Development of Thiazolidinone-Based Pyrazine Derivatives: Synthesis, Molecular Docking Simulation, and Bioevaluation for Anti-Alzheimer and Antibacterial Activities

Jehangir, Uzma; Khan, Shoaib; Hussain, Rafaqat; Khan, Yousaf; Ali, Farhan; Sardar, Asma; Aslam, Samina; Afshari, Mozhgan

doi:https://doi.org/10.1155/2024/8426930

Journal of Chemistry

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Abstract Introduction Materials and Methods Results and Discussion Conclusion Data Availability Conflicts of Interest References Copyright Related Articles

Research Article | Open Access

Volume 2024 | Article ID 8426930 | https://doi.org/10.1155/2024/8426930

Development of Thiazolidinone-Based Pyrazine Derivatives: Synthesis, Molecular Docking Simulation, and Bioevaluation for Anti-Alzheimer and Antibacterial Activities

Uzma Jehangir,¹Shoaib Khan,²Rafaqat Hussain,³Yousaf Khan,¹Farhan Ali,²Asma Sardar,³Samina Aslam,⁴and Mozhgan Afshari⁵

Academic Editor: Mohd Sajid Ali

Received09 Sept 2023

Revised19 Dec 2023

Accepted06 Jan 2024

Published22 Jan 2024

Abstract

It is well recognized that heterocyclic compounds have exceptional biomedical applications, which has led scientists to become increasingly interested in their use in this field in the recent past. It is the aim of this study, using a multistep method based on thiazolidinone derivative synthesis, to synthesize thiazolidinone derivatives derived from pyrazine molecules (1–12). As a result of analyzing 1H-NMR, 13C-NMR, and HREI-MS data, the structures of these derivatives were determined. The minimum inhibitory concentration (MIC) of these drugs was also determined alongside the donepezil (IC₅₀ = 10.10 ± 0.10 µM) to determine their potential as anti-Alzheimer agents. Among the screened derivatives, 1 (IC₅₀ = 4.10 ± 0.20 µM), 2 (IC₅₀ = 2.20 ± 0.20 µM), 4 (IC₅₀ = 2.30 ± 0.20 µM), 5 (IC₅₀ = 5.80 ± 0.30 µM), 6 (IC₅₀ = 6.30 ± 0.20 µM), 8 (IC₅₀ = 5.20 ± 0.10 µM), 9 (IC₅₀ = 5.20 ± 0.40 µM), 10 (IC₅₀ = 8.30 ± 0.40 µM), and 11 (IC₅₀ = 8.10 ± 0.70 µM) showed potent activity. In addition, the synthesized moieties were screened against E. coli to determine whether there were any antimicrobial properties. It was found that most of the compounds were more potent inhibitors of bacterial growth in comparison to streptomycin, the reference drug. There have been several molecular docking experiments conducted to gain a deeper understanding of how these compounds interact with the active sites of enzymes to gain a greater understanding of their functional mechanisms.

1. Introduction

Alzheimer’s disease primarily affects human brains, in which two enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), play crucial roles. Several enzymes are responsible for hydrolyzing acetylcholine, resulting in choline and acetic acid [1]. This enzyme hydrolyzes acetylcholine, which plays an important role in many cognitive functions of the brain, and a deficit in its production leads to cognitive decline [2]. Alzheimer’s disease is characterized as a persistent and chronic neurological condition that causes ongoing disturbances in the brain’s cholinergic system, leading to a diverse range of symptoms such as disorientation, cognitive impairment, challenges in problem solving, and memory decline [3–5]. The main objective in the endeavor to develop a treatment for Alzheimer’s disease is to specifically target the enzymes AchE and BuChE [6, 7].

Acetylcholinesterase is primarily found in cholinergic neurons, muscle tissue, and the brain, whereas butyrylcholinesterase is predominantly located in the lungs, heart, liver, kidneys, and intestines [8–10]. The enzymatic activity and physiological role of acetylcholinesterase (AchE), which is notably abundant in the brain, primarily include the hydrolysis of ester-containing compounds. When the functioning of acetylcholine decreases, the activity of BuChE increases. In instances of this kind, the use of powerful drugs remains imperative to alleviate enzyme activity [11]. Furthermore, it is worth noting that the Food and Drug Administration (FDA) has approved some pharmacological interventions aimed at treating Alzheimer’s disease. These drugs include donepezil, rivastigmine, tacrine, and galantamine [12]. Nevertheless, the efficacy of these treatments is constrained, and their possible adverse effects, such as gastrointestinal pain and liver damage, emphasize the necessity for additional progress in the development of treatment alternatives [13–16].

Pyrazines (1,4-diazabenzenes) are volatile chemical compounds having a monocyclic aromatic ring that have antibacterial characteristics [17, 18]. Pyrazine production occurs in both mammals and plants [19]. However, pyrazines are synthesized by a few bacterial species, including Pseudomonas, Bacillus, Streptomycin, and Paenibacillus [20–22]. Pyrazine has been found to exhibit therapeutic properties such as antithrombogenicity [23], antimicrobial activity, tuberculous activity [18, 24], and anticholinesterase [25] and also exhibited inhibition against thymidine phosphorylase [26]. Nature is hepatoprotective and rigorous. However, certain pyrazines are toxic, such as those that impede cytochrome P450 synthesis [27] or activate liver microsomal explode hydrolase, an enzyme used in mammalian detoxification [28, 29]. As pyrazine and thiazolidnone moieties are biologically active [30–40], herein the current work, N-containing derivatives such as pyrazine-based thiazolidinone derivatives were synthesized and tested for biological activity to analyze their substantial impacts on Alzheimer’s disease. Furthermore, the inhibitory actions were investigated further using molecular docking investigations (Figure 1).

2. Materials and Methods

2.1. General Information

The chemicals and reagents utilized in this research were predominantly obtained from commercial sources, with a particular emphasis on Sigma-Aldrich, a reputable supplier based in the United States. Nuclear magnetic resonance (NMR) examinations were performed using an Advanced Bruker AM 600 MHz spectrometer. The experimental procedure involved the acquisition of high-resolution electron impact mass spectra utilizing a Finnegan MAT-311A mass spectrometer manufactured in Germany. The procedure encompassed performing thin layer chromatography (TLC) on aluminum plates coated in advance with silica gel (Kieselgel 60,254, E. Merck, Germany). The chromatogram was visualized using UV light with wavelengths of 254 nm and 365 nm.

2.2. General Procedure for the Synthesis of Pyrazine-Based Thiazolidinone Derivatives (1–12)

Thiazolidinone derivatives (1–12) based on pyrazine were synthesized through a series of three consecutive phases. In the beginning, an equimolar amount of different substituted benzene isothiocyanates (1 mmol, 0.8 g) and 2-amino-5-chlorobenzaldehyde (1 mmol) (I) were mixed in 10 mL of ethanol, along with triethylamine (3–5 drops), resulting in the formation of a thiourea intermediate (II). The intermediate (1 mmol 0.6 g) (II) was subsequently cyclized by agitation for approximately 5 hours in a mixture including 1 equivalent of chloroacetic acid (1 mmol), 10 mL of glacial acetic acid, and sodium acetate as a catalyst, leading to the generation of the thiazolidinone substrate (III). The synthesis of pyrazine-based thiazolidinone derivatives (1–12) was achieved by combining 1 equivalent of thiazolidinone substrate (1 mmol 0.5 g) (III) with 1 equivalent of 5-chloropyrazin-2-amine in 10 mL of ethanol. The utilization of glacial acetic acid as a catalyst (12–15 drops) in this reaction led to the successful synthesis of the desired derivatives, achieving favorable yields.

2.3. Assay Protocol for the Molecular Docking Study

A molecular docking study was performed using the AutoDock Vina software tool to investigate the binding mechanisms of the synthesized compounds with the target enzyme, acetylcholinesterase (AChE). The outcomes of our investigation conformed to the conclusions obtained from both our laboratory experiments and computer simulations. Protein Data Bank crystal structures were used to perform the docking analysis. For AChE, we extracted the crystal structure using the PDB code 1ACL. Following that, we proceeded to enhance the enzyme and chemical structures by decreasing their energies via protonation, employing the default parameters of the MOE-Dock module. The revised enzyme and chemical structures were subsequently utilized for the subsequent docking analysis [41–49].

2.4. Assay Protocol for Acetylcholinesterase Inhibition

A previously utilized approach was implemented to evaluate the inhibition of acetylcholinesterase (AChE). To provide a concise overview of the procedure, stock solutions of the test analogs were produced by dissolving them in DMSO at a concentration of 1 mg/mL. Serial dilutions were performed to create working solutions within the concentration range of 1–100 µg/mL. Dimethyl sulfoxide (DMSO) and water were blended to make the solutions. As a result of serial dilution, different solutions are progressively diluted, resulting in concentrations such as 0.1 mg/mL and 0.2 mg/mL.

Afterwards, various concentrations of the test compounds (10 µL) were combined with a solution containing sodium phosphate buffer (0.1 M; pH 8.0; 150 µL) and acetylcholinesterase (0.1 U/mL; 20 µL). This mixture was then allowed to preincubate for 15 minutes at a temperature of 25°C. The reaction was initiated by adding DTNB (1 mM; 10 µL) and AChEI (1 mM; 10 µL). The reaction mixture was thoroughly mixed using a cyclomixer and then incubated at 25°C for 10 minutes. Following this, the measurement of absorbance was conducted at a specific wavelength of 410 nm utilizing a microplate reader, where a blank reading was employed as the reference. The space was filled with 10 µL of dimethyl sulfoxide (DMSO) instead of the experimental material. This solution consisted of 5% DMSO and 95% water.

The calculation of the inhibition % was performed using the formula specified in equation X, where donepezil (0.01–100 µg/mL) was utilized as the positive control.

The IC₅₀ value was determined by generating a nonlinear regression plot, which relates the percentages of inhibition to the concentration. GraphPad Prism software (version 5.3) was utilized for the analysis.

3. Results and Discussion

3.1. Chemistry

The synthetic procedure was initiated by the treatment of 2-amino-5-chlorobenzaldehyde (1 mmol 0.8 g) (I) with variously substituted phenyl isothiocyanates (1 mmol) in the presence of solvent ethanol. Triethylamine (ET₃N) (3–5 drops) was introduced into the reaction mixture and refluxed the reaction mixture for 4 hours, resulting in the formation of thiourea derivatives (II). These aforementioned derivatives (II) (1 mmol) were then subjected to further refluxing with chloroacetic acid (1 mmol) in the presence of glacial acetic acid (10 ml) and sodium acetate for about 5 hours, yielding thiazolidinone derivatives (III).

In the final step, thiazolidinone substrate (1 mmol, 0.5 g) (III) was reacted with 5-chloropyrazin-2-amine in a solvent ethanol, in the presence of glacial acetic acid (10 mL), under reflux conditions for approximately 3 hours. This step led to the synthesis of the targeted thiazolidinone-derived pyrazine-based Schiff base derivatives (1–12). The progress of the reaction was monitored with the help of TLC after every 45-minute interval during refluxing, and the resulting compounds were purified by washing with n-hexane.

Following the collecting process, the samples were subjected to additional characterization utilizing ¹H-NMR, ¹³C-NMR, and HREI-MS studies. These analytical techniques facilitated the identification of protons, carbons, and various functional groups present within the synthesized molecules, respectively (Scheme 1).

3.2. Biological Profile

The biochemical profiles describe the better biological potentials of the synthesized compounds against acetylcholinesterase (AchE) and Escherichia coli to investigate the antibacterial activity. A molecule’s biological effects are strongly influenced by several factors, such as the type of atom, the number of atoms, and the configuration of substituents attached to an aromatic ring. The present study aims to synthesize and evaluate for their biological significance a series of substituted analogs that have been substituted with different molecules.

3.2.1. Acetylcholinesterase Inhibitory Activity

In order to determine the ability of synthetic compounds to inhibit acetylcholinesterase, the compounds were tested against donepezil, a standard prescription drug for acetylcholinesterase inhibition. Several compounds were found to have significant potential due to the presence of various substituents that have properties that allow them to form hydrogen bonds with the active sites of enzymes, which reduces the enzymatic activity of the enzyme. It was discovered that these scaffolds had better binding interactions in structure-activity relationships (SARs), in which the same substituted scaffolds were compared with standard drug profiles, as shown in the figures below, to determine which scaffolds had better binding interactions (Figure 2) [50].

(1) Structure-Activity Relationship. In the present studies, different substituted pyrazine-based thiazolidinone scaffolds were synthesized (1–12) by different reaction procedures (Scheme 1). Based on substituents, these scaffolds have been classified on the position of substituents, meaning the same substituents present varied positions on aromatic rings [51]. The biological significances of these compounds were investigated which depend upon the position, number, and nature of substituents (Table 1). The comparison criteria were set for trifluoro-substituted scaffolds (1, 2, and 4), showing that the most potent profile might be attributed to the presence of three fluorine atoms which make strong hydrogen bonding with the enzyme’s active sites, therefore reported as the excellent acetylcholinesterase (AchE) inhibitors of the tested series along with minimum inhibitory concentration (MIC) such as IC₅₀ = 4.10 ± 0.20, 2.20 ± 0.20, and 2.30 ± 0.20 µM, respectively. The nitro group at the ortho position of these moieties also enhanced the inhibitory profile due to the presence of heteroatom such as nitrogen and oxygen, which are also involved in the formation of hydrogen bond through van der Waals interactions; this group also plays a significant role in the inhibitory profile of molecules; thus, these scaffolds (1, 2, and 4) showed many potentials compared to that of donepezil (IC₅₀ = 10.10 ± 0.10 µM). The excellent potential among the trifluoro-substituted scaffolds was shown by analog 2; it might be the presence of the trifluoro group at the para position of the aromatic ring which strongly binds with the enzyme, thus considered as ranked-1 scaffold. A similar relationship of scaffolds (5 (IC₅₀ = 5.80 ± 0.30 µM), 6 (IC₅₀ = 6.30 ± 0.20 µM), and 8 (IC₅₀ = 5.20 ± 0.10 µM) bearing two fluoro groups at varied positions on aromatic ring exhibited a significant biological profile. Among these scaffolds, the potent behavior was shown by analog 5; it might be the presence of the flouro group at para- and meta-positions of the ring which increased the nucleophilicity in the ring to enhance the interactions, thus reducing the enzyme activity. The remaining two scaffolds (6 and 8) were also found with good potential in comparison to the reference drug because they also possess fluoro groups on varied positions such as two meta-positions (scaffold 6) and ortho- and meta-positions (scaffold 8). Similarly, scaffolds bearing the nitro group (9 IC₅₀ = 5.20 ± 0.10 µM, 10 IC₅₀ = 8.30 ± 0.40 µM, and 11 IC₅₀ = 8.10 ± 0.70 µM) also displayed few folds better potentials than donepezil. It may be the result of the presence of a nitro group which involves the hydrogen bond formation. The presence of a chloro group at different positions of the ring also enhances the nucleophilicity of the ring which might also engage the enzyme. A comparable profile was also found in the case of scaffold 3 (IC₅₀ = 8.10 ± 0.10 µM) having groups such as chloro and methyl at meta- and para-positions, respectively. Among the scaffolds investigated, 7 and 12 showed moderate to poor inhibitory potential. In comparison with the standard drug donepezil, these scaffolds showed decreased inhibitory effectiveness due to the presence of bulky groups. This resulted in reduced activity of these moieties.

3.2.2. Antibacterial Profile

We also looked at the antibacterial implications of all the compounds we made by testing them against E. coli. We found that the synthetic compounds had stronger inhibitory action than the gold standard antibiotic streptomycin, and we measured the compounds’ zones of inhibition. The synthetic chemicals were also tested for their inhibitory efficacy against E. coli strains. There were maximal inhibitory concentrations (Max. inhibition % age) for the chosen scaffolds (1, 2, 4, 5, 6, 8, 9, 10, and 11). Due to the presence of distinct substituents at different places on the ring, it was further proved that these scaffolds displayed greater potential. This arrangement improved their performance while reducing any negative impacts. Figure 3 displays the inhibition percentages of various scaffolds. When compared to the standard medication streptomycin (37.5%), the other examined scaffolds had inhibition rates of 2, 3, 4, 5, 30, 1.1%, 6. 28.5%, 8. 30.3%, 9. 25.9%, 10. 25.2%, and 11. 28.8%, respectively. Analog 1 exhibited the highest inhibition rate among these scaffolds. The other scaffolds in the series that were tested showed very little promise, maybe because of the large groups that were linked to the aromatic ring [52].

3.3. Molecular Docking Studies

Pyrazine-based thiazolidinone derivatives (1–12) among better potentials shown by scaffolds (1, 2, 4, and 5) have been subjected to molecular docking studies to investigate the compounds’ potential for interacting with the enzyme’s active sites. Our research groups have also worked on a similar protocol of molecular docking which was performed, using different software such as the AutoDock tool (1.5.7), PyMol, and Discovery Studio visualizer [41–45]. The protein was obtained from a Protein Data Bank (PDB) with the PDB code 1Acl. Its protein-ligand interactions (PLIs) profile was explored in which receptor sites, type of bonding, and distance were calculated as shown in Table 2. The docking results showed the binding modalities in terms of active sites both in protein and synthesized compounds which are represented in 2D and 3D structures for the subjected compounds as shown in Figures 4–7.

3.4. Experimental Analysis

3.4.1. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(2-nitro-5-(trifluoromethyl)phenyl)thiazolidin-4-one (1)

Yield, 63%; pale yellow solid, value 0.52 (7 : 3 n-hex: EtOAc), m.p. 183-184°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.20 (s, 1H, N=CH), 8.86 (s, 1H, Cl-pyrazin-H), 8.68 (s, 1H, Cl-pyrazin-H), 8.42 (s, 1H, Ar-H), 8.36 (d, J = 8.4 Hz, 1H, Ar-H), 8.29 (s, 1H, Ar-H), 8.22 (d, 1H, J = 8.9 Hz, Ar-H), 8.14 (d, J = 8.4 Hz, 1H, Ar-H), 8.03 (d, J = 8.3 Hz, 1H, Ar-H), 3.59 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 182.3, 167.1, 164.2, 160.5, 157.6, 155.3, 154.9, 153.4, 152.6, 150.7, 149.2, 149.7, 148.0, 148.1, 147.6, 134.8, 130.4, 129.0, 123.1, 115.2, 40.2; HREI-MS: m/z calculated for C₂₁H₁₁Cl₂F₃N₆O₃S, [M]⁺ 555.1357 Found 555.1348.

3.4.2. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(2-nitro-4-(trifluoromethyl)phenyl)thiazolidin-4-one (2)

Yield, 66%; white solid, value 0.59 (7 : 3 n-hex: EtOAc) m.p. 199-200°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.19 (s, 1H, N=CH), 8.92 (s, 1H, Cl-pyrazin-H), 8.72 (s, 1H, Cl-pyrazin-H), 8.64 (s, Ar-H, 1H), 8.47 (d, J = 8.5 Hz, 1H, Ar-H), 8.42 (s, ArH, ArH, 1H), 8.37 (d, 1H, J = 8.0 Hz, Ar-H), 8.31 (d, J = 8.2 Hz, 1H, Ar-H), 8.13 (d, J = 8.3 Hz, 1H, Ar-H), 3.64 (s, 2H, S-CH2); ¹³C-NMR (150 MHz, DMSO-d6): δ 184.9, 164.9, 163.3, 162.2, 157.8, 156.6, 155.4, 153.8, 152.6, 150.3, 149.9, 149.7, 148.2, 147.5, 147.0, 136.4, 132.3, 127.6, 123.7, 118.5, 43.01; HREI-MS: m/z calculated for C₂₁H₁₁Cl₂F₃N₆O₃S, [M]⁺ 555.1453 Found 555.1421.

3.4.3. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(3-chloro-4-methylphenyl)thiazolidin-4-one (3)

Yield, 59%; white solid, value 0.49 (7,:3 n-hex: EtOAc) m.p. 194-195°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.27 (s, 1H, N=CH), 8.88 (s, 1H, Cl-pyrazin-H), 8.69 (s, 1H, Cl-pyrazin-H), 8.62 (s, Ar-H,1H), 8.41 (d, J = 8.4 Hz, Ar-H, 1H), 8.36 (s, Ar-H, 1H), 8.31 (d, 1H, Ar-H, J = 8.4 Hz), 8.20 (d, J = 8.0 Hz, Ar-H, 1H), 8.04 (d, J = 8.3 Hz, Ar-H, 1H), 3.57 (s, 2H, S-CH₂)2.54 (s, 3H, Ar-CH₃); ¹³C-NMR (150 MHz, DMSO-d6): δ 183.9, 168.0, 160.7, 159.8, 159.1, 157.6, 155.7, 155.2, 147.9, 141.5, 141.6, 139.7, 134.2, 130.5, 129.1, 119.3, 119.7, 117.4, 114.2, 54.3, 32.9; HREI-MS: m/z calculated for C₂₁H₁₄Cl₃N₅OS, [M]⁺ 490.9345 Found 490.9328.

3.4.4. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(2-nitro-6-(trifluoromethyl)phenyl)thiazolidin-4-one (4)

Yield, 68%; yellow solid, value 0.51 (7 : 3 n-hex: EtOAc) m.p. 189-190°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.21 (s, 1H, N=CH), 8.91 (s, 1H, Cl-pyrazin-H), 8.66 (s, 1H, Cl-pyrazin-H), 8.59 (dd, J = 8.6, 1.4 Hz, Ar-H, 1H), 8.47 (d, J = 8.5 Hz, Ar-H, 1H,), 8.33 (s, Ar-H, 1H), 8.29 (dd, Ar-H, 1H, J = 8.0, 1.5 Hz), 8.20 (t, J = 8.5 Hz, Ar-H, 1H), 7.97 (d, J = 8.1 Hz, Ar-H, 1H), 3.54 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 186.1, 171.3, 170.1, 157.6, 150.9, 150.2, 148.8, 148.2, 148.7, 148.4, 147.3, 147.2, 142.9, 141.2, 140.5, 137.2, 124.6, 116.4, 114.0, 113.5, 56.8; Found HREI-MS: m/z calculated for C₂₁H₁₁Cl₂F₃N₆O₃S, [M]⁺ 555.2387 Found 555.2373.

3.4.5. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(3,4-difluorophenyl)thiazolidin-4-one (5)

Yield, 61%; brown solid, value 0.58 (7 : 3 n-hex: EtOAc) m.p. 180-181°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.25 (s, 1H, N=CH), 8.92 (s, 1H, Cl-pyrazin-H), 8.73 (s, 1H, Cl-pyrazin-H), 8.68 (s, Ar-H, 1H), 8.52 (d, J = 8.7 Hz, Ar-H, 1H), 8.39 (s, Ar-H, 1H), 8.36 (d, Ar-H, 1H, J = 8.5 Hz), 8.28 (d, J = 8.5 Hz, Ar-H, 1H), 8.09 (d, J = 8.8 Hz, Ar-H, 1H), 3.51 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 187.3, 172.1, 170.8, 162.3, 160.3, 160.1, 155.5, 155.7, 153.1, 146.4, 141.5, 139.4, 133.1, 132.4, 129.8, 124.5, 122.1, 121.7, 120.0, 54.9; HREI-MS: m/z calculated for C₂₀H₁₁Cl₂F₂N₅OS, [M]⁺ 478.1609 Found 478.1632.

3.4.6. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(3,5-difluorophenyl)thiazolidin-4-one (6)

Yield, 66%; white solid, value 0.59 (7 : 3 n-hex: EtOAc) m.p. 185-186°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.24 (s, 1H, N=CH), 8.87 (s, 1H, Cl-pyrazin-H), 8.73 (s, 1H, Cl-pyrazin-H), 8.65 (s, Ar-H, 1H), 8.50 (d, J = 8.3 Hz, Ar-H, 1H), 8.40 (s, Ar-H, 1H), 8.31 (d, Ar-H, 1H, J = 8.0 Hz), 8.29 (s, Ar-H, 1H,), 8.13 (s, Ar-H, 1H), 3.49 (s, 2H, S-CH₂); ¹³C-NMR 150 MHz, DMSO-d6): δ 189.3, 176.1, 173.3, 170.1, 163.5, 162.3, 161.9, 150.1, 146.5, 143.3, 139.2, 137.3, 136.0, 132.0, 126.1, 122.3, 117.2, 116.7, 115.1, 54.9; HREI-MS: m/z calculated for C₂₀H₁₁Cl₂F₂N₅OS, [M]⁺ 478.3256 Found 478.3221.

3.4.7. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(naphthalen-1-yl)thiazolidin-4-one (7)

Yield, 58%; dark brown solid, value 0.62 (7 : 3 n-hex: EtOAc) m.p. 213-214°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.19 (s, 1H, N=CH), 8.83 (s, 1H, Cl-pyrazin-H), 8.73 (s, 1H, Cl-pyrazin-H), 8.64 (s, Ar-H, 1H), 8.53 (dd, J = 8.4, 1.6 Hz, 1H, Naph-H), 8.32 (dd, 2H, J = 8.0, 1.5 Hz, Naph-H), 8.24 (dd, 1H, J = 8.2, 1.8 Hz, Naph-H), 8.11 (t, J = 8.7 Hz, 1H, Naph-H), 8.01 (t, J = 8.2 Hz, 2H, Naph-H), 7.87 (d, J = 8.0 Hz, Ar-H, 1H), 7.82 (d, J = 8.6 Hz, Ar-H, 1H), 3.49 (s, 2H, S-CH2); ¹³C-NMR (150 MHz, DMSO-d6): δ 188.4, 177.8, 176.5, 174.5, 173.5, 170.2, 169.8, 163.5, 163.2, 161.8, 160.9, 160.4, 146.3, 143.2, 139.8, 137.9, 136.5, 136.7, 129.8, 128.9, 118.2, 116.1, 113.1, 55.9; HREI-MS: m/z calculated for C₂₄H₁₅Cl₂N₅OS, [M]⁺ 492.9736 Found 492.9711.

3.4.8. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(2,5-difluorophenyl)thiazolidin-4-one (8)

Yield, 60%; white solid value 0.53 (7 : 3 n-hex: EtOAc) m.p. 180-181°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.17 (s, 1H, N=CH), 8.93 (s, 1H, Cl-pyrazin-H), 8.74 (s, 1H, Cl-pyrazin-H), 8.69 (s, Ar-H, 1H), 8.53 (d, J = 9.0 Hz, Ar-H, 1H), 8.38 (s, Ar-H,1H), 8.33 (d, Ar-H, 1H, J = 8.0 Hz), 8.25 (d, J = 8.9 Hz, Ar-H, 1H), 8.02 (d, J = 8.4 Hz, Ar-H, 1H), 3.52 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 189.3, 175.4, 173.7 162.2, 161.2, 160.9, 157.6, 156.2, 155.9, 149.8, 147.5, 138.2, 136.5, 132.8, 129.9, 124.4, 122.6, 122.2, 121.0, 54.9; HREI-MS: m/z calculated for C₂₀H₁₁Cl₂F₂N₅OS, [M]⁺ 478.0854 Found 478.0835.

3.4.9. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(3-chloro-4-nitrophenyl)thiazolidin-4-one (9)

Yield, 67%; pale green solid, value 0.48 (7 : 3 n-hex: EtOAc) m.p. 203-204°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.18 (s, 1H, N=CH), 8.96 (s, 1H, Cl-pyrazin-H), 8.70 (s, 1H, Cl-pyrazin-H), 8.64 (s, Ar-H, 1H), 8.58 (d, J = 8.9 Hz, Ar-H, 1H), 8.43 (s, Ar-H, 1H), 8.38 (d, 1H, Ar-H, J = 8.8 Hz), 8.29 (d, J = 8.7 Hz, Ar-H, 1H), 8.12 (d, J = 8.4 Hz, Ar-H, 1H), 3.58 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 187.4, 173.1, 172.7 169.2, 167.2, 163.9, 159.3, 158.2, 158.0, 152.8, 147.4, 139.1, 138.6, 136.7, 131.9, 127.4, 125.6, 124.2, 121.6, 58.0; HREI-MS: m/z calculated for C₂₀H₁₁Cl₃N₆O₃S, [M]⁺ 521.3214 Found 521.3185.

3.4.10. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(3-chloro-5-nitrophenyl)thiazolidin-4-one (10)

Yield, 65%; white solid, value 0.52 (7 : 3 n-hex: EtOAc) m.p. 208-209°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.22 (s, 1H, N=CH), 8.81 (s, 1H, Cl-pyrazin-H), 8.79 (s, 1H, Cl-pyrazin-H), 8.69 (s, Ar-H, 1H), 8.56 (d, J = 8.4 Hz, Ar-H, 1H), 8.49 (s, Ar-H, 1H), 8.38 (d, 1H, Ar-H, J = 8.6 Hz), 8.31 (s, Ar-H, 1H), 8.19 (s, Ar-H, 1H), 3.59 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 186.7, 173.8, 172.9, 171.3, 168.2, 167.8, 165.7, 160.9, 156.9, 149.8, 143.6, 141.5, 139.3, 137.8, 129.8, 128.9, 127.2, 119.7, 118.2, 56.1; HREI-MS: m/z calcld for C₂₀H₁₁C_l3N₆O₃S, [M]⁺ 521.9851 Found 521.9811.

3.4.11. (E)-2-((4-Chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)-3-(5-chloro-2-nitrophenyl)thiazolidin-4-one (11)

Yield, 62%; pale white solid, value 0.54 (7 : 3 n-hex: EtOAc) m.p. 198-199°C; ¹H-NMR (600 MHz, DMSO-d6): δ 9.18 (s, 1H, N=CH), 8.90 (s, 1H, Cl-pyrazin-H), 8.67 (s, 1H, Cl-pyrazin-H), 8.64 (s, Ar-H, 1H), 8.57 (d, Ar-H, J = 9.2 Hz, 1H), 8.43 (s, Ar-H, 1H), 8.36 (d, Ar-H, 1H, J = 8.8 Hz), 8.31 (d, J = 8.2 Hz, Ar-H, 1H), 8.22 (d, J = 8.9 Hz, Ar-H, 1H), 3.51 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 188.4, 174.7, 172.6 166.5, 163.5, 150.9, 149.6, 146.2, 145.9, 139.8, 137.5, 133.2, 130.5, 122.8, 122.5, 121.4, 120.6, 120.2, 119.0, 54.9; HREI-MS: m/z calculated for C₂₀H₁₁Cl₃N₆O₃S, [M]⁺ 521.1259 Found 521.1231.

3.4.12. (E)-3-([1,1′-Biphenyl]-4-yl)-2-((4-chloro-2-((E)-((5-chloropyrazin-2-yl)imino)methyl)phenyl)imino)thiazolidin-4-one (12)

Yield, 69%; off-white solid, value 0.50 (7 : 3 n-hex: EtOAc) m.p. 218-219°C; ¹H-NMR (600 MHz, DMSO-d6): δ9.16 (s, 1H, N=CH), 8.84 (s, 1H, Cl-pyrazin-H), 8.76 (s, 1H, Cl-pyrazin-H), 8.69 (s, 1H, Ar-H), 8.59 (d, J = 8.4 Hz, 2H, Biph-H), 8.44 (d, 2H, J = 8.2 Hz, Biph-H), 8.25 (dd, 2H, J = 8.8, 2.6 Hz, Naph-H), 8.17 (t, J = 8.7 Hz, 2H, Naph-H), 8.08 (m, J = 8.7 Hz, 1H, Naph-H), 7.88 (d, J = 8.4 Hz, Ar-H, 1H), 7.80 (d, Ar-H, J = 8.0 Hz, 1H), 3.59 (s, 2H, S-CH₂); ¹³C-NMR (150 MHz, DMSO-d6): δ 181.4, 169.8, 168.5, 165.5, 163.6, 160.0, 159.8, 153.9, 153.7, 151.8, 150.9, 150.4, 146.5, 145.6, 142.4, 139.4, 137.5, 138.7, 134.8, 133.2, 132.5, 116.5, 114.6, 112.9, 112.6, 55.0; HREI-MS: m/z calculated for C₂₆H₁₇Cl₂N₅OS, [M]⁺ 518.9512 Found 518.9481.

4. Conclusion

The molecular structures of pyrazine-based thiazolidinone derivatives (1–12) were verified using different characterization methods such as NMR (¹H and ¹³C) and HREI-MS. The therapeutic potential of these derivatives for the treatment of Alzheimer’s disease was then assessed by examining their inhibitory effects in comparison to donepezil (IC₅₀ = 10.10 ± 0.10 µM). Specifically, the compounds 1, 2, 4, 5, 6, 8, 9, 10, and 11 exhibited significant activity having IC₅₀ values of 4.10 ± 0.20, 2.20 ± 0.20, 2.30 ± 0.20, 5.80 ± 0.30, 6.30 ± 0.20, 5.20 ± 0.10, 5.20 ± 0.40, 8.30 ± 0.40, and 8.10 ± 0.70 µM, respectively. Furthermore, the synthesized chemical entities underwent screening to evaluate their effectiveness against E. coli bacteria. All of the aforementioned compounds exhibited improved levels of inhibition in comparison to the reference antibiotic agent, streptomycin. Further investigation was undertaken on these synthesized compounds using molecular docking analysis to elucidate their interactions with the active sites of enzymes. Suboptimal performance was discovered in several compounds, namely, 3, 7, and 12. The diminished biological efficacy of these analogs can be ascribed to the existence of a bulky group attached to these moieties on the aromatic ring.

Data Availability

The data used to support the findings of this study are confidential.

Conflicts of Interest

The authors declare that they have no conflicts of interest in this study.

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