Introduction

Thiazolidinones are considered the saturated form of a thiazole, 1,3-thiazolidin-4-one. Thiazolidinones consist of a five-membered ring containing a sulfur, nitrogen, and carbonyl group [1,2] (Figure 1). Sulfur occupies position 1 in the five-membered ring, while nitrogen is in position 3, and the carbonyl group is in position 4 [3-5].

Figure 1: Thiazolidinone ring

Thiazolidinones have three isomeric [6], and they have the following structures:

Figure 2: Isomeric structures of thiazolidines

The thiazolidinedione ring is of great importance because it is a structure in many naturalproducts and medicines, for example thiazolidine-4-one derivatives (Figure 3). It indicates the activity against inflammatory, analgesic, and anti-ulcer [7].

Figure 3:3-phenyl-2-(ρ-toyl)thiazolidin-4-one

Also, the prepared compound 2-aryl-4-oxothiazoilidin-3-ylamides showed the activity against prostate cancer cells (Figure 4) [8].

Figure 4: Prepared thiazolidine compounds as against prostate cancer cells

Materials and methods

Synthesis of imines [9,10]

(E)-N-(4-fluorophenyl)-1-(1H-indol-34-yl)methanimine (a)

It was prepared by the reaction of indol-3-carboxyaldehyde (1 g, 6.89 mmol) with 4-fluroanline (0.77 g, 6.89 mmol) and (10 drops) of (CH₃COOH) glacial acetic acid was added, and then they were refluxed in water bath for 16 hours. The product was precipitated and recrystallized with the addition of methanol droplets, (M.p=223-225°C), (R_f = 0.8), IR (KBr disk): (1632.62) cm^-1 (C=N), yield = 74% (Figure 5).

Figure 5: Preparation of (E)-N-(4-fluorophenyl)-1-(1H-indol-34-yl)methanimine

(E)-4-(((1H–indol-3-yl) methylene)amino)–N,N-dimethylaniline (b)

It was prepared by the reaction of Indol-3-carboxyaldehyde (1 g, 6.9 mmol) with N, N-dimethylbenzen-1,4-diamine (0.93 g,6.9 mmol) and (10 drops) of (CH₃COOH) glacial acetic acid was added, and then they were refluxed in water bath for 20 hours. The product was precipitated and recrystallized with the addition of methanol droplets, (M.p = 220-222°C), (R_f = 0.9), IR (KBr disk): (1603.65) cm^-1 (C=N), yield = 80% (Figure 6).

Figure 6: Preparation of (E)-4-(((1H–indol-3-yl) methylene)amino)–N,N-dimethylaniline

Synthesis of thiazoledinones [11,12]

3-(4-fluorophenyl)-2-(1H-indol-3-yl)thiazolidin-4-one(I)

It was prepared by the reactant (1 g, 4.2 mmol) (E)-N-(4-fluorophenyl)-1-(1H-indol-3-yl)methanimine with (0.39 g, 4.2 mmol) thioglycolic acid acid in (15 ml) chloroform, and then it was refluxed for 18 hours with stirring. The product was precipitated and recrystallized with the addition of ethanol R_f =0.7, yield=70%, M.p=229-231 °C (Figure 7).

Figure 7: Preparation of 3-(4-fluorophenyl)-2-(1H-indol- 3-yl)thiazolidin-4- one

3- (4- (dimethylamino)phenyl)-2-(1H-indol-3-yl)thiazolidin-4-one(II)

It was prepared by reactant (1g, 3.8 mmol) (E)-4-(((1H-indol-3-yl) methylene)amino)-N,N-dimethylaniline with (0.36 g, 3.8 mmol) thioglycolic acid acid in 15 ml chloroform, and then it was refluxed for 18 hours with stirring. The product was precipitated and recrystallized with the addition of ethanol R_f =0.8, yield = 75%, M.p=230-232 °C (Figure 8).

Figure 8: Preparation of 3-(4-(dimethylamino)phenyl)-2-(1H-indol-3-yl)thiazolidin-4-one

Quantum chemical calculations

Gaussian 09 W program was used to calculate EHOMO, ELUMO, energy gap (ΔE), and other parameters of the prepared compounds by implementing density function theory (DFT).

Results and discussion

The mechanism of preparing imines

Imine formation is a reversible process that starts with the nucleophilic addition of a primary amine to the carbonyl group of an aldehyde or ketone. Next, a proton transfer forms a neutral amino alcohol called a carbinolamine. Acid protonation of the carbinolamine oxygen converts it into a better leaving group which is subsequently eliminated as water producing an iminium ion. De-protonation of nitrogen gives the final imine product, as displayed in Scheme 1.

Scheme 1: Mechanism of imines formation

Table 1 shows the melting point measurement for the prepared compounds (a and b) diagnosed by (FT-IR) (Table 2), whose bands correspond to the vibration bands aliphatic (C-H), (aromatic C-H), (C=C)), and (azomethine band C=N). These bands occur (2925, 2923), (3037, 3042, 3097), (1591, 1567), and (1603, 1632), respectively.

Table 1: physical properties of imines

Table 2: IR spectra of imines

Synthesis of Thiazolidinones

The mechanism of preparing thiazolidinediones includes the reaction of the prepared Schiff bases with thioglycolic acid. The following scheme shows the reaction mechanism involving cycloaddition to form thiazolidinediones [13].

Scheme 2: Mechanism of thiazoldinone formation

FT-IR data

The prepared compounds (I,II) melting point and physical properties for prepared compounds are represented in Table 3. Compounds diagnosed specifying (FT-IR) listed in Table 4, demonstrated the featured packages most notably, C-H aromatic, aromatic C=C, aliphatic C-H, and carbonyl amide group which occur within (3041.48, 3104.91), (1574.91, 1576.47), (2976.37, 2811.03), (1686.24, 1646.81), respectively.

Table 3: Physical properties of thiazoledinones

Table 4: FTIR spectral data of thiazolidinones

¹H NMR spectral

¹H-NMR data of thiazoledinones are indicated in Table 5.

Table 5: ¹H-NMR data of thiazolidinones

Quantum chemical calculations

In computational study of the prepared compounds, Table 6 indicates the calculation of the most important chemical parameters of the prepared compounds.

Whether a molecule is hard or soft, the HOMO-LUMO energy gap represents the chemical reaction of that molecule. Compound 2 is characterized by a small energy gap (ΔE gap=1.17 eV), while compound 1 has a slightly higher energy gap (ΔE gap=1.8 eV). Therefore, compound 2 has a large susceptibility to polarization because its excitation energy is small, so compound 2 is soft [14].

In addition, compound 2 has a low ionization potential IP=4.23 and this indicates a high reactivity of the molecules [15,16].

 Low electron affinity values enhanced the electron-donating property of the molecule. Thus, the most donating molecule is compound 2 (EA = 3.06 eV) and the most acceptable molecule is compound 1 (EA = 3.12 eV) [17,18].

The stability and reactivity of the molecule can be known by the factors of hardness (ɳ) and chemical softness (ς) [19-22]. Hence, compound 1(ς =1.11 eV) is the more softness with the lowest hardness. Meanwhile, compound 2 (ς =1.71 eV) is the more hardness and less softness molecule (Figure 10-13).

Table 6: Quantum chemical parameters of the prepared compounds

Figure 10: (HOMO) of compound 1

Figure 11: (LUMO) of compound 1

Figure 12: (HOMO) of compound 2

Figure 13: (LUMO) of compound 2

Conclusion

The present study includes the synthesis and characterization of imine compounds, in addition to the synthesis of thiazolidinones from the reaction of the corresponding imine compounds with thioglycolic acid. These compounds were characterized with various spectral methods like (IR) and (¹H-NMR). Gaussian program was used to computational study thiazolidinones and the thermodynamic variables were calculated for these compounds.

Acknowledgment

The author thanks the College of Science/ University of Thi-Qar.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.

Conflict of Interest

The author declared that they have no conflict of interest.

ORCID:

Auhood Kadhim Zaid

https://orcid.org/0000-0002-5912-5372

HOW TO CITE THIS ARTICLE

Auhood Kadhim Zaid. Synthesis, Characterization, and Computational Study of Novel Thiazolidinone Derivatives Containing the Indole. J. Med. Chem. Sci., 2023, 6(2) 346-354

https://doi.org/10.26655/JMCHEMSCI.2023.2.15

URL: http://www.jmchemsci.com/article_156196.html