s three parameters hybrid functional for the exchange part and the Lee-Yang-Parr (B3LYP) correlation function with 6-31G(d,p) basis set using Gaussian 09 program [5]. The optimized structure of the titled compound is depicted in (Figure 2). The optimized structure acquired structural parameters such as bond distance, angles, and dihedral angles are calculated [6, 7, 8].

Figure 2.

Optimized structure of the compound 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl] benzofuran.

3.1.2 Mulliken atomic charge distribution

The calculations of atomic charges explain the changes in dipole moment, molecular electronic structure as well as molecular polarizability. The partial atomic charges are a useful part of quantum mechanical calculation The calculated atomic charge values are taken from the B3LYP/6-31G(d,p) method. This calculation depicts the charges of all atoms in the titled compound. The Mulliken atomic charge of all hydrogen atoms is positive, all nitrogen and oxygen possess a negative charge and all sulfur carry a positive charge (Figure 3).

Figure 3.

Mulliken charge distribution of the compound 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.

3.1.3 Analysis of frontier molecular orbitals

HOMO-LUMO energy gap explains the chemical reactivity of the molecule. If the energy gap is less, it is more reactive and if it is high, the compound is thermally stable [9]. The thermal stability of the compound is related to the hardness of the molecule. It is found that the charge distribution of the HOMO level of the titled compound is mostly localized on the thiazole and phenyl rings and the charge distribution of the LUMO level is delocalized throughout the molecule. The energy gap is found to be less than −0.1256 a.u (Figure 4).

Figure 4.

HOMO-LUMO energy diagram of the compound 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.

3.1.4 Vibrational analysis

The spectroscopic signature of the titled compound was performed by FT-IR spectra. The theoretical vibrational frequency of the compound was calculated using the B3LYP/6-31G method. The titled compound consists of 50 atom that produces 144 normal modes of vibrations.

The bands at 3497 cm−1 are due to the N-H stretching vibration of the secondary amine. The bands at 3125 cm−1, 3096 cm−1 are due to the C-H stretching vibration. The bands at 1637 cm−1 are due to the C=O stretching vibration. The C-N stretching modes were observed in 1554 cm−1 (Figure 5) [9, 10].

Figure 5.

Calculated IR spectrum of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.

3.1.5 Molecular docking

HEX is an interactive molecular graphics program for calculating and displaying feasible docking modes among the protein and the DNA molecules. To find out the antibacterial activity and binding energy of the titled compound, the molecule should bring to minimized energy level using 6-31 g(d,p) software system, and also the compound should obey the Lipinski rule of five shown in (Table 1). The molecule is docked into the active site of the CDK2 in cancer cells (PDB code: 2KW6, 6DL7, 6VJO, 6WMW, and 7LAE). Docking results were analyzed based on binding energy and hydrogen bonding [11, 12]. The correct interaction conformation between ligand and protein receptor is explained by the π–σ, π–cation, π–π interaction and Van der Wall interaction (Figure 6 and Table 2). Based on the results, it is clear that the compound binds favorably with the protein receptor.

CompoundMolecular weight (<500 Da)HB donar (<5)HB acceptor (<10)Log P< 5Molecular refractivity (40–130)

Table 1.

LIPINSKI RULE OF 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.

Figure 6.

(i)–(v) 3D docking structure of the titled compound with the protein receptors 2KW6, 6DL7, 6VJO, 6WMW, and 7LAE.

Cancer cell (PDB code)Binding energy (kJ/mol)Active sites of interactions
π–σ interactionsπ–cation interactionsπ–π interactionElectrostaticVan der Waals
2KW6−294.25ARG A:103ARG A:103, ARG A:99, GLY A:100HIS B:254, HIS A:97, GLY B:252
6DL7−356.35ILE B:59TYR B:76ASP B:74, SER B:77, TYR B:76ILE B:59
6VJO−287.89TYR B:178, VAL B:170, ILE A:454ASP B: 177, ASP A:455
6WMW−270.58ARG B:313, LYS B:314, LYS B:202HIS B:206,ARG B:313, LYS B:314, LYS B:202TYR B:175, LEU B:186, GLY L:33, ALA B: 187
7LAE329.14CYS D1CYS D1, GLU A:38, ASP A:39VAL A:51, THR A:48, TYR A:45

Table 2.

Docking score and interaction of the compounds with cancer cell line.


4. Conclusion

Benzofuran derivatives have a broad spectrum of biological activities such as antimicrobial, antifungal, anti-inflammatory, anticancer, and analgesic and it is understood that many natural products with benzofuran moiety exhibit interesting biological and pharmacological activities. We have established the modest synthetic techniques of benzofuran analogs of dendrodoine viz. 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran and characterized by IR, 1H NMR, 13CNMR, and mass spectra. Theoretical information on the optimized geometry, atomic charges, and frontier molecular orbitals in the ground state were obtained using density functional theory (DFT) using standard B3LYP/6-31G basis sets with Gaussian ’09 software. Mulliken population analysis was performed on the atomic charges distribution and the HOMO-LUMO energies were calculated and found that the compound is more reactive which is clearly shown in the docking study. The compound was docked with five CDK2 cancer cells. Among them, the cancer cell with PDB code 6DL7 binds more favorable with the titled compound and shows relative binding energy of −356.35 kcal/mol.


Conflict of interest

All authors declare no conflict of interest.


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Written By

Yardily Amose, Fathima Shahana and Abbs Fen Reji

Submitted: July 7th, 2021 Reviewed: July 20th, 2021 Published: May 11th, 2022