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Article

Eco-Friendly Synthesis of Thiazole Derivatives Using Recyclable Cross-Linked Chitosan Hydrogel Biocatalyst Under Ultrasonic Irradiation as Anti-Hepatocarcinogenic Agents

by
Sobhi M. Gomha
1,*,
Nahed A. Abd El-Ghany
2,
Manal S. Ebaid
3,
Tariq Z. Abolibda
1,
Magdi E. A. Zaki
4,*,
Mohammad Alhilal
5,
Suzan Alhilal
6 and
Nadia A. Mohamed
7
1
Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah 42351, Saudi Arabia
2
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
3
Department of Chemistry, College of Science, Northern Border University, Arar 91431, Saudi Arabia
4
Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
5
Department of Nursing, Faculty of Health Sciences, Mardin Artuklu University, Mardin 47200, Turkey
6
Department of Medical Services and Techniques, Vocational School of Health Services, Mardin Artuklu University, Mardin 47200, Turkey
7
Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Catalysts 2024, 14(12), 840; https://doi.org/10.3390/catal14120840
Submission received: 20 October 2024 / Revised: 19 November 2024 / Accepted: 20 November 2024 / Published: 21 November 2024
(This article belongs to the Special Issue Catalytic Energy Conversion and Catalytic Environmental Purification)
Browse Figures
Versions Notes

Abstract

:
In the current study, pyromellitimide benzoyl thiourea cross-linked chitosan (PIBTU-CS) hydrogel, was evaluated as a green biocatalyst for the efficient synthesis of novel thiazole derivatives. The PIBTU-CS hydrogel showcased key advantages, such as an expanded surface area and superior thermal stability, establishing it as a potent eco-friendly catalyst. By employing PIBTU-CS alongside ultrasonic irradiation, we successfully synthesized a series of novel thiazoles through the reaction of 2-(4-((2-carbamothioylhydrazineylidene)methyl)phenoxy)-N-(4-chlorophenyl)acetamide with a variety of hydrazonoyl halides (6a–f) and α-haloketones (8a–c or 10a,b). A comparative analysis with TEA revealed that PIBTU-CS hydrogel consistently delivered significantly higher yields. This synthetic strategy provided several benefits, including mild reaction conditions, reduced reaction times, and consistently high yields. The robustness of PIBTU-CS was further underscored by its ability to be reused multiple times without a substantial reduction in catalytic efficiency. The structures of the synthesized thiazole derivatives were meticulously characterized using a range of analytical techniques, including IR, 1H-NMR, 13C-NMR, and mass spectrometry (MS), confirming their successful formation. These results underscore the potential of PIBTU-CS hydrogel as a sustainable and recyclable catalyst for the synthesis of heterocyclic compounds. Additionally, all synthesized products were tested for their anticancer activity against HepG2-1 cells, with several new compounds exhibiting good anticancer effects.

Graphical Abstract

1. Introduction

Green chemistry has gained significant attention in recent years due to its potential to reduce human risk, minimize environmental pollution, decrease chemical hazards, and reduce waste generation. In organic synthesis, catalysts play a crucial role by reducing reaction times and enhancing product yields [1]. The development of heterogeneous catalytic systems for liquid-phase chemical and biochemical transformations has become a major research focus. These systems offer the advantage of ease of catalyst separation, recovery, and reusability, which are key for cleaner and more efficient processes [2].
Chitosan, a biopolymer derived from chitin, has attracted considerable attention in both scientific and engineering fields [3]. As a renewable and biodegradable material, chitosan-based catalysts are seen as promising candidates for organic catalysis due to their environmental friendliness [4]. Numerous studies have focused on modifying chitosan to enhance its hydrophilicity, chemical stability, solubility, and biological activity, making it suitable for a variety of applications [5].
Hydrophilic gels, known as hydrogels, are cross-linked materials that absorb significant amounts of water without dissolving. Their softness, smartness, and water retention capabilities make hydrogels unique materials. The water absorption capacity arises from hydrophilic functional groups on the polymer backbone, while their resistance to dissolution results from cross-links between polymer chains. In acidic environments, the amino groups of cross-linked chitosan are protonated, forming a cationic hydrogel that swells within the network. Various strategies, including cross-linking, grafting, and blending, have been employed to prepare chitosan hydrogels [6]. Reagents such as dialdehydes [7] and diisothiocyanates [8] are commonly used as chemical cross-linkers for chitosan.
Moreover, chitosan hydrogels have been successfully utilized as cationic catalysts in organic transformations [4,9]. Chitosan hydrogel offers several advantages as a catalyst, including the ability to retain reactant molecules within its cavities, facilitating their interactions and leading to higher product yields. In this work, a chitosan hydrogel was prepared by cross-linking with a functionalized crosslinker containing thiourea and imide moieties. These moieties, when protonated in acidic conditions, enhance the cationic nature of the polymeric matrix.
Ultrasound-assisted reactions offer several benefits, including shorter reaction times, simple experimental setups, high yields, improved selectivity, and cleaner processes [10,11]. Ultrasonic irradiation plays a pivotal role in such reactions, especially in cases where conventional methods require harsh conditions or prolonged reaction times [12,13].
The liver plays a vital role in regulating essential metabolic functions, including bile acid, fatty acid, cholesterol, and glucose metabolism [14,15,16]. Cancer is a complex and varied group of diseases that can affect almost any organ or tissue in the body, characterized by uncontrolled and accelerated cell growth, resulting in malignant tumors [17]. Globally, cancer remains one of the leading causes of death, posing a significant barrier to improving life expectancy across many countries [18,19]. According to GLOBOCAN 2020, around 19.3 million deaths worldwide were attributed to cancer [20]. Although chemotherapy is one of the primary treatments for cancer, its effectiveness is often compromised by a lack of selectivity and the development of drug resistance [21,22]. As a result, the development of safer and more effective anticancer therapies has become a major focus of global research. While several anticancer drugs, including the antitumor antibiotic doxorubicin, are currently in clinical use, recent research has increasingly concentrated on developing new chemically synthesized compounds to enhance cancer treatment.
The 1,3-thiazole core has been extensively explored as a key structure in the search for new lead compounds in drug discovery. Various thiazole-containing therapies have gained recognition, including tiazofurin, an inhibitor of IMP dehydrogenase [23]; dasatinib, a Bcr-Abl tyrosine kinase inhibitor [24]; dabrafenib, which inhibits the enzyme B-RAF [25]; ixabepilone, known for stabilizing microtubules [26]; and epothilone, which disrupts microtubule function (Figure 1) [27]. These compounds either became top-selling drugs or served as foundational lead structures in drug development. Several research teams have also investigated the thiazole scaffold’s potential for designing anticancer drugs [28,29,30,31].
Considering the favorable results achieved in our previous studies on green synthesis [32,33,34], we now introduce an eco-friendly protocol for the synthesis of 1,3-thiazole derivatives using PIBTU-CS hydrogel as an efficient and recyclable base catalyst. This method utilizes ultrasonic irradiation, offering a mild and energy-efficient alternative to conventional heating while maintaining high product yields and reaction efficiency. Building on our earlier work, this study further emphasizes the eco-friendly characteristics and catalytic efficiency of the PIBTU-CS hydrogel. The reusability of the hydrogel, coupled with its minimal environmental impact, highlights its potential as a sustainable catalyst for green chemistry applications.

2. Results and Discussion

2.1. Synthesis and Characterization of PIBTU-CS Hydrogel

Using a previously reported three-step method [8], N,N′-bis [4-(chlorocarbonyl)phenyl] pyromellitimide was synthesized and further reacted to form PIBTU-CS hydrogel. Pyromellitic anhydride and p-aminobenzoic acid were dissolved in DMF, followed by sequential reactions with acetic anhydride and thionyl chloride, yielding N,N′-bis[4-(isothiocyanate carbonyl)phenyl]pyromellitimide. This compound was then reacted with chitosan, producing PIBTU-CS hydrogel (Scheme 1; details in SI).
The hydrogel’s structure was confirmed using elemental analysis, FTIR, 1H-NMR, XRD, and SEM, aligning with previous findings [8]. Elemental analysis showed increased nitrogen (8.95%) and sulfur (3.13%), confirming successful preparation. FTIR indicated NH, C=O, and N–C–S groups, while 1H-NMR revealed characteristic signals for glucose and aromatic rings. XRD showed reduced crystallinity due to crosslinking, and SEM displayed a porous and channel-like surface, enhancing water permeation compared to smooth chitosan.
PIBTU-CS-2 was selected for this study based on its superior properties observed in previous research [12]. Among the four hydrogels synthesized with varying degrees of crosslinking, PIBTU-CS-2 demonstrated an optimal balance of porosity, thermal stability, and catalytic efficiency, making it the most suitable candidate for the synthesis of thiazole derivatives. These properties, combined with its reusability, highlight PIBTU-CS-2 as a robust and eco-friendly catalyst for green synthetic applications.

2.2. Thermogravimetric (TG) Analysis

The application of chitosan as an eco-friendly green biocatalyst for organic synthesis needs to reinforce its stabilization against thermal deterioration. There are many strategies suggested to improve the stability of chitosan against elevated temperatures, including the formation of chitosan derivatives, chitosan copolymers, chitosan blends, and chitosan metal nanocomposites. The chemical cross-linking process has already been established as an effective way to boost chitosan for high heat resistance. In the current study, we used chitosan that has previously been crosslinked with N,N′-bis [4-(isothiocyanate carbonyl)phenyl]pyromellitimide to obtain chitosan/pyromellitimide benzoyl thiourea super-porous hydrogel (PIBTU-CS).
The alteration that arose in the thermal stability of chitosan subsequent to crosslinking could be evaluated employing thermogravimetric analysis (TG) mensuration. The degradation demeanor and the heat stability of PIBTU-CS hydrogel were inspected via temperatures with a scope of 25 and 500 °C, in a nitrogen atmosphere at a flow rate of 30 mL min−1, and at a rate of heating of 10 °C min−1.
Table 1 and Figure 2 showed the loss in mass that was observed during the measuring of TG of chitosan and PIBTU-CS hydrogel. Both of them showed a similar degradation pattern, encompassing double-steps event at which remarkable losses in mass were noticed.
In the early stage, at temperatures between 25 and 150 °C, the recorded first losses in mass of PIBTU-CS was 1.00% versus 9.00% for parent chitosan (Table 1). During this stage, the adsorbed water was vaporized from the inspected samples. The losses in mass at temperatures over 100 °C could be ascribed to breaking down the hydrogen bonding that formed between H2O and the functional groups of the examined samples.
In the subsequent stage, a steep thermal deterioration operation was noticed which initiated at around 250 °C. At 500 °C, PIBTU-CS showed a 37.16% loss in mass in comparison to 47.06% of the virgin chitosan (Table 1). The decomposition process is proceeded by multi-steps reaction, comprising dehydrating and indiscriminate splitting of the saccharide nuclei as well as the emancipation and fumigation of the decomposition products. The results confirmed that PIBTU-CS has better thermal stability than that of chitosan. This was clarified not only from its lesser mass losses but also from its greater mass residues at all the inspected temperatures. This is associated with the possession of the cross linkages in the imide moieties, thiourea groups, and aromatic nuclei that are known by their high ability to tolerate the high heat.

2.3. Synthesis of Thiazole Derivatives Using PIBTU-CS Hydrogel as Basic Heterogeneous Catalyst

In this study, we present a simple and efficient method for the synthesis of novel thiazoles. The key intermediate, thiosemicarbazone derivative 5, was initially prepared by condensing N-(4-chlorophenyl)-2-(4-formylphenoxy)acetamide 3 [35] with thiosemicarbazide 5 in acidic ethanol solution following the reported method [36] (Scheme 2). The structure of thiosemicarbazone derivative 5 was confirmed through spectroscopic data, including IR, 1H NMR, and MS.
Subsequently, new thiazole derivatives 7a–f were synthesized by reacting equimolar amounts of thiosemicarbazone derivative 5 with 2-oxo-N-arylpropanehydrazonoyl halides 6a–f in ethanol, using either triethylamine (TEA) or PIBTU-CS hydrogel as a base catalyst (Scheme 2). The structures of the newly synthesized thiazoles 7a–f were validated through various spectral techniques (IR, MS, 1H-NMR, 13C-NMR) and elemental analysis. For example, the 1H-NMR spectrum of compound 7a displayed the expected signals, including five singlets at 2.46 ppm (thiazole-CH3), 4.79 ppm (CH2O), 8.10 ppm (CH=N), and two D2O-exchangeable NH signals at 10.24 and 11.31 ppm, along with thirteen multiplet aromatic proton signals between 6.98 and 7.95 ppm. The infrared spectrum of 7a also showed characteristic bands at 3413, 3306, and 1681 cm−1, corresponding to the two NH and C=O groups, respectively.
The heightened catalytic activity of PIBTU-CS can be attributed to the presence of amine groups (CS–NH and CS–NH2), which facilitate proton abstraction from the thiol form of the thiosemicarbazone derivative 5. This process enables the formation of a thiolate intermediate that reacts with hydrazonoyl halide, producing the S-alkylated product. The S-alkylated product subsequently undergoes dehydrative cyclization, yielding the desired thiazole derivatives (7a–f) as shown in Scheme 3. This mechanism highlights the critical role of PIBTU-CS’s functional groups in promoting efficient and selective catalysis under mild conditions.
Similarly, the reaction of compound 5 with 2-bromo-1-arylethan-1-ones 8a–c, 3-chloropentane-2,4-dione 10a, and ethyl 2-chloro-3-oxobutanoate 10b, using TEA and PIBTU-CS hydrogel as basic catalysts under the same conditions described in Scheme 4, led to the formation of thiazoles 9a–c and 11a,b as the final products. The chemical structures of the target compounds 9a–c and 11a,b were verified through comprehensive analysis of their IR, 1H-NMR, 13C-NMR, and MS spectra, as outlined in the Experimental section. The progress of all reactions was monitored using thin-layer chromatography (TLC).
The yields of products 7a–f, 9a–c, and 11a,b were evaluated and are summarized in Table 2.
The investigation into the most effective basic catalyst commenced at the start of the study (Table 2).
As demonstrated in Table 2, PIBTU-CS hydrogel outperformed traditional TEA as a basic catalyst under ultrasonic irradiation. Replacing triethylamine with PIBTU-CS hydrogel resulted in higher yields of the desired products (7a–f, 9a–c, and 11a,b) and shorter reaction times, all under the same reaction conditions.
To identify the optimal conditions and variables for the reaction of 5 with 6a to synthesize thiazole derivative 7a, we explored factors such as catalyst loading, temperature, solvent, and reaction time, using PIBTU-CS hydrogel under ultrasonic irradiation (USI).
We first investigated the effect of catalyst concentration on the yield of 7a (Table 3, entries 1–3). The highest yield (87%) was obtained with a catalyst loading of 15 mol% (Table 3, entry 3), while reducing the catalyst amount resulted in lower yields (Table 3). Next, we examined the performance of various solvents under ultrasonic irradiation (USI) (Table 3, entries 3, 4, and 5). Ethanol proved to be the most effective, providing the highest yield and the fastest reaction rate (Table 3, entry 3). We then optimized the reaction time (Table 3, entries 3, 6, and 7), identifying 25 min as the most efficient for producing 7a (Table 3, entry 3). Lastly, we explored the impact of temperature (Table 3, entries 3, 8, 9, and 10). As the temperature increased from 25 °C to 35 °C and 50 °C, the yields improved from 75% to 82% and ultimately 87%. The optimal temperature for the reaction was determined to be 40 °C (Table 3, entry 3).
The recyclability of PIBTU-CS hydrogel as a basic catalyst was evaluated by assessing its performance over multiple reaction cycles. After each use, the catalyst was cleaned with distilled water and dried at 60 °C for 30 min before being reused. The catalyst maintained high catalytic activity over three consecutive cycles with only a slight decrease in efficiency, demonstrating its potential for reuse under optimal conditions, as detailed in Table 4.
Based on the data in Table 4, the catalyst retained approximately 90.8% of its performance after three runs, with an average reduction of about 2.6% per run. However, in the fourth run, it lost around 30.4% of its performance, dropping to a 55% yield.
The optimal reaction conditions for synthesizing product 7a, as shown in Table 3, involve the reaction of 5 with 6a in ethanol under ultrasonic irradiation (USI) with PIBTU-CS hydrogel (15% wt) at 40 °C for 25 min. Under these conditions, the irradiation of 5 with 6b–f resulted in the successful formation of thiazole derivatives 7b–f (Scheme 2), along with 9a–c and 11a,b (Scheme 3).

2.4. Antitumor Activity

The synthesized compounds (7a–f, 9a–c, and 11a,b) were evaluated for cytotoxicity against the liver carcinoma cell line (HEPG2-1) using the MTT assay, with doxorubicin serving as the control drug. Data from these tests were used to generate dose–response curves, which helped determine the concentration (µM) of each compound required to achieve a 50% reduction in cell viability (IC50). The cytotoxicity findings were expressed as mean IC50 values, derived from three independent experiments (Table 5, Figure 3).
The structure-activity relationship (SAR) analysis for the synthesized compounds (7a–f, 9a–c, and 11a,b) against the HEPG2-1 liver carcinoma cell line reveals key trends in cytotoxic activity based on the nature of the substituents at R1 and R2.
For compounds 7a–f, electron-donating groups like methoxy (-OMe) and methyl (-Me) at the para position significantly enhance cytotoxicity. Compound 7c, with a methoxy group, showed the highest potency (IC50 = 0.73 µM), while 7b with a methyl group followed closely (IC50 = 1.25 µM). In contrast, the unsubstituted 7a (IC50 = 2.31 µM) had moderate activity, and electron-withdrawing groups like chloro (-Cl) in 7d (IC50 = 9.04 µM) and nitro (-NO2) in 7e (IC50 = 14.36 µM) reduced potency. Bulky phenyl groups in 7f led to the lowest activity (IC50 = 35.27 µM).
In compounds 9a–c, halogen substituents, such as chlorine (-Cl) in 9a (IC50 = 8.08 µM) and bromine (-Br) in 9b (IC50 = 7.06 µM), maintained moderate activity. However, the nitro group in 9c resulted in lower potency (IC50 = 17.35 µM), reinforcing the negative impact of electron-withdrawing groups.
Compounds 11a and 11b, with carbonyl substituents, showed strong cytotoxicity. Compound 11b, containing an ethyl ester (-COOEt), exhibited an IC50 of 1.03 µM, while 11a, with an acetyl group (-COCH3), showed an IC50 of 1.42 µM, indicating that carbonyl groups enhance activity, with esters being slightly more favorable.
Compared to doxorubicin (IC50 = 0.31 µM), compounds 7c and 11b showed good cytotoxicity, though not exceeding the reference drug’s potency. The SAR analysis indicates that electron-donating groups (e.g., methoxy, methyl) and carbonyl-containing substituents enhance cytotoxicity, while electron-withdrawing groups and bulky substituents reduce activity.

3. Materials and Methods

3.1. Apparatus and Instrumentations

Details Were Inserted in SI.

3.2. Synthesis and Characterization of (PIBTU-CS) Hydrogel

N,N′-Bis[4-(chlorocarbonyl)phenyl]pyromellitimide was reacted with ammonium thiocyanate in methylene chloride using polyethylene glycol-400 as a catalyst. The resulting N,N′-bis[4-(isothiocyanate carbonyl)phenyl]pyromellitimide was combined with a chitosan solution in acetic acid and stirred at 60 °C to form the PIBTU-CS hydrogel (Scheme 1). The hydrogel was neutralized, dewatered, dried, and labeled as PIBTU-CS, corresponding to PIBTU-CS-2 in previous research [12]. The structure and morphology were confirmed using elemental analysis, FTIR, 1H-NMR, XRD, and SEM.

3.3. Synthesis of 2-(4-((2-Carbamothioylhydrazineylidene)Methyl)Phenoxy)-N-(4-Chlorophenyl)Acetamide (5)

A mixture of N-(4-chlorophenyl)-2-(4-formylphenoxy)acetamide 3 (2.89 g, 10 mmol) and thiosemicarbazide 4 (0.91 g, 10 mmol) was dissolved in 30 mL of EtOH and treated with a catalytic amount of concentrated hydrochloric acid. The reaction mixture was subjected to ultrasonic irradiation in a water bath at 50 °C for 20 min. After cooling, the resulting precipitate was filtered, washed with ethanol, and recrystallized from acetic acid to yield thiosemicarbazones 5 as a yellowish-white solid with a 77% yield: m.p. 258–260 °C (Lit. m.p. 256–260 °C [37]).

3.4. Synthesis of Thiazole Derivatives 7a–f, 9a–c, and 11a,b

Method A: An equivalent amount of triethylamine (0.101 g, 1 mmol) was added to a solution containing equimolar amounts of thiosemicarbazone derivative 5 (0.362 g, 1 mmol) and the corresponding hydrazonoyl halides 6a–f or α-haloketones 8a–c or 10a,b (1 mmol each) in 20 mL of ethanol. The mixture was irradiated in a water bath at 40 °C for 30–60 min using an ultrasonic generator operating at a frequency of 40 kHz and a power of 250 W. The reaction progress was monitored by thin-layer chromatography (TLC), and irradiation was continued until the starting materials were fully consumed and the desired product formed. Upon completion, the reaction mixture was allowed to cool, and the resulting red precipitate was filtered, washed with ethanol, and dried. The product was then recrystallized from the proper solvent to afford the thiazole derivatives 7a–f, 9a–c, and 11a,b. The physical constants for the synthesized thiazoles 7a–f, 9a–c, and 11a,b are provided below.
Method B: A PIBTU-CS hydrogel (15% wt) was added to a solution of equimolar amounts of thiosemicarbazone derivative 5 (0.362 g, 1 mmol) and the appropriate hydrazonoyl halides 6a–f or α-haloketones 8a–c or 10a,b (1 mmol each) in 20 mL of ethanol. The mixture was subjected to ultrasonic irradiation using a generator operating at 40 kHz and 250 W in a water bath at 40 °C for 20–35 min. After completion, the PIBTU-CS hydrogel was removed by filtration, and the excess solvent was evaporated under reduced pressure. The resulting residue was treated with methanol to remove impurities and facilitate the isolation of the crude products. The solid products were then filtered, recrystallized from the appropriate solvent, and their purity was confirmed by melting point analysis and microanalysis.
N-(4-Chlorophenyl)-2-(4-((E)-(2-(4-methyl-5-((E)-phenyldiazenyl)thiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (7a).
Red solid, mp. 195–197 °C (EtOH); IR (KBr): v 3413, 3306 (2NH), 3052, 2924 (CH), 1681 (C=O), 1607 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.46 (s, 3H, CH3), 4.79 (s, 2H, -CH2O), 6.98–7.95 (m, 13H, Ar-H), 8.10 (s, 1H, CH=N), 10.24 (br s, 1H, NH), 11.31 (br s, 1H, NH) ppm; MS m/z (%): 504 (M+, 38). Anal. Calcd for C25H21ClN6O2S (504.99): C, 59.46; H, 4.19; N, 16.64. Found: C, 59.37; H, 4.06; N, 16.55%.
N-(4-Chlorophenyl)-2-(4-((E)-(2-(4-methyl-5-((E)-p-tolyldiazenyl)thiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (7b).
Red solid, mp. 181–183 °C (EtOH); IR (KBr): v 3403, 3326 (2NH), 3044, 2927 (CH), 1679 (C=O), 1609 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.29 (s, 3H, CH3), 2.46 (s, 3H, CH3), 4.73 (s, 2H, -CH2O), 6.98–7.96 (m, 12H, Ar-H), 8.09 (s, 1H, CH=N), 10.24 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 519 (M+, 33). Anal. Calcd for C26H23ClN6O2S (519.02): C, 60.17; H, 4.47; N, 16.19. Found: C, 60.01; H, 4.33; N, 16.03%.
N-(4-Chlorophenyl)-2-(4-((E)-(2-(5-((E)-(4-methoxyphenyl)diazenyl)-4-methylthiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (7c).
Red solid, mp. 175–177 °C (EtOH); IR (KBr): v 3417, 3273 (2NH), 3058, 2929 (CH), 1683 (C=O), 1603 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.46 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.72 (s, 2H, -CH2O), 6.98–7.96 (m, 12H, Ar-H), 8.09 (s, 1H, CH=N), 10.23 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 535 (M+, 47). Anal. Calcd for C26H23ClN6O3S (535.02): C, 58.37; H, 4.33; N, 15.71. Found: C, 58.21; H, 4.25; N, 15.57%.
N-(4-Chlorophenyl)-2-(4-((E)-(2-(5-((E)-(4-chlorophenyl)diazenyl)-4-methylthiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (7d).
Red solid, mp. 207–209 °C (Dioxan); IR (KBr): v 3402, 3298 (2NH), 3052, 2927 (CH), 1680 (C=O), 1609 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.46 (s, 3H, CH3), 4.73 (s, 2H, -CH2O), 6.98–7.96 (m, 12H, Ar-H), 8.11 (s, 1H, CH=N), 10.22 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 539 (M+, 56). Anal. Calcd for C25H20Cl2N6O2S (539.441): C, 55.66; H, 3.74; N, 15.58. Found: C, 55.53; H, 3.71; N, 15.47%.
N-(4-Chlorophenyl)-2-(4-((E)-(2-(4-methyl-5-((E)-(4-nitrophenyl)diazenyl)thiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (7e).
Brown solid, mp. 193–195 °C (EtOH); IR (KBr): v 3415, 3299 (2NH), 3055, 2931 (CH), 1688 (C=O), 1613 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.46 (s, 3H, CH3), 4.79 (s, 2H, -CH2O), 6.98–7.95 (m, 12H, Ar-H), 8.16 (s, 1H, CH=N), 10.22 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 549 (M+, 100). Anal. Calcd for C25H20ClN7O4S (549.99): C, 54.60; H, 3.67; N, 17.83. Found: C, 54.39; H, 3.44; N, 17.72%.
N-(4-Chlorophenyl)-2-(4-((E)-(2-(4-phenyl-5-((E)-phenyldiazenyl)thiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (7f).
Orange solid, mp. 219–241 °C (DMF); IR (KBr): v 3409, 3302 (2NH), 3039, 2927 (CH), 1681 (C=O), 1603 (C=N) cm−1; 1H NMR (DMSO-d6): δ 4.73 (s, 2H, -CH2O), 6.98–7.96 (m, 18H, Ar-H), 8.12 (s, 1H, CH=N), 10.22 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 567 (M+, 58). Anal. Calcd for C30H23ClN6O2S (567.06): C, 63.54; H, 4.09; N, 14.82. Found: C, 63.42; H, 4.01; N, 14.73%.
(E)-N-(4-Chlorophenyl)-2-(4-((2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazineylidene) methyl)phenoxy)acetamide (9a).
Red solid, mp. 254–256 °C (DMF); IR (KBr): v 3399, 3297 (2NH), 3038, 2979 (CH), 1674 (C=O), 1602 (C=N) cm−1; 1H NMR (DMSO-d6): δ 4.73 (s, 2H, -CH2O), 6.98–7.96 (m, 13H, 12Ar-H and thiazole-H5), 8.09 (s, 1H, CH=N), 10.23 (br s, 1H, NH), 11.33 (br s, 1H, NH) ppm; MS m/z (%): 497 (M+, 32). Anal. Calcd for C24H18Cl2N4O2S (497.39): C, 57.95; H, 3.65; 11.26. Found: C, 57.72; H, 3.49; 11.17%.
(E)-2-(4-((2-(4-(4-Bromophenyl)thiazol-2-yl)hydrazineylidene)methyl)phenoxy)-N-(4-chlorophenyl)acetamide (9b).
Brown solid, mp. 241–243 °C (DMF); IR (KBr): v 3413, 3305 (2NH), 3051, 2926 (CH), 1679 (C=O), 1601 (C=N) cm−1; 1H NMR (DMSO-d6): δ 4.73 (s, 2H, -CH2O), 7.34–7.96 (m, 13H, 12Ar-H and thiazole-H5), 8.10 (s, 1H, CH=N), 10.23 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 541 (M+, 60). Anal. Calcd for C24H18BrClN4O2S (541.85): C, 53.20; H, 3.35; N, 10.34. Found: C, 53.13; H, 3.31; N, 10.25%.
(E)-N-(4-Chlorophenyl)-2-(4-((2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazineylidene)methyl)phenoxy)acetamide (9c).
Brown solid, mp. 247–249 °C (DMF); IR (KBr): v 3422, 3325 (2NH), 3050, 2932 (CH), 1682 (C=O), 1618 (C=N) cm−1; 1H NMR (DMSO-d6): δ 4.74 (s, 2H, -CH2O), 7.35–8.08 (m, 13H, 12Ar-H and thiazole-H5), 8.23 (s, 1H, CH=N), 10.22 (br s, 1H, NH), 11.33 (br s, 1H, NH) ppm; MS m/z (%): 507 (M+, 92). Anal. Calcd for C24H18ClN5O4S (507.95): C, 56.75; H, 3.57; N, 13.79. Found: C, 56.68; H, 3.52; N, 13.61%.
(E)-2-(4-((2-(5-Acetyl-4-methylthiazol-2-yl)hydrazineylidene)methyl)phenoxy)-N-(4-chlorophenyl)acetamide (11a).
Yellow solid, mp. 213–215 °C (DMF); IR (KBr): v 3419, 3283 (2NH), 3037, 2924 (CH), 1707, 1680 (2C=O), 1604 (C=N) cm−1; 1H NMR (DMSO-d6): δ 2.37 (s, 3H, CH3), 2.46 (s, 3H, CH3), 4.73 (s, 2H, -CH2O), 7.00–7.96 (m, 8H, Ar-H), 8.09 (s, 1H, CH=N), 10.23 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 442 (M+, 63). Anal. Calcd for C21H19ClN4O3S (442.92): C, 56.95; H, 4.32; N, 12.65. Found: C, 56.64; H, 4.27; N, 12.49%.
Ethyl (E)-2-(2-(4-(2-((4-chlorophenyl)amino)-2-oxoethoxy)benzylidene)hydrazineyl)-4- methylthiazole-5-carboxylate (11b).
Yellow solid, mp. 191–193 °C (EtOH); IR (KBr): v 3426, 3305 (2NH), 3044, 2927 (CH), 1729, 1680 (2C=O), 1606 (C=N) cm−1; 1H NMR (DMSO-d6): δ 1.25 (t, 3H, CH3CH2), 2.37 (s, 3H, CH3), 4.27 (q, 2H, CH3CH2), 4.72 (s, 2H, -CH2O), 6.98–7.96 (m, 8H, Ar-H), 8.09 (s, 1H, CH=N), 10.22 (br s, 1H, NH), 11.32 (br s, 1H, NH) ppm; MS m/z (%): 472 (M+, 33). Anal. Calcd for C22H21ClN4O4S (472.94): C, 55.87; H, 4.48; N, 11.85. Found: C, 55.71; H, 4.39; N, 11.77%.

3.5. Anticancer Activity

The assessment of cytotoxicity for the synthesized compounds was measured following the method reported in reference [33,34,38].

4. Conclusions

In conclusion, the PIBTU-CS hydrogel proved to be an effective and eco-friendly biocatalyst for the synthesis of novel thiazole derivatives, offering numerous advantages such as high yields, mild reaction conditions, and reusability without significant loss in efficiency. The use of ultrasonic irradiation further enhanced the reaction process, making it a sustainable approach. The synthesized thiazole derivatives were successfully characterized and showed good anticancer activity against HepG2 cells, indicating potential for future development as hepatocarcinogenic agents.

Supplementary Materials

Supporting information is available for download at https://www.mdpi.com/article/10.3390/catal14120840/s1. This includes Figure S1, demonstrating the synthesis of N,N′-bis[4-(chlorocarbonyl)phenyl] pyromellitimide; Figure S2, presenting the FTIR spectra of chitosan and PIBTU-CS hydrogel; Figure S3, showcasing the 1H-NMR spectrum of PIBTU-CS hydrogel; Figure S4, illustrating the powder X-ray diffraction of chitosan and PIBTU-CS hydrogel; and Figure S5, featuring SEM images of chitosan and PIBTU-CS hydrogel. Additionally, detailed descriptions of the Chemicals and Materials and Measurements are included.

Author Contributions

Conceptualization: S.M.G. and M.E.A.Z.; Methodology: S.M.G., N.A.A.E.-G. and M.S.E.; Software: M.S.E. and T.Z.A.; Validation: N.A.M., S.M.G. and M.E.A.Z.; Formal analysis: M.A., N.A.M. and T.Z.A.; Investigation: M.S.E., T.Z.A., M.A. and S.A.; Resources: M.A. and M.E.A.Z.; Data curation: M.A. and N.A.M.; Writing—original draft preparation: M.E.A.Z. and S.A.; Writing—review and editing: S.M.G., T.Z.A. and M.E.A.Z.; Visualization: M.S.E. and N.A.M.; Supervision: S.M.G. and N.A.M.; Funding acquisition: M.S.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Deanship of Scientific Research at Northern Border University, Arar, KSA, through project number “NBU-FFR-2024-80-04”.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at Northern Border University, Arar, KSA for funding this research through the project number “NBU-FFR-2024-80-04”.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 14 00840 g001
Figure 1. Examples of thiazole-bearing anticancer drugs.
Figure 1. Examples of thiazole-bearing anticancer drugs.
Catalysts 14 00840 g001
Catalysts 14 00840 sch001
Scheme 1. Synthesis of PIBTU-CS hydrogel.
Scheme 1. Synthesis of PIBTU-CS hydrogel.
Catalysts 14 00840 sch001
Catalysts 14 00840 g002
Figure 2. TG analysis of chitosan and PIBTU-CS hydrogel.
Figure 2. TG analysis of chitosan and PIBTU-CS hydrogel.
Catalysts 14 00840 g002
Catalysts 14 00840 sch002
Scheme 2. Synthesis of arylazothiazoles 7a–f.
Scheme 2. Synthesis of arylazothiazoles 7a–f.
Catalysts 14 00840 sch002
Catalysts 14 00840 sch003
Scheme 3. Proposed mechanism for synthesis of arylazothiazoles 7a–f.
Scheme 3. Proposed mechanism for synthesis of arylazothiazoles 7a–f.
Catalysts 14 00840 sch003
Catalysts 14 00840 sch004
Scheme 4. Synthesis of thiazoles 9a–c and 11a,b.
Scheme 4. Synthesis of thiazoles 9a–c and 11a,b.
Catalysts 14 00840 sch004
Catalysts 14 00840 g003
Figure 3. Cytotoxic effects of the tested compounds on HEPG2-1 cells.
Figure 3. Cytotoxic effects of the tested compounds on HEPG2-1 cells.
Catalysts 14 00840 g003
Table 1. TG measurements data of chitosan and PIBTU-CS hydrogel.
Table 1. TG measurements data of chitosan and PIBTU-CS hydrogel.
Temperature (°C)Weight Loss (%) a
ChitosanPIBTU-CS
250.410.00
501.660.00
1006.040.00
1509.001.00
20010.482.50
25012.534.70
26014.267.59
27017.538.51
28022.2010.00
29027.2911.35
30031.4113.63
31033.8016.51
32035.4919.44
33037.0722.00
34038.3024.65
35039.3627.00
40042.6029.00
45044.7733.99
50047.0637.16
a Weight loss (%) indicates thermal stability under test conditions.
Table 2. The reaction time and yield percentages of thiazoles 7a–f, 9a–c, and 11a,b were compared using two different basic catalysts under ultrasonic irradiation.
Table 2. The reaction time and yield percentages of thiazoles 7a–f, 9a–c, and 11a,b were compared using two different basic catalysts under ultrasonic irradiation.
Catalysts 14 00840 i001
Compound.R1R2TEAPIBTU-CS Hydrogel
Time (min)(%) Yield bTime (min)(%) Yield b
7aMeC6H548692587
7bMe4-MeC6H451712789
7cMe4-MeOC6H457723586
7dMe4-ClC6H447702290
7eMe4-NO2C6H4 32732087
7fPhPh49743090
9a4-ClC6H4H53712688
9b4-BrC6H4H39722887
9c4-NO2C6H4 H44682189
11aMeCOCH349702987
11bMeCOOEt60673185
b Yield (%) represents the isolated product after purification.
Table 3. The synthesis of compound 7a was optimized by adjusting catalyst loading, solvent, reaction time, and temperature.
Table 3. The synthesis of compound 7a was optimized by adjusting catalyst loading, solvent, reaction time, and temperature.
EntryCatalyst (Wt%)SolventTime (min)Temperature (°C)Yield (%)
15EtOH254061
210EtOH254083
3 a15EtOH254087
415DMSO254078
515Dioxan254080
615EtOH204081
715EtOH304087
815EtOH252575
915EtOH253582
1015EtOH255087
a The optimal reaction condition for synthesizing compound 7a.
Table 4. Recyclability of PIBTU-CS hydrogel as basic catalyst.
Table 4. Recyclability of PIBTU-CS hydrogel as basic catalyst.
State of CatalystFresh CatalystRun 1 Run 2Run 3Run 4
Product 7a (% Yield) b8785827955
b Yield (%) represents the isolated product after purification.
Table 5. Cytotoxic activity of the tested compounds against HEPG2-1.
Table 5. Cytotoxic activity of the tested compounds against HEPG2-1.
Catalysts 14 00840 i002
CompoundR1R2IC50 (µM) a
7aMeC6H5N=N-2.31 ± 0.57
7bMe4-MeC6H4N=N-1.25 ± 0.67
7cMe4-MeOC6H4N=N-0.73 ± 0.48
7dMe4-ClC6H4N=N-9.04 ± 0.77
7eMe4-NO2C6H4N=N-14.36 ± 0.53
7fPhPh35.27 ± 0.75
9a4-ClC6H4H8.08 ± 0.96
9b4-BrC6H4H7.06 ± 0.48
9c4-NO2C6H4 H17.35 ± 0.94
11aMeCOCH31.42 ± 0.71
11bMeCOOEt1.03 ± 0.29
Doxorubicin--0.31 ± 0.48
a IC50 (µM) shows the concentration needed for 50% inhibition of cell viability.
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Gomha, S.M.; El-Ghany, N.A.A.; Ebaid, M.S.; Abolibda, T.Z.; E. A. Zaki, M.; Alhilal, M.; Alhilal, S.; Mohamed, N.A. Eco-Friendly Synthesis of Thiazole Derivatives Using Recyclable Cross-Linked Chitosan Hydrogel Biocatalyst Under Ultrasonic Irradiation as Anti-Hepatocarcinogenic Agents. Catalysts 2024, 14, 840. https://doi.org/10.3390/catal14120840

AMA Style

Gomha SM, El-Ghany NAA, Ebaid MS, Abolibda TZ, E. A. Zaki M, Alhilal M, Alhilal S, Mohamed NA. Eco-Friendly Synthesis of Thiazole Derivatives Using Recyclable Cross-Linked Chitosan Hydrogel Biocatalyst Under Ultrasonic Irradiation as Anti-Hepatocarcinogenic Agents. Catalysts. 2024; 14(12):840. https://doi.org/10.3390/catal14120840

Chicago/Turabian Style

Gomha, Sobhi M., Nahed A. Abd El-Ghany, Manal S. Ebaid, Tariq Z. Abolibda, Magdi E. A. Zaki, Mohammad Alhilal, Suzan Alhilal, and Nadia A. Mohamed. 2024. "Eco-Friendly Synthesis of Thiazole Derivatives Using Recyclable Cross-Linked Chitosan Hydrogel Biocatalyst Under Ultrasonic Irradiation as Anti-Hepatocarcinogenic Agents" Catalysts 14, no. 12: 840. https://doi.org/10.3390/catal14120840

APA Style

Gomha, S. M., El-Ghany, N. A. A., Ebaid, M. S., Abolibda, T. Z., E. A. Zaki, M., Alhilal, M., Alhilal, S., & Mohamed, N. A. (2024). Eco-Friendly Synthesis of Thiazole Derivatives Using Recyclable Cross-Linked Chitosan Hydrogel Biocatalyst Under Ultrasonic Irradiation as Anti-Hepatocarcinogenic Agents. Catalysts, 14(12), 840. https://doi.org/10.3390/catal14120840

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