LIPINSKI RULE OF 2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran.
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 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,
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-(
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].
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).
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).
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.
Compound | Molecular weight (<500 Da) | HB donar (<5) | HB acceptor (<10) | Log | Molecular refractivity (40–130) |
---|---|---|---|---|---|
2-[2-(4-methylphenylamino)-4-phenylthiazol-5-yl]benzofuran | 425 | 2 | 5 | 6.91 | 125.94 |
Cancer cell (PDB code) | Binding energy (kJ/mol) | Active sites of interactions | ||||
---|---|---|---|---|---|---|
π–σ interactions | π–cation interactions | π–π interaction | Electrostatic | Van der Waals | ||
2KW6 | −294.25 | — | ARG A:103 | — | ARG A:103, ARG A:99, GLY A:100 | HIS B:254, HIS A:97, GLY B:252 |
6DL7 | −356.35 | ILE B:59 | — | TYR B:76 | ASP B:74, SER B:77, TYR B:76 | ILE B:59 |
6VJO | −287.89 | — | — | — | TYR B:178, VAL B:170, ILE A:454 | ASP B: 177, ASP A:455 |
6WMW | −270.58 | — | ARG B:313, LYS B:314, LYS B:202 | — | HIS B:206,ARG B:313, LYS B:314, LYS B:202 | TYR B:175, LEU B:186, GLY L:33, ALA B: 187 |
7LAE | 329.14 | — | — | CYS D1 | CYS D1, GLU A:38, ASP A:39 | VAL A:51, THR A:48, TYR A:45 |
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
References
- 1.
Brad KC. Biomedical Potential of Marine Natural Product. Bioscience. 1996; 46 :271-286 - 2.
Thomas KK, Reshmy R, Ushadevi KS. Synthesis of a novel bioactive 2-substituted amino-5-indol-3-oyl-4-phenylthiazoles. Journal of the Indian Chemical Society. 2007; 84 :1016-1019 - 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 - 4.
Silverstein RM, Bassler GC, Morrill TC. Spectrometric Identification of Organic Compounds. 4th ed. New York, USA: John Wiley & Sons, Inc.; 1981 - 5.
Ganesan MS, Kanmani Raja K, Murugesan S, Kumar BK, Rajagopal G, Thirunavukkarasu S. Synthesis, biological evaluation, molecular docking, molecular dynamics and DFT studies of quinoline-fluoroproline amide hybrids. Journal of Molecular Structure. 2020; 1217 :128360 - 6.
Becke AD. Density-functional thermo chemistry. III. The role of exact exchange. The Journal of Chemical Physics. 1993; 98 :5648 - 7.
Khalid M, Ullah MA, Adeel M, Khan MU, Tahir MN, Braga AAC. Synthesis, crystal structure analysis, spectral IR, UV-Vis, NMR assessment, electronic and non-linear optical properties of potent quinolone based derivatives: Interplay of experimental and DFT study. Journal of Saudi Chemical Society. 2019; 23 (5):546-560 - 8.
Boukabcha N, Benhalima N, Rahmani R, Chouaih A, Hamzaoui F. Theoretical investigation of electrostatic potential and non-liner optical properties of m-nitroacetanilide. Rasayan Journal of Chemistry. 2015; 8 (4):509-516 - 9.
Kecel-Gunduz S, Bicak B, Celik S, Akyuz S, Ozel AE. Structural and spectroscopic investigation on antioxidant dipeptide, l-methionyll-serine: A combined experimental and DFT study. Journal of Molecular Structure. 2017; 1137 :756-770 - 10.
Celik S, Akyuz S, Ozel AE. Vibrational spectroscopic and structural investigations of bioactive molecule glycyl-tyrosine (Gly-Tyr). Vibrational Spectroscopy. 2017; 92 :287-297 - 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