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

*Yardily Amose, Fathima Shahana and Abbs Fen Reji*

## **Abstract**

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.

**Keywords:** 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

**Figure 1.** *Structure of 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.*

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.

## **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 <sup>1</sup> H 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 [6–8].

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

**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

*Density Functional Theory and Molecular Modeling of the Compound… DOI: http://dx.doi.org/10.5772/intechopen.99577*

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**).

## *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].

## *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.

**Figure 5.**

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


#### **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.*


*Density Functional Theory and Molecular Modeling of the Compound… DOI: http://dx.doi.org/10.5772/intechopen.99577*


**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, 1 H 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.

## **Author details**

Yardily Amose1 \*, Fathima Shahana1 and Abbs Fen Reji<sup>2</sup>

1 Department of Chemistry and Research Centre, Scott Christian College, Nagercoil, Tamil Nadu, India

2 Department of Chemistry, Nesamony Memorial Christian College, Kanyakumari, Tamil Nadu, India

\*Address all correspondence to: ayardily@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Density Functional Theory and Molecular Modeling of the Compound… DOI: http://dx.doi.org/10.5772/intechopen.99577*

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[3] Alwin T, Abbs Fen Reji TF. Synthesis, antioxidant and antibacterial studies on 2-(2-arylamino-4-phenylthiazol-5-yl) benzofuran derivatives. International Research Journal of Pure and Applied Chemistry. 2017;**15**(1):1-8

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[11] Shahana MF, Yardily A. Synthesis, spectral characterization, DFT, and docking studies of (4-amino-2- (phenylamino) thiazol-5-yl) (thiophene-2-yl)methanone and (4-amino-2-(4-chlorophenyl)(amino) thiazol-5-yl)(thiophene-2-yl) methanone. Journal of Structural Chemistry. 2020;**61**:1367-1379

[12] Shahana MF, Yardily A. Synthesis, quantification, DFT calculation and molecular docking of (4-amino-2- (4-methoxyphenyl)aminothiazol-5yl) (thiophene-2-yl)methanone. Indian Journal of Biochemistry and Biophysics. 2020;**57**:606-612

## **Chapter 3**

Synthesis and Characterization of New Racemic α-Heterocyclic α,α-Diaminoester and α,α-Diamino Acid Carboxylic: 2-Benzamido-2- [(Tetrahydro-Furan-2-Ylmethyl) Amino]Acetate and 2-Benzamido-2-[(Tetrahydro-Furan-2-Ylmethyl) Amino] Acetic Acid

*El Houssine Mabrouk*

## **Abstract**

We reported here the synthesis of new α,α-diaminoester and α,α-diamino acid derivatives, as 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid through alkaline hydrolysis reaction of corresponding N-benzoylated methyl α,α-diamino ester. The α,α-diaminoester derivative was synthesized by nucleophilic substitution of methyl α-azido glycinate N-benzoylated with 2-tetrahydrofuran-2-ylmethan-amine. The structure of these products were established on the basis of NMR spectroscopy (1 H, 13C), and MS data.

**Keywords:** Amino acid, Amine, Heterocyclic molecules, Nucleophilic substitution, Methyl α-azido glycinate, α,α-Diamino ester, α,α-diamino acid, alkaline hydrolysis reaction

## **1. Introduction**

α-amino acids are a considerable interest due to their diversity in several fields of research (asymmetric organic synthesis and medicine) and applications (food industry and drugs). Given the very broad activity they present, research teams are interested in evaluating and developing their role for very effective use [1–5]. This has led to the development of numerous synthetic methods for a variety of compounds [6]. Heterocyclic chemistry is the basis for the discovery of the importance of the multiple medical properties of these compounds [7–12].

Because of their multiple functionalities, heterocyclic amino acids play a considerable role in the biologic processes [13, 14]. Therefore, a large number of between them isolated of plants have a very varied biologic activity [15].

Heterocyclic compounds have a wide spectrum activities, including antimicrobial [16, 17] and antibacterial properties [18, 19], anticancer agents [20], antiviral [21], antitumor activity [22], and in agricultural science as potent fungicides, herbicides and insecticides [23]. Heterocyclic amino acids and their derivatives represent a well-known group of organic compounds also presenting biological activity [24–26]. Considering the interest in these heterocyclic amino acids, several structurally related nonproteinogenic amino acids and their derivatives have been the subject of various investigations [27–29]. We present herein a convenient and easy procedure for the preparation of new racemic carboxylic α,α-diamino acid derivative with the aim to have access to new active biomolecule with a good yield.

For this reason, we considered it interesting to synthesize new compounds containing 2-tetrahydrofuran-2-ylmethanamine [30, 31] fused with an amino acid, in order to study their biological activities. The present study describes the synthesis and characterization of new α,α-diamino ester and α,α-diamino acid derivatives.

## **2. Results and discussions**

## **2.1 Synthesis of new racemic α-carboxylic α,α-diamino ester**

## *2.1.1 Preparation of azide dipole*

The first step of the synthesis strategy that we have developed consists in preparing the methyl ester of glycine N-protected by benzoyl chloride. Thus, the esterification of the starting amino acid is carried out by the action of thionyl chloride in anhydrous methanol on glycine and leads to the corresponding hydrochloride **1** with good yield (Yield = 92%). The hydrochloride is neutralized by adding triethylamine or bubbling gaseous ammonia (**Figure 1**).

The methyl glycinate **2** thus prepared is protected with benzoyl chloride. The protection reaction is carried out in dichloromethane in the presence of triethylamine or pyridine. After chromatography on a silica gel column, the N-protected aminoester **3** is obtained in good yields. Different protecting groups may protect the methyl glycinate **2**: trifluoroacetic anhydride, trichloroethoxycarbonyl chlorides and acetyl chloride.

The bromination reaction of N-protected amino ester is carried out by bromine in the presence of α,α'-azo-bis-isobutyronitrile (AIBN) in a catalytic amount or by N-bromosuccinimide, in reflux of carbon tetrachloride and under the irradiating action of a 300 W lamp. In general, methyl N-benzoyl α-bromoglycinate **4** is obtained in excellent yields. This product is used in most cases without purification in the next step (**Figure 1**).

The substitution of bromine by the azide group is effected by the action of sodium azide, in acetone, at room temperature for a period ranging from 4 to 5 hours. Purification of the reaction crude by chromatography on a silica gel column (eluent: 50/50 ether/hexane) allows substitution product **5** to be obtained with excellent yield. The title compound is stable and can be stored for an unlimited time without any signs of decomposition. The methyl α-bromo glycinate **4** also can be used and gives satisfactory results; the azide **5** is used especially for its stability.

## *2.1.2 N-alkylation of the amine by N-protected methyl* α*-azidoglycinate 5*

We continued our investigations on the use of organic azides [30, 32–37] in heterocyclic synthesis; we reported in this paper another part of our investigations concerning the preparation of new carboxylic α,α-diaminoester carrying *Synthesis and Characterization of New Racemic α-Heterocyclic α,α-Diaminoester... DOI: http://dx.doi.org/10.5772/intechopen.98408*

heterocyclic in position α. Our strategy is based on the nucleophilic substitution of methyl α-azido glycinate N-benzoylated **5** with 2-tetrahydrofuran-2-ylmethanamine (**Figure 2**).

In order to make a comparative study and to find the best experimental mode for this synthesis strategy, we carried out the synthesis reaction of the α,α-diaminoester in the absence and in the presence of a base (triethylamine (Et3N) or diisopropylethylamine (DIEPA)) in a solvent (dichloromethane (DCM) or acetone). The results in **Table 1** clearly show that the good yield is obtained using acetone in the presence of DIEPA.

## **2.2 Synthesis of new racemic α-carboxylic α,α-diamino acid**

In continuation of our research, we will present in this work, our results concerning the synthesis of new α,α-diamino acid derivative, as 2-benzamido-2-[(tetrahydrofuran-2-ylmethyl)amino] acetic acid through alkaline hydrolysis reaction of corresponding *N*-benzoylated methyl α,α-diamino ester [31]. After the obtaining of the *N*-protected methyl α,α-diamino ester **6**, we proceeded to the cleavage of the protecting groups to obtain the corresponding α,α-diamino acid **7**. The hydrolysis reaction of the α,α-diamino ester methyl 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)

**Figure 2.** *2-Benzamido-2-[(tetrahydro-furan-2-ylmethyl) amino] methyl acetate 6.*


**Table 1.**

*Different operating conditions for the synthesis reaction of 2-benzamido-2 - [(tetrahydro-furan-2-ylmethyl) amino] methyl acetate 6.*

**Figure 3.** *2-Benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid 7.*

amino]acetate **6** in a basic medium is carried out for approximately 30 minutes and leads, after acidification of the reaction medium with sulfuric acid or hydrochloric acid, to the corresponding α,α-diamino acid 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl) amino] acetic acid **7** in good yield (**Figure 3**).

## **3. Conclusion**

The first step in our synthesis strategy is to prepare the azide dipole. In the second step, our objective is the preparation of carboxylic α,α-diaminoester and diamino acid carrying a heterocycle in position α. This method provides an easy procedure for the preparation of new carboxylic α,α-diamino acids derivatives in very satisfactory yields starting from the appropriate azide derivative **5**. The nucleophilic substitution of methyl α-azido glycinate N-benzoylated **5** by 2-tetrahydrofuran-2-ylmethanamine occurred under very mild conditions and led to the 2-benzamido-2-[(tetrahydrofuran-2-ylmethyl)amino]acetate in good yield. 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid was synthesized through alkaline hydrolysis reaction of corresponding N-benzoylated methyl α,α-diaminoester.

## **4. Experimental**

### **4.1** *N***-alkylation reaction procedure**

To facilitate the nucleophilic attack of 2-tetrahydrofuran-2-ylmethanamine (5.72. 10−3 moles) on methyl α-azido glycinate (5.2. 10−3 moles), one adds at the start (6.24. 10−3 moles) of diisopropylethylamine on the amine in 20 ml of dry acetone. Deprotonation of the amine is carried out with stirring for one hour before adding the azide. At the end of the reaction which takes place for 48 hours, the evaporation of the solvent takes place under reduced pressure, decantation is ensured by dichloromethane or ethyl acetate using (Na2SO4) as desiccant, the product N-alkylated is purified by recrystallization or chromatography on a silica gel column (hexane/ether).

*Synthesis and Characterization of New Racemic α-Heterocyclic α,α-Diaminoester... DOI: http://dx.doi.org/10.5772/intechopen.98408*

## **4.2** *N***-benzoylated methyl α,α-diaminoester: Methyl 2-benzamido-2- [(tetrahydro-furan-2-ylmethyl)amino]acetate 6**

Yield = 72.0%; m. p. °C (hexane/ether (1/1)): 130–132; Rf (ether) = 0.63; M.S. (electrospray) m/z = 292.3 [M]; 293.3 [M + 1]; C15H20N2O4. 13C NMR (δppm, CDCl3): (2CO): 171.98, 169.07; C6H5 (aromatic): 135.77, 131.33, 129.54, 128.34; (OCH): 77.23; (-CH-): 71.32; (OCH3): 54.49; 4· (CH2): 66.12, 50.25, 27.07, 24.13. 1 H NMR (δppm, CDCl3): 8.02–7.40 (5H, NHamid + Ar, 3 m); 5.60 (1H, Hα, br s); 4.45–4.10 (3H, NH + HTHF, 2 m); 3.75 (3H, OCH3, s); 2.90 (2H, NCH2, m); 1.75–1.20 (5H, HTHF, 2 m).

## **4.3 Deprotection of acid function: Synthesis of** *N***-benzoylated α,α-diamino acid derivative 7**

To a solution of the *N-benzoylated* α,α-diamino ester *derivative* (1 mmole) in 10 mL of dioxane/water mixture (8/2), one adds 1.5 mmole of NaOH (0.5 N) with stirring and at 0°C. The stirring is maintained at room temperature until disappearance of the starting material. The reaction is always followed by TLC. The solvent is then evaporated and the pH of the aqueous phase is adjusted to 6 using a solution of sulfuric acid or hydrochloric acid (0.5 N). One extracts with ethyl acetate and the organic layers recovered, are dried and concentrated under vacuum. The product is recrystallized from ether/hexane.

## **4.4 2-Benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino]acetic acid 7**

Yield: 88%; Rf: 0.7 (ether); <sup>1</sup> HNMR (CDCl3): δppm: 1.25–1.80 (2 m, 5H, HT.H.F); 2.85 (m, 2H, NCH2); 4.20–4.50 (2 m, 3H, HT.H.F + NH); 5.5 (br s, 1H, Hα); 7.45–8.00 (3 m, 5H, Ar + N-Hamid). 13C NMR (CDCl3): δppm: 4 (CH2) 25.45, 27.18, 52.05, 66.42; 72.12 (-CH-); 77.26 (OCH); 127.84, 129.34, 131.72, 135.68 (C6H5 aromatic carbons); 169.12, 171.92 (2CO). MS (electrospray) m/z = 279.2 [M + 1]; 278.2 [M]; C14H18N2O4.

*Furan Derivatives - Recent Advances and Applications*

## **Author details**

El Houssine Mabrouk Laboratory of Materials Engineering for the Environment and Natural Resources, Faculty of Sciences and Technologies, Moulay Ismail University, Errachidia, Morocco

\*Address all correspondence to: mabrouk.elhoussine@gmail.com; e.mabrouk@umi.ac.ma

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Synthesis and Characterization of New Racemic α-Heterocyclic α,α-Diaminoester... DOI: http://dx.doi.org/10.5772/intechopen.98408*

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Section 2
