Green synthesis and catalytic efficiency of [BCMAB][2Cl] ionic liquid for the synthesis of bioactive 1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives via Biginelli condensation: BSA binding affinity and molecular docking studies

Avadhesh Kumar; Uzma; Suad Al Kindi; Mohd Amir; Syed Najmul Hejaz Azmi; Saleem Javed; Mehtab Parveen; Mahboob Alam

doi:10.25259/AJC_267_2024

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Original Article

2025

:18;

2672024

doi:

10.25259/AJC_267_2024

Green synthesis and catalytic efficiency of [BCMAB][2Cl] ionic liquid for the synthesis of bioactive 1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives via Biginelli condensation: BSA binding affinity and molecular docking studies

Avadhesh Kumar^a, Uzma^a, Suad Al Kindi^b, Mohd Amir^c, Syed Najmul Hejaz Azmi^d, Saleem Javed^c, Mehtab Parveen^a, Mahboob Alam^e,*

aDepartment of Chemistry, Aligarh Muslim University, Aligarh, Aligrah-202002, UP-India

bGlobal College of Engineering and Technology, Muscat, Oman

cDepartment of Biochemistry, Aligarh Muslim University Faculty of Life Sciences, Aligarh, Aligarh-202002, UP-India

dApplied Sciences Department, College of Applied Sciences and Pharmacy, University of Technology and Applied Sciences, Muscat, Sultanate of Oman

eDepartment of Safety Engineering, Dongguk University WISE, Gyeongju-si, Gyeongsangbuk-do 38066, Republic of Korea

* Corresponding author: E-mail address: mahboobchem@gmail.com (M. Alam)

Received: 2024-12-16, Accepted: 2025-05-08, Epub ahead of print: 2025-09-09, Published: 2025-09-20

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Abstract

A newly developed ionic liquid (IL) catalyst, 1,4-bis(carboxymethyl)benzene-1,4-diaminium chloride ([BCMAB][2Cl]), was synthesized via a straightforward reaction between p-phenylenediamine and chloroacetic acid. This eco-friendly catalyst efficiently promotes multicomponent reactions (MCRs) such as Biginelli, Hantzsch, and Niementowski syntheses to yield 1,2,3,4-tetrahydropyrimidine-5-carboxylates, while eliminating the use of hazardous volatile organic solvents. The IL was thoroughly evaluated with the help of Fourier transform-infrared (FT-IR), powder-X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) methods, demonstrating its stability in both air and water. Its acidity was found to play a pivotal role in catalytic performance, with [BCMAB][2Cl] outperforming other tested ILs in catalytic activity. The synthetic protocol is cost-effective, environmentally benign, and sustainable, as validated by green chemistry parameters, including E-factor, atom economy, reaction mass efficiency, and process mass intensity. Furthermore, the IL catalyst is reusable without significant loss of activity, simplifying product recovery. The reactions were carried out under reflux conditions, efficiently synthesizing bioactive compounds from heterocyclic aldehydes, methyl acetoacetate, and urea. The resulting compounds (4a–k) were analyzed for their binding interaction with bovine serum albumin (BSA) via molecular docking. Compounds 4a, 4g, and 4i exhibited the strongest binding affinities, while all derivatives demonstrated significant docking scores and notable BSA binding activity. Overall, these findings underline the dual functionality of [BCMAB][2Cl] as both an effective catalyst and a promoter of biologically active compounds.

Keywords

BSA binding

Green chemistry

Ionic liquid catalysts

Multicomponent reactions

Molecular docking

Sustainable synthesis

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1. Introduction

Significant interest has been directed toward advanced organic chemistry and the design of therapeutic drugs, as heterocyclic compounds play a vital role in life processes. These compounds, abundant in heterocyclic rings, share structural similarities with numerous natural products such as hormones, vitamins, and antibiotics.[1] The basic structures of some commercial chemicals and several physiologically active scaffolds are composed of heterocyclic rings. [2–4]

Heterocycles such as indole, pyrimidine, pyrazole, morpholine, piperidine, pyrrolidine, and triazine serve as the backbone for various therapeutic drugs with anti-inflammatory, antifungal, antileukemic, and neuroprotective properties.[5] Dihydropyrimidinones (DHPMs) and their derivatives have gained prominence due to their wide range of biological activities, showcasing significant potential in natural product chemistry, synthetic methodologies, pharmacology, and medicinal research.[6] Compounds like tetrahydropyrimidines, DHPMs, and pyridinones are particularly notable for their extensive bioactivity profiles. Their utilization in pharmacological research has prompted the development of synthetic approaches for their preparation and chemical modification.[7] Essential oils, coal tar, molasses tar, and pus from the liver, pancreas, brain, and bile also possess indole. Numerous physiologically relevant substances, including lysergic acid, diethyl amide, abrine, reserpine, yohimbine, physostigmine, serotonin, tryptophan, indole-3-acetic acid, gramine, and significant antibiotics, including mitomycin and gliotoxin, consist of indole.[8] For many years, indole has been connected with the pyrimidine moiety.[9] It has been found to exhibit diverse pharmacological activities and is presently available as a commercially marketed drug. Figure 1 highlights some active pharmaceutical compounds that contain pyrimidine, indole, and other hetero pyrimidine, showcasing diverse biological activities. The hybrid indole-pyrimidine nucleus exhibits numerous biological effects, including antibacterial, antifungal, and anticancer. The synthesis of the indole-pyrimidine scaffold is advantageous for obtaining novel physiologically active derivatives.

Chemical structures of bioactive pharmaceuticals featuring the tetrahydropyrimidine-5-carboxylate moiety and their associated biological activities.

Multicomponent reactions (MCRs) represent one of the most efficient approaches in modern synthetic organic chemistry, as they incorporate all the key attributes necessary for ideal synthesis, such as high atom efficiency, ease of use, reduction of time and energy consumption, environmental friendliness, provision of a target, and diversity-oriented synthesis.[10] As a result, it is currently unavoidable that novel MCRs will arise in response to industrial and biological scaffolds. The integration of MCRs with subsequent transformations enables the synthesis of a wide variety of complex and diverse products. Examples of such post-MCR transformations include Knövenagel condensations, metathesis reactions, aza-Wittig reactions, Mitsunobu reactions, and intramolecular cycloaddition reactions [11,12].

More than a decade has passed since the synthesis of Biginelli compounds came to light.[13] The synthesis of Dihydropyrimidinone (DHPM) is of interest not only because of its structural resemblance to the best-known calcium channel modulator, Hantzsch dihydropyridine, but also because of its many biological and medicinal applications.[14,15] The synthesis of DHPM involves either the one-pot coupling of urea, ethyl acetoacetate, and an aldehyde or the reaction of protected urea with enones.[16] The most versatile components, 1,3-dicarbonyl compounds or commercially accessible aldehydes, have been utilized in most procedures, including combinatorial chemistry approaches, to synthesize DHPMs. It has been demonstrated that the cardiotonic activities of 4a–e is higher than those of Digoxin [17], which motivated us to produce highly functionalized DHPMs to enhance the activity even more. The synthesis of DHPM scaffolds with precise substitution patterns is frequently hindered by restricted starting materials and low yields of one-pot condensations, which demand structurally complex building blocks [18].

Historically, heterogeneous catalysts were made up of metal-based systems. Recently, various heterogeneous organo-catalysts that are easily recovered and recycled have been designed to mimic the distinctive properties of heterogeneous catalytic systems. Driven by the pursuit of sustainable and environmentally friendly catalytic systems, recent studies have highlighted the versatility of ionic liquids (ILs) as mediators and catalysts in organic transformations. This versatility has been well demonstrated in studies [19–21], highlighting the importance of developing novel IL catalysts for MCRs. Currently, metal-free heterogeneous catalysts have been documented using carbo-catalysts (materials similar to graphene) and supported organo-catalysts, which are either supported on inorganic (silica-based materials) [22] or organic (covalent organic frameworks) [23], basic IL functionalized magnetically response used for biodiesel production. Based on current information, all heterogeneous organocatalysts reported in the literature rely on a support system. Our research group appreciates the significance of identifying sustainable methods. Therefore, we believe that finding both heterogeneous and homogeneous catalytic systems is crucial to achieving this goal. This way, affordable starting materials and straightforward procedures can synthesize imidazole derivatives with carboxyl moieties. Numerous catalytic systems can be designed using these chemicals. To synthesize N-heterocyclic carbene (NHC) ligands for palladium-catalyzed organic transformations, functionalized imidazolium derivatives were employed as precursors [24]. Imidazolium salts can be combined with metal salts, such as iron (III) chloride, to form Iron-Based Lewis Acid ILs (IBLAILs), demonstrating excellent versatility as catalytic systems. Additionally, we used imidazolium-dicarboxylate-based organic frameworks as reliable and effective catalysts for chemical conversions [25]. Imidazole derivatives with carboxylic acids are now attracting our attention as isolated catalytic systems. In this paper, we describe the catalytic application of 1,4-bis(carboxymethyl)benzene-1,4-diaminium chloride [BCMAB][2Cl], an organic salt. Although resembling ILs, which are commonly employed as catalysts, this Ionic Organic Solid (IOS) offers the advantage of easier separation from the reaction mixture through filtration due to its solid state. The structural diversity of ILs is a key factor in their versatility. As shown in Figure 2, ILs can be synthesized with a variety of cations (e.g., imidazolium, pyridinium, piperidinium) and anions (e.g., BF₄^-, HSO₄^-, Cl^-, Br^-, PF^6-, CH₃SO₄^-), allowing their physicochemical properties to be fine-tuned. This structural flexibility enables the design of ILs to be tailored for specific applications. Figure 3 provides a comparative analysis of synthetic strategies employed for heterocyclic compound generation, with particular emphasis on the catalytic role of ILs. The previous work (Figure 3a-c), including the present work (Figure 3d), describes established methods for the synthesis of dihydropyrimidines, 2-aminothiazoles, and 3-phenylquinazolin-4-ones, respectively, using ILs. These examples highlight the adaptability of ILs to achieve a wide range of chemical reactions under relatively mild conditions, often with reduced reaction times and more environmentally friendly properties compared to traditional methods. For example, the synthesis of dihydropyrimidines (Figure 3a) demonstrates the effectiveness of ILs-BMImBF₄ as a catalyst at 10°C, affording the desired product within 30 min. Similarly, the formation of 2-aminothiazole (Figure 3b) and 3-phenylquinazolin-4-one (Figure 3c) further demonstrates the broad applicability of ILs in heterocyclic compound synthesis. Based on our literature analysis, this behavior is unprecedented. Furthermore, [BCMAB][2Cl] may be made in two easy and effective steps using easily accessible starting ingredients (p-phenylenediamine 1 and chloroacetic acid 2), and the preparation can be done on a multigram scale (Scheme 1).

Synthesis of 1,4-bis(carboxymethyl)benzene-1,4-diaminium chloride ([BCMAB][2Cl]) (4). p-Phenylenediamine (1) and chloroacetic acid (2) are reacted to form an intermediate (3), which is then acidified with concentrated HCl to produce the final product (4).

Representative examples of IL structures, showcasing diverse cation and anion combinations.

Route for the synthesis of various heterocyclic compounds using ILs as catalysts. Parts (a–c) represent previous work, while (d) describes the modified Biginelli condensation reaction developed in this study.

The synthesis of tetrahydropyrimidine-5-carboxylate derivatives from the Biginelli reaction associated with pyrimidine is reported in this article. Multiple reactions were conducted using an acid catalyst made of recyclable ILs to obtain title compounds (4a-k) that comply with the scheme shown to obtain the desired biological activities. Figure 1 illustrates the chemical structures and biological activities of previously reported bioactive pharmaceutical compounds containing the tetrahydropyrimidine-5-carboxylate moiety.

This report presents the unique synthesis and application of a new solid IL catalyst, 1,4-bis(carboxymethyl)benzene-1,4-diamine chloride ([BCMAB][2Cl]), for the synthesis of tetrahydropyrimidine-5-carboxylate derivatives via a MCR. Unlike conventional IL catalysts, [BCMAB][2Cl] is solid at room temperature, making it easier to separate and recover from the reaction mixture [26]. In addition, this catalyst operates without the need for a support system, which is very different from previously reported heterogeneous organocatalysts.[27] Within the scope of our investigation, the application of this specific IL as a catalyst for Biginelli, Hantzsch, and Niementowski reactions is unprecedented. Compared to other ILs tested, [BCMAB][2Cl] exhibited superior catalytic activity, achieving high yields under mild reaction conditions. This catalyst also exhibited excellent reusability, in line with the principles of green chemistry, and provided a sustainable alternative to conventional catalytic systems.[28] The synthetic route to [BCMAB][2Cl] is simple and straightforward, using readily available starting materials, which further enhances its practical applicability. Recent studies have demonstrated that ILs can be effectively used as catalysts for various organic syntheses, including the Biginelli reaction for the synthesis of DHPM derivatives.[27,29] The use of ILs as catalysts in MCRs has attracted attention due to their potential to improve reaction efficiency and selectivity while adhering to the principles of green chemistry.[27,28]

2. Materials and Methods

2.1. General

All chemical compounds have been purchased from widely accessible commercial sources and were used without undergoing additional purification. Silica gel 60 F254-coated thin-layer chromatography (TLC) plates (Merck) were employed to track the completion of the reaction. Melting points were measured using the open capillary tube method with Stuart’s (SMP30) apparatus and were uncorrected. Structure confirmation of synthesized compounds, ILs, and bovine serum albumin (BSA) were examined spectroscopic characterization like UV recorded using a Shimadzu UV-visible spectrophotometer, IR spectra were recorded on PerkinElmer spectrum (version 10.4.00) spectrophotometer and the JEOL 400 MHz frequency spectrometer was used to record the ¹H NMR and ¹³C NMR spectral studies, using tetramethyl silane (TMS) as reference. Thermogravimetric and morphological analysis, like thermogravimetric analysis/ differential scanning calorimetry (TGA/DSC), P-XRD, and SEM with EDX, were used to investigate the synthesis of the (IL) catalyst.

2.2. Motivation and outreach strategy

A new approach was developed for synthesizing heterocyclic compounds like 1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives that employ simple amino benzenaminium [BCMAB][2Cl] ILs as catalysts (Scheme 1). These ILs have gained attention for their unique physicochemical properties, such as low vapor pressure, non-flammability, and easy product isolation. They are also recyclable and recoverable, making them suitable for further use in subsequent reactions. The aim is to incorporate metal-free synthesis and maintain the environmental sustainability of these materials. The method aims to promote cleaner and greener technologies for synthesizing heterocyclic compounds.

Here, we report the one-pot MCRs to synthesize heterocyclic compounds using simple amino benzenaminium [ILs]. In MCRs, the combination of three or more versatile components in a single-pot reaction leads to the formation of complex structures through the simultaneous formation of two or more bonds [30]. Adding to their ecological credentials are the unique advantages of MCRs, which incorporate sustainable, eco-friendly approaches that reduce the number of synthetic steps and utilize waste-free techniques. This study successfully synthesizes some new biologically significant 1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives using a simple aminobenzenaminium-based IL (Scheme 2).

Synthesis of 1,2,3,4-tetrahydropyrimidine-5-carboxylates 4a-k via the Biginelli reaction catalyzed by [BCMAB][2Cl]. aReaction Conditions: urea/thiourea (1 mmol), methyl acetoacetate (1 mmol), substituted aromatic/heterocylic aldehydes (1 mmol), ILs (8 mol%). bYield denotes to isolated yields.

2.3. Experimental section

2.3.1. Preparation of ILs salt, 1,4-bis(carboxymethyl)benzene-1,4-diaminium chloride [BCMAB][2Cl].

A modified version of the previously published methodology was used to synthesize the ILs [31,32]. To prepare the ILs, 200 mL of acetonitrile solvent was used to dissolve 1.62 g of p-phenylenediamine 1 (1.0 equiv. 0.15 mol) and 2.05 g of chloroacetic acid (2.0 equiv. 0.30 mol) in a 500 mL RB flask. NaOH (0.86 g, 1.2 equivalents, 0.18 mol) was added to the reaction mixture. A reflux condenser was used to maintain the reaction at 120°C for 18 hrs. Once the reaction was complete, the mixture was allowed to cool before the salt was filtered. In the rota evaporator, the filtrate volume was reduced by the lower pressure, producing liquid intermediate 3 (35.2 g, 97% yield). After treating intermediate 3 for 24 hrs. in RT with cold concentrated HCl (37%), crude solid crystal ionic salt 4 was produced. The final 1,4-bis(carboxymethyl)benzene-1,4-diaminium chloride [BCMAB][2Cl] ILs salt is depicted in Scheme 1 after additional washing with dichloromethane and ether. IL salt [BCMAB][2Cl] (32.8 g, 94% yield) was obtained. Using spectral analysis techniques such as ¹H NMR, ¹³C NMR, and IR, the products were characterized and determined to be identical to those reported in the literature [33–40], and thermal & morphological analyses, like powder-XRD, TGA/DSC, and SEM with EDX, were studied.

2.3.2. Synthesis of modified Biginelli products (4a-k)

A reaction mixture of substituted heterocyclic aldehyde (1 mmol), methyl acetoacetate (1 mmol), and urea/thiourea (1 mmol) was treated with 8 mol% of [BCMAB][2Cl] catalyst. The mixture was refluxed at 60°C with continuous stirring. The reaction progress was monitored using TLC with a benzene:chloroform (6:4) solvent system. Upon completion, the reaction mixture was allowed to cool to room temperature and poured into 20 mL of cold water. The resulting yellow precipitate was collected via filtration. The crude product was purified through recrystallization from hot ethanol, yielding pure 1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-k) (Scheme 2). The structures of the synthesized compounds were confirmed through ¹H and ¹³C NMR spectroscopy.

2.3.3. Spectral data of synthesized compound

The Supplementary Information provides a comprehensive set of spectral data and elemental analyses for all heterocycles, [33-40] including those previously reported.

Supplementary Information

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2.4. Biological activity

2.4.1. Reagents

BSA (Sigma-Aldrich) was solubilized in a 20 mM sodium phosphate buffer at pH 7.4 to prepare a 3 µM stock solution. Compounds 4a, 4gc, and 4i were synthesized in the laboratory and made into a 1 mM solution using distilled water. All experiments were performed using double-distilled water and analytical-grade chemicals.

2.4.2. Ultraviolet-visible (UV-vis) absorption spectroscopy

UV-visible absorption spectra of a 5 µM BSA solution were obtained using a Shimadzu UV-visible spectrophotometer. Spectra were collected across a wavelength range of 200-450 nm. To investigate the interaction between BSA and the compounds, increasing concentrations of 4a, 4g, and 4i (0-15 µM) were added to the BSA solution under ambient conditions.

2.4.3. Fluorescence measurement

Fluorescence measurements were carried out at 298 K, 303 K, and 308 K. BSA solutions were prepared in the presence and absence of compounds 4a, 4g, and 4i. Excitation at 280 nm was used to record emission spectra from 290 to 450 nm. For excitation and emission, a 1 cm quartz cuvette with 5 nm slit widths was used.

2.5. Molecular docking

Protein databases were used to obtain the crystallographic data of BSA (4F5S), which was then treated to exclude non-significant molecules and water. Point charges and hydrogenation charges were determined for the protein’s crystallographic structure. AutoDock 4.2 Tools were used to generate a useful docking space, and Discovery Studio Visualizer was utilized to simulate BSA’s microenvironment. Molecular docking was performed on a grid map with 120 × 120 × 120 points spaced 0.375 Å apart. Considering the geometry, the most favorable molecular docking conformations were generated after 100 GA runs following the lowest energy docked structure. The Venn diagram, constructed using Venny 2.1 software, visualized the shared and unique amino acids among the three compounds [41]. This analysis facilitated the identification of common residues crucial for binding and unique residues specific to individual compounds. Comparing these interactions improved our understanding of the binding modes and compound-specific interactions.

3. Results and Discussion

3.1. Chemistry

The product of the Biginelli reaction, methyl 6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, was produced through the condensation of heterocyclic aldehyde 1, methyl acetoacetate 2, and urea 3 using an IL acid catalyst 4 (8 mol%) under reaction conditions at 60°C, as depicted in Scheme 2. Synthesized all expected substituted tetrahydropyrimidine-5-carboxylate (4a-k) compounds have been obtained at different temperatures, solvents, and ILs catalysts that were previously listed. The 4a-k compound series takes a longer time, a larger amount of catalyst, and a trace yield. In this article, when ILs [BCMAB][2Cl] were tested as the catalyst by applying a lower amount (8 mol%) and refluxing with ethanol at 60°C, 4a-k were 98% rapidly formed in a shorter time. The substituted title compound structures were verified by using spectrometry and elemental analysis, IR, ¹H, and ¹³C NMR, as mentioned in the supplementary information (SI) and in Scheme 2. A representation of a chemical compound, illustrating its molecular structure and functional groups in Figure 4.

Molecular structure of a chemical compound, highlighting its functional groups.

The IL salt [BCMAB][2Cl] catalyst 4 was prepared according to the modified method by the simple addition method of p-phenylenediamine with the appropriate chloroacetic acid. Structural details of the final compound were characterized by different physicochemical and morphological analyses, such as Fourier transform-infrared (FT-IR), Powder-XRD, TGA/DSC, and SEM with EDX. The structures and details of the title compounds are listed in Scheme 2, which summarizes the substrate scope of the Biginelli condensation products. The reaction was catalyzed by the IL [BCMAB][2Cl] and employed different heterocyclic aldehyde substrates (1.0 mmol), urea (1.0 mmol), methyl acetoacetate (1.0 mmol), and catalyst (8 wt% of the reaction mixture) under reflux conditions.

3.2. Optimizing reaction conditions

Using [BCMAB][2Cl] as a catalyst and a range of reaction settings, we experimented with benzaldehyde (1, 1 mmol), ethyl acetoacetate (2, 1 mmol), and urea (3, 1 mmol) to optimize the reaction conditions. (Table 1).

Optimizing a process to run at room temperature is our first goal; however, room temperature yields were lower than desired for this reaction. As a result, we varied the catalyst concentrations and reaction times while conducting the reactions at 60°C to 100°C. The highest results were achieved with 8 mol% of [BCMAB][2Cl] after 60 mins (Table 1) as compared to other reaction conditions and catalysts[15,32,40,42–48]. Additionally, the reaction was tuned with various solvents; however, in the solvent-free state, we obtained the crude product, while on workup, we obtained the sticky product (excluding DMF, which is laborious to handle). The targeted compounds (4a-k) were synthesized from aromatic/heterocyclic aldehyde (1, 1 mmol), ketoester (2a–2e, 1 mmol), and urea/thiourea (3a-3b, 1 mmol) utilizing [BCMAB][2Cl] (8 mol%) as a catalyst and ethanol used as a solvent. The reaction takes an average of 60–90 mins. to complete. Spectral analysis was used to confirm the structures of the synthesized compound. Spectral data are available in the supplementary materials.

3.3. Catalytic evaluation

The efficacy of the catalyst was evaluated by its ability to catalyze the three-component condensation of urea, methyl acetoacetate, and benzaldehyde in ethanol at reflux temperature. The experimental details have been provided in Scheme 2. Following a 25-min reaction and reaction mixture workup, the product was separated with 98% yield at a 10 mmol scale. The identical reaction was carried out with six other catalysts for comparison, and the results are summarized in Table 2. The comparative analysis presented in Table 2 demonstrates [BCMAB][2Cl] as a highly efficient catalyst for the Biginelli reaction, achieving a 98% yield within 25 min, significantly surpassing the performance of other catalysts, which exhibited lower yields and longer reaction times.

3.4. Effect of solvent

Here, to determine the optimal response condition shown in Table 3, we analyzed and investigated how the solvent affected the Biginelli reaction. Acetonitrile was the most practical solvent (entry 3), but the product yield was 40%, and the toluene yield was also rather high (entry 2). This is most likely because acetonitrile has a boiling point of 82°C, while toluene has a substantially higher boiling point of 112°C. Remarkably, the reaction carried out in a solvent-free medium at 60°C for 20 hrs. (Table 3, entry 1) produced the product with a yield of 52%. It seems like the solvent’s coordination at the cation’s coordination sphere controls the catalyst activity, increasing the product yield. Ultimately, the final factor required to enhance the reaction conditions was the impact of catalyst quantity on product yield (Table 3). The influence of catalyst quantity on product yield (Table 3) was the final parameter required to optimize the reaction environment.

Table 3. The impact of the solvent on the model reaction of 1,2,3,4-THPM 4a-k yield.

Entry	Solvent	Temperature (°C)	Time (hrs.)	Yield (%)
1.	Neat	60	20	52
2.	Toluene	60	25	56
3.	CH₃CN	60	10	40
4.	THF	60	2	38
5.	DMSO	60	12	35
6.	CH3OH	60	12	40
7.	EtOH	rt	24	52
8.	EtOH	60	0.25	98

^a Reflux temperature; rt; room temperature

^b 100°C, solvent less media.

^c Isolated yield.

3.5. Plausible mechanism of the reaction: Catalytic mechanism

The proposed Biginelli condensation reaction mechanism for the one-pot multicomponent synthesis of 1,2,3,4-tetrahydropyrimidine derivatives using [BCMAB][2Cl] ILs has been outlined in Figure 5, referencing established literature [51]. Initially, the catalyst facilitates the activation of the heterocyclic aldehyde, followed by nucleophilic addition of urea or thiourea, leading to the formation of the N-acylimine intermediate. Subsequently, this intermediate reacts with ethyl acetoacetate enolate to form an open-chain ureide intermediate, followed by intramolecular cyclization. Finally, aromatization of the tetrahydropyrimidinone under an air atmosphere leads to the desired 1,2,3,4-tetrahydropyrimidin-2-one/thiones. As a result, a condensation reaction occurs, forming compound A. In this step, the activated aldehyde undergoes a Michael addition with A to generate intermediate B. After that, NH₂CONH₂ attacks B’s nucleophiles, which starts a cyclization process that gets rid of water molecules and makes the final product P [52].

Possible mechanism and role of IL catalysts in the formation of 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid derivatives.

3.6. Sustainability metrics in Biginelli condensation reaction

The E-factor measures the amount of waste generated per unit of product, with a lower value indicating a more sustainable process. For the Biginelli condensation reaction, the E-factor is 7.7, suggesting moderate waste production. Process Mass Intensity (PMI) quantifies the mass of raw materials used relative to the mass of the desired product. The calculated PMI is 8.7, reflecting the ratio of reactive and non-reactive materials used. Improving material efficiency by reducing excess reagents and solvents could lower the PMI. Reaction Mass Efficiency (RME) assesses how effectively reactants are converted into the final product, excluding solvents and by-products. With an RME of 63.9%, there is room for improvement by optimizing reaction conditions to minimize side reactions and excess materials. Atom Economy (AE = Molar mass of desired product/Total molar mass of all reactants x 100) evaluates how well the atoms from reactants contribute to the final product, with a higher AE indicating a greener process. The Atom Economy for this reaction is 75.1%, which could be increased by streamlining reaction steps and reducing by-products. Carbon Efficiency (CE) measures the proportion of carbon atoms from reactants that are incorporated into the final product, with a value of 77.8%. Efforts to optimize reaction pathways and minimize unnecessary carbon-based waste could enhance this efficiency.

3.7. Recyclability of ILs catalyst

It was discovered that, offered appropriate conditions, the catalyst ILs [BCMAB][2Cl] could be recycled and utilized again at different points following the completion of the condensation processes of methyl acetoacetate, urea/thiourea, and heterocyclic aldehydes (4a-k) in ethanol. After the reaction, the resulting mixture was filtered, mixed with ether, then washed with hexane in a separate beaker to create pure ILs for use in the model process. After that, ether and dichloromethane (DCM) were used to clean the reaction vessel. The catalyst’s ionic nature made it insoluble in dichloromethane and ether. Without any additional treatment, it was recycled and used it six times for specific model reactions. Finally, Table 4 shows that there is no significant loss in catalytic activity. Even after six recycling cycles, no characteristic structural changes were observed, indicating that the IL catalyst’s chemical structure and crystalline phase remained unaltered. This supports its recyclability and confirms the stability of the [BCMAB][2Cl] catalyst under the reaction conditions.

Table 4. Reusability of [BCMAB][2Cl] ILs catalyst for the reaction between heterocyclic aldehyde, methylacetoacetate, and urea/thiourea.

Run	Time (min.)	Yield (%)
1.	10	95
2.	13	94
3.	16	93
4.	16	93
5.	18	92
6.	20	90

3.8. Characterization of [BCMAB][2Cl] ILs catalyst.

Herein, [BCMAB][2Cl] IL salt catalyst is synthesized by the modified previously reported procedure [53] (Scheme 1). Various characterization techniques, including FT-IR, Thermal Gravimetric Analysis/Differential Scanning Calorimetry (TGA/DSC), Powder X-ray Diffraction (PXRD), and Scanning Electron Microscopy (SEM), were employed to evaluate the characterization of IL catalysts.

3.8.1. Fourier transform infrared (FT-IR) analysis

FT-IR spectra of ILs [BCMAB][2Cl] catalyst: significant bands at 1754 and 1406 cm⁻¹ corresponded to C=O and O-H bending, while bands appearing at 3124 cm⁻¹ in the FT-IR spectra of ILs (Figure 6) were caused by the C–H and N–H stretching vibrations of the p-phenylenediamine. The stretching vibration of the alkyl chain’s C=C bond was attributed to the band that appeared at 2012 cm⁻¹, while the bands at 1068 cm⁻¹ and 686 cm⁻¹ were related to the C=C bond of the phenyl amine ring and the stretching mode [54].

FT-IR spectrum of ILs catalyst [BCMAB][2Cl].

3.8.2. Powder-X-ray diffraction (XRD) analysis

From the PXRD calculation and the percentage of crystalline nature of compounds, they may be amorphous and crystalline. In order of characterization techniques, the PXRD spectrum of IL [BCMAB][2Cl] catalyst has been shown in Figure 7. Here, characteristic sharp peaks 2θ at 23° to 32° appeared and were distributed in the range of 2θ from 5° to 70°. The intense peak at 32.5 degrees 2θ is attributed to ordered aromatic ring packing, indicating a preferred orientation within the crystal. The peak near 22.5 degrees 2θ indicates a lamellar arrangement, reflecting the repeating distances of the organic cations and counterions. Peaks at larger angles, such as those near 45, 52, and 58 degrees 2θ, correspond to smaller d-spacings, representing specific interatomic distances and bond orientations within the lattice. Peaks at lower and higher angles provide information about interlayer spacing and specific interatomic distances within the crystal lattice, respectively. In general, ILs are usually amorphous, whereas [BCMAB][2Cl] is a solid ionic compound (ionic salt) with partial crystallinity. The sharp peaks in the XRD pattern confirm its crystalline nature, representing specific crystal planes and ordered structure.

PXRD pattern of [BCMAB][2Cl] IL catalyst.

3.8.3. TGA analysis

Thermogravimetric analyses demonstrated the presence of an IL catalyst [BCMAB][2Cl] in Figure 8. The oxidative breakdown of the organic moieties in the ILs caused them to exhibit their initial weight loss in the TGA curve at 355°C [55]. Due to the evaporation of absorbed moisture, the first weight loss in the [BCMAB][2Cl] instance began between 200 and 355°C. The catalyst is far more stable, as thermogravimetric measurements clearly show. The N–C bonds from piperazine-based ILs are responsible for the stability since they improved the catalyst’s thermal stability and allowed it to remain stable even when temperatures reach 400°C.

3.8.4. SEM analysis with EDX

SEM analysis was used to investigate the morphology of the ionic salt catalyst [BCMAB][2Cl] (Figure 9a). It illustrates how IL’s surface shape is impregnated on its surface. The SEM image of [BCMAB][2Cl] showed that the IL particles were consistently dispersed, indicating that the desired material had been formed. Subsequently, the presence of each element in the generated catalyst was ascertained using EDX analysis (Figure 9b). The elements of C, H, O, N, and Cl in the EDX spectrum confirmed the structural integrity of [BCMAB][2Cl]. The EDX spectrum’s strong peak at 0 KeV was caused by noise in the acquisition circuitry of the EDX spectrometer detector [56].

(a) SEM images and (b) EDX of ILs catalyst [BCMAB][2Cl].

3.9. Biological evaluation of 1,2,3,4 tetrahydropyrimidine-5-carboxylate derivatives

3.9.1. UV–visible (UV-vis) spectroscopic studies

UV-vis absorption spectroscopy is a widely used and practical method to investigate the interactions between small compounds and proteins [57]. In the absorption spectra of BSA, three aromatic amino acids display bands around 280 nm due to combined absorption and electron transfer [58]. When analyzed individually, 4a, 4g, and 4i show absorption peaks at approximately 282 nm, 265 nm, and 353 nm, respectively (Figure 10). Figure 11(a-c) illustrates BSA absorption spectra with varying concentrations of 4a, 4g, and 4i. As the concentrations of 4a, 4g, and 4i increased, the UV-vis spectra of BSA also increased, suggesting the formation of new complexes BSA-4a, BSA-4g, and BSA-4i.

The UV-vis spectra of BSA and all three compounds 4a, 4g, and 4i.

The UV-vis spectra of BSA (5.0 × 10−6 M) with increasing concentrations (0 to 15 × 10−6 M) of (a) 4a, (b) 4g, and (c) 4i. Fluorescence quenching of BSA in the presence of (d) 4a, (e) 4g, and (f) 4i, with the same parameters as that of the absorption spectra.

3.9.2. Fluorescence quenching and binding characteristics

Upon excitation at 280 nm, BSA exhibited a strong fluorescence emission peak at 336 nm [59]. However, upon gradually adding 4a, 4g, and 4i to the BSA solution, the fluorescence intensity decreased, and the peak shifted to 334 nm (Figure 11d-f). The intrinsic fluorescence of BSA is primarily attributed to tryptophan, tyrosine, and phenylalanine amino acids. The fluorescence emission at 336 nm is attributed to the Trp (tryptophan) residues within BSA, accounting for its characteristic fluorescence. The results indicated that 4a, 4g, and 4i led to the quenching of BSA fluorescence, resulting in blue shifts and increased hydrophobicity around the Trp residues. “Fluorescence quenching” refers to any process that reduces the sample’s fluorescence, which can be caused by various molecular interactions, including collisional quenching, the formation of ground-state complexes, energy transfer, molecular rearrangements, and reactions occurring in excited states [60].

The Stern-Volmer Eq. (1) was used to assess the quenching data for drug and protein binding [61]:

(1)

\frac{F_{0}}{F} = 1 + K_{q} {\ddot{A}}_{0} [Q] = 1 + K_{SV} [Q]

F denotes the fluorescence intensity of the protein in the presence of the quencher, whereas F₀ represents the fluorescence intensity in its absence. [Q] corresponds to the quencher’s concentration, with Ksv indicating the Stern-Volmer quenching constant and Kq representing the bimolecular quenching rate constant. The fluorescence lifetime of the fluorophore, τ₀, is approximately 10⁻⁹ s. Using Eq. (2), the calculated Kq value exceeds the upper limit typically reported for collisional quenching [62].

(2)

K_{q} = \frac{K_{SV}}{{\ddot{A}}_{0}}

Figure 12(a-c) illustrates Stern-Volmer plots for the BSA-4a, BSA-4g, and BSA-4i complexes, which were analyzed as a function of temperature. The values of K_q and K_sv have been presented in Table 5. The data revealed a decline in both the quenching constant (Ksv) and the quenching rate constant (Kq) with increasing temperature. Additionally, the Kq values were notably higher than the upper limit of the dynamic quenching collision rate constant (2 × 10¹⁰ L mol⁻¹ s⁻¹). The findings from the Stern-Volmer investigation suggested that BSA was quenched by each of the compounds 4a, 4g, and 4i through a static quenching process.

The modified Stern–Volmer plots for (a) BSA-4a, (b) BSA-4g, and (c) BSA-4i at three different temperatures, 298 K, 303 K, and 308 K. The plot of log (F0 – F)/F as a function of (d) log [4a], (e) log [4g], and (f) log [4i] for the determination of the binding constants (Kb) and the number of binding sites (n).

Table 5. The Stern-Volmer quenching constant K_sv and the quenching rate constants K_q of BSA-4a, BSA-4g, and BSA-4i complexes at different temperatures.

Complex	Temperature (K)	K_sv (x 10⁴ L mol^-1)	K_q (x 10¹³ mol^-1s^-1)	r^*
BSA-4a	298	2.90	2.90	0.9998
	303	1.59	1.59	0.9997
	308	0.91	0.91	0.9995
BSA-4g	298	1.04	1.04	0.9998
	303	0.76	0.76	0.9997
	308	0.43	0.43	0.9999
BSA-4i	298	2.53	2.53	0.9998
	303	1.47	1.47	0.9999
	308	1.01	1.01	0.9999

* Regression coefficient.

3.9.3. Binding parameters

For the determination of binding constants (Kb) and the number of binding sites (n) in the case of static quenching, an enhanced Eq. (3) was employed [63,64]:

(3)

log \frac{(F_{0} - F)}{F} = {log K}_{b} + n \log [Q]

K_b signifies the binding constant, while n signifies the number of binding sites. The concentration of the compounds (4a, 4g, or 4i) is represented by [Q]. A double logarithmic plot was utilized to calculate the values of Kb and n (Figure 12(d-f); the results are depicted in Table 6. As the temperature increased, the binding constants showed the following trend: K_b (298 K) > K_b (303 K) > K_b (308 K). This observation further supports the notion that quenching of BSA by each compound (4a, 4g, or 4i) occurred through a static mechanism [65,66].

Table 6. The binding constants (K_b) and number of binding sites (n) of BSA in presence of 4a, 4g, and 4i at various temperatures.

Complex	Temperature (K)	K_b (10⁶ L mol^-1)	n	r^*
BSA-4a	298	5.02	1.07	0.9953
	303	4.41	1.01	0.9991
	308	3.76	0.99	0.9964
BSA-4g	298	3.97	1.02	0.9951
	303	2.90	0.97	0.9891
	308	2.54	0.96	0.9990
BSA-4i	298	4.6	1.10	0.9978
	303	3.9	1.08	0.9989
	308	3.2	0.98	0.9798

* Regression coefficient.

3.10. Molecular docking

Molecular docking technology was employed to validate the experiments, simulating the binding of 4a, 4g, and 4i to BSA [66]. This approach helped to understand the binding domains of the ligands and validate the optimal docking energy model with BSA [67]. Figure 13 displays the molecular docking of 4a, 4g, and 4i with BSA, revealing that subdomain IIA of drug binding site I (Sudlow’s binding site I) on BSA was the binding site for all three compounds. The figure also illustrates the proximity of amino acid residues TRP213, ARG217, LEU237, HIS241, ARG198, ARG194, SER191, GLU152, TYR156, HIS287, ALA290, ARG256, and TYR149, which interacted with 4a, 4g, and 4i. The binding energies of BSA with 4a, 4g, and 4i were found to be -16.8 kcal mol^-1, -15.3 kcal mol^-1, and -16.5 kcal mol^-1, respectively. These docking results closely align with the experimental outcomes. Table 7 details the specific amino acids participating in non-bonding interactions with compounds 4a, 4g, and 4i.

illustrates the interaction of compounds 4a, 4g, and 4i with BSA (PDB ID: 4F5S). The BSA structure is highlighted as a red ribbon, while the ball-and-stick representations within the circled regions indicate the docked positions of (a) 4a, (c) 4g, and (e) 4i. Panels (b), (d), and (f) provide detailed snapshots of the BSA-4a, BSA-4g, and BSA-4i complexes, respectively, highlighting the residues involved in these interactions.

Table 7. Non-bonding interactions between compounds 4a, 4g, and 4i and amino acids, including hydrophobic interactions, hydrogen bonds, and salt bridges/π interactions, highlighting the potential binding mechanisms.

Compd.	Hydrophobic interactions		Hydrogen bonds		Salt bridges/pi
Compd.	Amino acid	Distance Å	Amino acid	Distance (D-A) Å	Amino acid	Distance Å
4a	TRP213, ALA290	3.11, 2.85	ARG256, ARG256, TYR149, ARG198, HIS287	2.54, 2.84, 2.67, 2.54, 2.71	ARG198, ARG198	3.66,4.94
4g	TRP213, ALA290	2.93, 2.93	TYR149, TYR156, ARG256,	2.60 3.09, 3.36	ARG198, ARG217, GLU152, ARG198	3.64,3.37, 3.44,3.36
4i	TYR149, LEU237, LEU237, ALA290,	3.47,3.14, 3.04, 3.44	GLU152, SER191, ARG198	4.03, 2.35, 2.35	HIS287, ARG198	4.62, 4.45

The important amino acids involved in non-bonded interactions were identified through molecular docking analysis of compounds 4a, 4g, and 4i with BSA. These amino acids were used to construct a Venn diagram (Figure 14) to classify and compare the amino acid residues involved in binding interactions among the three compounds. Each circle in the Venn diagram represents a compound, while the overlapping area indicates the common amino acid residues involved in the docking interaction. The central region of the graph shows that 13 amino acid residues are common among the three compounds, accounting for 81.3% of the observed interactions. Examples of these residues include TRP A:213, ARG A:217, and TYR A:156, suggesting that a conserved binding region within BSA is critical for ligand interaction. These residues may represent hydrophobic or energetically favorable binding sites on the receptor. Each compound also exhibited unique interactions: Compound 4g interacted with an additional residue (LEU A:237) specific to its binding mode. Compound 4i similarly interacted with a unique residue (GLN A:195). Unique interactions highlight subtle differences in binding preferences and affinities between compounds. Unlike 4g and 4i, compound 4a did not display any amino acid residues exclusive to its interactions, suggesting that its binding may align primarily with conserved residues. These results highlight that all three compounds bind similarly to conserved residues in the BSA receptor, likely in its hydrophobic pocket, but their unique interactions suggest slightly different orientations or microenvironmental preferences. This could affect their binding strength, specificity, or bioavailability. The findings suggest that while the binding of compounds 4a, 4g, and 4i to BSA is driven by a common set of key residues, subtle differences in their interaction profiles may contribute to differences in their bioactivity or trafficking efficiency.

Venn diagram showing shared and unique amino acid residues involved in binding compounds 4a, 4g, and 4i to BSA from molecular docking studies, with 13 conserved residues and distinct interactions for compounds 4g and 4i.

4. Conclusions

As a conclusion, we report that the synthesis of bioactive 1,2,3,4-tetrahydropyrimidine via a Biginelli MCR can be achieved with ease, efficiency, and ecologic sustainability using simple ILs (ILs) [BCMAB][2Cl]. Some significant advantages of this protocol: (I) The synthesis of 1,2,3,4-tetrahydropyrimidine was found to be highly efficient and selective in the presence of (ILs). The Biginelli condensation reaction demonstrated excellent alignment with green chemistry principles, as reflected by its favorable metrics: process mass intensity of 8.7, an E-factor of 7.7, reaction mass efficiency of 63.9%, atom economy of 75.1%, and CE of 77.8%. Furthermore, the method utilized readily available starting materials, exhibited high functional group compatibility, enabled a straightforward one-pot sequential transformation, and employed an IL catalyst that was easily recoverable and reusable for at least four consecutive cycles. The stability of the synthesized 1,2,3,4-tetrahydropyrimidine derivatives and ILs was verified through a range of spectroscopic and physicochemical techniques, including FT-IR, Powder-XRD, TGA/DTA, NMR, and SEM analyses. Furthermore, this approach may be beneficial for synthesizing an architecture relevant to pharmaceuticals and for widespread organic transformations. In the docking study, compound 4a has excellent binding energies of BSA, found to be -16.8 kcal mol-1, and compounds 4g & 4i have -15.3 kcal mol^-1 -16.5 kcal mol^-1, respectively. Further insights into the interaction of docked compounds show excellent binding capacity with BSA (PBD ID 4F5S).

Acknowledgment

The authors are grateful to Global College of Engineering and Technology, Muscat, Oman for providing funding for the open access publication of this paper.

CRediT authorship contribution statement

Avadhesh Kumar: Literature search, experimental studies, data analysis. Uzma: Methodology, data analysis, literature search, manuscript preparation. Suad Al Kindi: Concepts, validation, literature search, data analysis. Mohd Amir: Experimental studies, data acquisition, data analysis, manuscript preparation. S N Hejaz Azmi: Manuscript editing and review, data analysis, statistical analysis. Saleem Javed: Experimental studies, data analysis, manuscript preparation. Mehtab Parveen: Manuscript editing and review, data analysis, experimental studies, validation, research conducted under the supervision. Mahboob Alam: Data analysis, design, manuscript editing and review, software.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Supplementary data

Supplementary material to this article can be found online at https://dx.doi.org/10.25259/AJC_267_2024.

References

Sharma V., Chitranshi N., Agarwal A.K.. Significance and biological importance of pyrimidine in the microbial world. International Journal of Medicinal Chemistry. 2014;2014:202784. https://doi.org/10.1155/2014/202784
[Google Scholar]
Menor-Salván C., ésar, Marín-Yaseli M.R.. Prebiotic chemistry in eutectic solutions at the water–ice matrix. Chemical Society Reviews. 2012;41:5404. https://doi.org/10.1039/c2cs35060b
[Google Scholar]
Quin L.D., Tyrell J.A.. Fundamentals of heterocyclic chemistry: Importance in nature and in the synthesis of pharmaceuticals. John Wiley & Sons; 2010. ISBN: 978-0-470-62653-5
Pozharskii A.F., Soldatenkov A.T., Katritzky A.R.. Heterocycles in life and society: an introduction to heterocyclic chemistry, biochemistry and applications (2nd ed.). John Wiley & Sons; 2011. https://doi.org/10.1002/9781119998372
Kaur S., Kumari P., Singh G., Bhatti R., Singh P.. Design and synthesis of Aza-/Oxa heterocycle-based conjugates as novel anti-inflammatory agents targeting cyclooxygenase-2. ACS Omega. 2018;3:5825-5845. https://doi.org/10.1021/acsomega.8b00445
[Google Scholar]
Zhang Y., Wang B., Zhang X., Huang J., Liu C.. An efficient synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and thiones catalyzed by a novel Brønsted acidic ionic liquid under solvent-free conditions. Molecules (Basel, Switzerland). 2015;20:3811-3820. https://doi.org/10.3390/molecules20033811
[Google Scholar]
Mushtaq A., Munawar A., Parveen B., Javed S., Zahoor A.F., Ali K.G., Mansha A., Irfan A.. Recent advances in the synthesis of dihydropyrimidinones via biginelli reaction. J. Iran. Chem. Soc.. 2024;21:2565-2586. https://doi.org/10.1007/s13738-024-03100-z
[Google Scholar]
Melo M.F.F., Da Silva B.A., Mukherjee R.. Spasmolytic actions of the new indole alkaloid Trinervine from Strychnos trinervis root. Phytomedicine. 1994;1:205-207. https://doi.org/10.1016/S0944-7113(11)80066-8
[Google Scholar]
Diao P.C., Li Q., Hu M.J., Ma Y.F., You W.W., Hong K.H., Zhao P.L.. Synthesis and biological evaluation of novel indole-pyrimidine hybrids bearing morpholine and thiomorpholine moieties. European Journal of Medicinal Chemistry. 2017;134:110-118. https://doi.org/10.1016/j.ejmech.2017.04.011
[Google Scholar]
Wender P.A.. Toward the ideal synthesis and molecular function through synthesis-informed design. Natural Product Reports. 2014;31:433-440. https://doi.org/10.1039/c4np00013g
[Google Scholar]
Zhu J., Bienaymé H., eds. Multicomponent Reactions. John Wiley & Sons; 2005. ISBN: 978-3-527-60511-8
Parveen M., Uzma, Azam M., Azeem M., Aslam A., Bashir M., Alam M.. Catalytic activity of TiO2 nanoparticles in cyclization reactions for pyrazolone formation: DNA binding analysis via spectroscopy, X-ray crystallography, and molecular docking. Journal of Saudi Chemical Society. 2024;28:101881. https://doi.org/10.1016/j.jscs.2024.101881
[Google Scholar]
Zhu Y.‐Lin, Huang S.‐Lin, Pan Y.‐Jiang. Highly chemoselective multicomponent Biginelli‐type condensations of cycloalkanones, urea or thiourea and aldehydes. European Journal of Organic Chemistry. 2005;2005:2354-2367. https://doi.org/10.1002/ejoc.200400845
[Google Scholar]
Marzabadi M.R., Hong X., Nagarathnam D., Miao S.W., Chiu G., Wong W.C., Wetzel J.M., Fang J., Forray C., Chen T.B., O.’Malley S.S., Chang R.S., Gluchowski C.. Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorganic & Medicinal Chemistry Letters. 1999;9:2843-2848. https://doi.org/10.1016/s0960-894x(99)00484-9
[Google Scholar]
Rovnyak G.C., Kimball S.D., Beyer B., Cucinotta G., DiMarco J.D., Gougoutas J., Hedberg A., Malley M., McCarthy J.P., Zhang R.. Calcium entry blockers and activators: Conformational and structural determinants of dihydropyrimidine calcium channel modulators. Journal of Medicinal Chemistry. 1995;38:119-129. https://doi.org/10.1021/jm00001a017
[Google Scholar]
Dallinger D., Stadler A., Kappe C.O.. Solid- and solution-phase synthesis of bioactive dihydropyrimidines. Pure and Applied Chemistry. 2004;76:1017-1024. https://doi.org/10.1351/pac200476051017
[Google Scholar]
Sujatha K., Shanmugam P., Perumal P.T., Muralidharan D., Rajendran M.. Synthesis and cardiac effects of 3,4-dihydropyrimidin-2(1H)-one-5 carboxylates. Bioorganic & Medicinal Chemistry Letters. 2006;16:4893-4897. https://doi.org/10.1016/j.bmcl.2006.06.059
[Google Scholar]
Dondoni A., Massi A., Minghini E., Sabbatini S., Bertolasi V.. Model studies toward the synthesis of dihydropyrimidinyl and pyridyl α-amino acids via three-component biginelli and hantzsch cyclocondensations. The Journal of Organic Chemistry. 2003;68:6172-6183. https://doi.org/10.1021/jo0342830
[Google Scholar]
Xie W., Wang H.. Immobilized polymeric sulfonated ionic liquid on core-shell structured Fe₃O₄/SiO₂ composites: A magnetically recyclable catalyst for simultaneous transesterification and esterifications of low-cost oils to biodiesel. Renewable Energy. 2020;145:1709-1719. https://doi.org/10.1016/j.renene.2019.07.092
[Google Scholar]
Xie W., Wan F.. Basic ionic liquid functionalized magnetically responsive Fe3O4@HKUST-1 composites used for biodiesel production. Fuel. 2018;220:248-256. https://doi.org/10.1016/j.fuel.2018.02.014
[Google Scholar]
Xie W., Wan F.. Immobilization of polyoxometalate-based sulfonated ionic liquids on UiO-66-2COOH metal-organic frameworks for biodiesel production via one-pot transesterification-esterification of acidic vegetable oils. Chemical Engineering Journal. 2019;365:40-50. https://doi.org/10.1016/j.cej.2019.02.016
[Google Scholar]
Chatterjee R., Bhattacharjee S., Bhaumik A.. Bifunctional metal‐free heterogeneous catalyst for the synthesis of methanol and diols from CO2 and epoxide. Asian Journal of Organic Chemistry. 2022;11 https://doi.org/10.1002/ajoc.202200317
[Google Scholar]
Debruyne M., Van Speybroeck V., Van Der Voort P., Stevens C.V.. Porous organic polymers as metal free heterogeneous organocatalysts. Green Chemistry. 2021;23:7361-7434. https://doi.org/10.1039/d1gc02319e
[Google Scholar]
Liu Y., Li S., Chen Y., Hu T., Pudukudy M., Shi L., Shan S., Zhi Y.. Modified melamine-based porous organic polymers with imidazolium ionic liquids as efficient heterogeneous catalysts for CO₂ cycloaddition. Journal of Colloid and Interface Science. 2023;652:737-748. https://doi.org/10.1016/j.jcis.2023.07.127
[Google Scholar]
Migowski P., Lozano P., Dupont J.. Imidazolium based ionic liquid-phase green catalytic reactions. Green Chemistry. 2023;25:1237-1260. https://doi.org/10.1039/d2gc04749g
[Google Scholar]
Wolny A., Chrobok A.. Silica-based supported ionic liquid-like phases as heterogeneous catalysts. Molecules (Basel, Switzerland). 2022;27:5900. https://doi.org/10.3390/molecules27185900
[Google Scholar]
Jadhav C.K., Nipate A.S., Chate A.V., Songire V.D., Patil A.P., Gill C.H.. Efficient rapid access to Biginelli for the multicomponent synthesis of 1,2,3,4-tetrahydropyrimidines in room-temperature Diisopropyl ethyl ammonium acetate. ACS Omega. 2019;4:22313-22324. https://doi.org/10.1021/acsomega.9b02286
[Google Scholar]
Selva M., Perosa A., Guidi S., Cattelan L.. Ionic liquids as transesterification catalysts: Applications for the synthesis of linear and cyclic organic carbonates. Beilstein Journal of Organic Chemistry. 2016;12:1911-1924. https://doi.org/10.3762/bjoc.12.181
[Google Scholar]
Suwito H., Zulianto L., Ul Haq K., Erwanto E., Abdulloh A., Novi Kristanti A., Indriani I.. Ethyl (E)-4-(2,4-Dimethoxyphenyl)-6-(2,4-dimethoxystyryl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Molbank. 2017;2017:M946. https://doi.org/10.3390/m946
[Google Scholar]
Anvar S., Mohammadpoor-Baltork I., Tangestaninejad S., Moghadam M., Mirkhani V., Khosropour A.R., Landarani Isfahani A., Kia R.. New pyridinium-based ionic liquid as an excellent solvent–catalyst system for the one-pot three-component synthesis of 2,3-disubstituted quinolines. ACS Combinatorial Science. 2014;16:93-100. https://doi.org/10.1021/co400144b
[Google Scholar]
Kumar A., Parveen M., A.A. Nami S., Azam M., Sajid Ansari M., Farooq I., Alam M.. Efficacy of the ionic liquid 1,4-Bis(carboxymethyl)piperazine-1,4-diium chloride as a catalyst for xanthenes/acridines synthesis: Spectral characterization, X-ray structure, and nematicidal activity. Journal of Saudi Chemical Society. 2024;28:101807. https://doi.org/10.1016/j.jscs.2024.101807
[Google Scholar]
Madivalappa Davanagere P., Maiti B.. 1, 3-Bis (carboxymethyl) imidazolium chloride as a sustainable, recyclable, and metal-free ionic catalyst for the Biginelli multicomponent reaction in neat condition. ACS Omega. 2021;6:26035-26047. https://doi.org/10.1021/acsomega.1c02976
[Google Scholar]
Srinuvasu V., Rao N.K.. Solvent free synthesis of derivatives of 4-(indolyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate and bioevluation. World Journal of Pharmaceutical Research. 2024;13:2015-2022. https://doi.org/10.20959/wjpr20249-32272
[Google Scholar]
Kamat V., Reddy D.S., Kumar A.. Catalytic role in Biginelli reaction: synthesis and biological property studies of 2‐oxo/thioxo‐1,2,3,4‐tetrahydropyrimidines. Archiv Der Pharmazie. 2023;356 https://doi.org/10.1002/ardp.202300008
[Google Scholar]
Majellaro M., Jespers W., Crespo A., Núñez M.J., Novio S., Azuaje J., Prieto-Diaz R., Gioe C., Alispahic B., Brea J.. 3,4-Dihydropyrimidin-2 (1 H)-ones as antagonists of the human a2b adenosine receptor: optimization, structure–activity relationship studies, and enantiospecific recognition. Journal of Medicinal Chemistry. 2020;64:458-480. https://doi.org/10.1021/acs.jmedchem.0c01431
[Google Scholar]
Fu Z., Shen T., Du Z., Qiao Z., Song Q.. An efficient one-pot synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones/thiones catalysed by 2-thienylboronic acid. Journal of Chemical Research. 2012;36:200-202. https://doi.org/10.3184/174751912X13318375421
[Google Scholar]
Ali F., Khan K.M., Salar U., Iqbal S., Taha M., Ismail N.H., Perveen S., Wadood A., Ghufran M., Ali B.. Dihydropyrimidones: As novel class of β-glucuronidase inhibitors. Bioorganic & Medicinal Chemistry. 2016;24:3624-3635. https://doi.org/10.1016/j.bmc.2016.06.002
[Google Scholar]
Kaur K., Knaus E. E.. Synthesis of alkyl 6‐methyl‐4‐(2‐pyridyl)‐1, 2, 3, 4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates for evaluation as calcium channel antagonists. Journal of Heterocyclic Chemistry. 2007;44(3):745-747. https://doi.org/10.1002/jhet.5570440339
[Google Scholar]
Fadda A.A., Bondock S.B., Khalil A.M., Tawfik E.H.. Synthesis of some new 1, 2, 3, 4‐tetrahydropyrimidine‐2‐thione and their thiazolo [3, 2‐a] pyrimidine, thiazino and benzothiazepine derivatives. Journal of Heterocyclic Chemistry. 2013;50:838-843. https://doi.org/10.1002/jhet.1573
[Google Scholar]
Mobinikhaledi A., Forughifar N.. Microwave-assisted synthesis of some pyrimidine derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements. 2006;181:2653-2658. https://doi.org/10.1080/10426500600862977
[Google Scholar]
Oliveros J.C.. Venny. An interactive tool for comparing lists with venn diagrams. 2007 http://bioinfogp.cnb.csic.es/tools/venny/index.html
[Google Scholar]
Litvić M., Večenaj I., Ladišić Z.M., Lovrić M., Vinković V., Filipan-Litvić M.. First application of hexaaquaaluminium (III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3, 4-dihydropyrimidinones by Biginelli reaction. Tetrahedron. 2010;66:3463-3471. https://doi.org/10.1016/j.tet.2010.03.024
[Google Scholar]
Sujatha K., Shanthi G., Selvam N. P., Manoharan S., Perumal P. T., Rajendran M.. Synthesis and antiviral activity of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) against peste des petits ruminant virus (PPRV) Bioorganic & Medicinal Chemistry Letters. 2009;19:1 4501-45. https://doi.org/10.1016/j.bmcl.2009.02.113
[Google Scholar]
Atwal K.S., Rovnyak G.C., Schwartz J., Moreland S., Hedberg A., Gougoutas J.Z., Malley M.F., Floyd D.M.. Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. Journal of Medicinal Chemistry. 1990;33:1510-1515. https://doi.org/10.1021/jm00167a035
[Google Scholar]
Kidwai M., Jahan A., Bhatnagar D.. Polyethylene glycol: A recyclable solvent system for the synthesis of benzimidazole derivatives using CAN as catalyst. Journal of Chemical Sciences. 2010;122:607-612. https://doi.org/10.1007/s12039-010-0095-7
[Google Scholar]
More S.V., Sastry M.N.V., Yao C.-F.. Cerium (iv) ammonium nitrate (CAN) as a catalyst in tap water: A simple, proficient and green approach for the synthesis of quinoxalines. Green Chem.. 2006;8:91-95. https://doi.org/10.1039/b510677j
[Google Scholar]
Liang X., Gao S., Gong G., Wang Y., Yang J.-G.. Synthesis of a novel heterogeneous strong acid catalyst from p-Toluenesulfonic acid (PTSA) and its catalytic activities. Catalysis Letters. 2008;124:352-356. https://doi.org/10.1007/s10562-008-9474-9
[Google Scholar]
Thorat B. R., Gurav A., Dalvi B., Sawant A., Lokhande V., Mali S. N.. Green synthesis of substituted dihydropyrimidin-2(1H)-one by using zinc chloride /acetic acid catalytic system. Current Chinese Chemistry. 2021;11:30-46. https://doi.org/10.2174/2665997201999200512110147
[Google Scholar]
Litvić M., Večenaj I., Ladišić Z.M., Lovrić M., Vinković V., Filipan-Litvić M.. First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: A simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction. Tetrahedron. 2010;66:3463-3471. https://doi.org/10.1016/j.tet.2010.03.024
[Google Scholar]
Rovnyak G.C., Kimball S.D., Beyer B., Cucinotta G., DiMarco J.D., Gougoutas J., Hedberg A., Malley M., McCarthy J.P., Zhang R.. Calcium entry blockers and activators: Conformational and structural determinants of dihydropyrimidine calcium channel modulators. Journal of Medicinal Chemistry. 1995;38:119-129. https://doi.org/10.1021/jm00001a017
[Google Scholar]
Kakati P., Singh P., Yadav P., Awasthi S.K.. Aiding the versatility of simple ammonium ionic liquids by the synthesis of bioactive 1,2,3,4-tetrahydropyrimidine, 2-aminothiazole and quinazolinone derivatives. New Journal of Chemistry. 2021;45:6724-6738. https://doi.org/10.1039/d1nj00280e
[Google Scholar]
Masoud N.-E., Hoseini S.J., Mohammadi F.. Fe₃O₄ nanoparticles as an efficient and magnetically recoverable catalyst for the synthesis of 3,4-dihydropyrimidin-2 (1H)-ones under solvent-free conditions. Chinese Journal of Catalysis. 2011;32:1484-1489. https://doi.org/10.1016/S1872-2067(10)60263-X
[Google Scholar]
Geng Z., Zhang H., Yin G., Zhang Y., Zhao J.. A one-pot synthesis of benzimidazoles via aerobic oxidative condensation of benzyl alcohols with o-phenylenediamines catalyzed by [MIMPs]+ Cl-/NaNO2/TEMPO. Journal of Chemical Research. 2020;44:557-565. https://doi.org/10.1177/1747519820912163
[Google Scholar]
Pell A.J., Pintacuda G., Grey C.P.. FT-IR and Raman study of organic ionic liquids: spectral assignments and structure spectroscopy. Chem. Rev.. 2019;119:6821-6905. https://doi.org/10.1021/acs.chemrev.8b00451
[Google Scholar]
Ghasemi Karaj-Abad S., Abbasian M., Hosseinzadeh M., Nasry Saheb S., Esmaeily Shoja Bonab S.. Synthesis and characterization of phenylene diamine and poly (Methyl Methacrylate) coupled with multi-walled carbon nanotubes by in situ oxidation polymerization. Journal of Nanostructures. 2022;12:510-520. https://doi.org/10.22052/JNS.2022.03.004
[Google Scholar]
Zoromba M.S., Al-Hossainy A.F., Mahmoud S.A., Bourezgui A., Shaaban E.R.. Improvement of the thermal stability and optical properties for poly (ortho phenylene diamine) using soft templates. Journal of Molecular Structure. 2020;1221:128792. https://doi.org/10.1016/j.molstruc.2020.128792
[Google Scholar]
Amir M., Javed S.. Elucidation of binding dynamics of tyrosine kinase inhibitor tepotinib, to human serum albumin, using spectroscopic and computational approach. International Journal of Biological Macromolecules. 2023;241:124656. https://doi.org/10.1016/j.ijbiomac.2023.124656
[Google Scholar]
Dahiya V., Anand B.G., Kar K., Pal S.. In vitro interaction of organophosphate metabolites with bovine serum albumin: A comparative 1H NMR, fluorescence and molecular docking analysis. Pesticide Biochemistry and Physiology. 2020;163:39-50. https://doi.org/10.1016/j.pestbp.2019.10.004
[Google Scholar]
Aamir Qureshi M., Javed S.. Structural dynamics studies on the binding of aflatoxin B1 to chicken egg albumin using spectroscopic techniques and molecular docking. Journal of Biomolecular Structure & Dynamics. 2020;38:3144-3155. https://doi.org/10.1080/07391102.2019.1652690
[Google Scholar]
Amir M., Qureshi M.A., Javed S.. Biomolecular interactions and binding dynamics of tyrosine kinase inhibitor erdafitinib, with human serum albumin. Journal of Biomolecular Structure & Dynamics. 2021;39:3934-3947. https://doi.org/10.1080/07391102.2020.1772880
[Google Scholar]
Jahanban-Esfahlan A., Panahi-Azar V.. Interaction of glutathione with bovine serum albumin: Spectroscopy and molecular docking. Food Chemistry. 2016;202:426-431. https://doi.org/10.1016/j.foodchem.2016.02.026
[Google Scholar]
Ravindran A., Singh A., Raichur A.M., Chandrasekaran N., Mukherjee A.. Studies on interaction of colloidal Ag nanoparticles with bovine serum albumin (BSA) Colloids and Surfaces. B, Biointerfaces. 2010;76:32-37. https://doi.org/10.1016/j.colsurfb.2009.10.005
[Google Scholar]
Li X., Sun X., Zhao R., Shao D., Bi S.. Study on the binding of sulfaclozine sodium monohydrate with bovine and human serum albumins using multi-spectroscopy and molecular docking. Journal of Biomolecular Structure & Dynamics. 2021;39:4835-4844. https://doi.org/10.1080/07391102.2020.1780945
[Google Scholar]
Parveen M., Uzma N., Khan A.A., Nami S.A.A., Kataria R., Malik A., Amali N.A.M., Abd Kadir N.H., Alam M.. Isolation, characterization, and single-crystal X-ray analysis of lantabetulic acid from rhus alata: Insights into HSA and BSA binding interactions, with in-silico study. ACS Omega. 2024;9:39484-39502. https://doi.org/10.1021/acsomega.4c03406
[Google Scholar]
Shaghaghi M., Dehghan G., Rashtbari S., Sheibani N., Aghamohammadi A.. Multispectral and computational probing of the interactions between sitagliptin and serum albumin. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy. 2019;223:117286. https://doi.org/10.1016/j.saa.2019.117286
[Google Scholar]
Qureshi M.A., Amir M., Khan R.H., Musarrat J., Javed S.. Glycation reduces the binding dynamics of aflatoxin B1 to human serum albumin: A comprehensive spectroscopic and computational investigation. Journal of Biomolecular Structure & Dynamics. 2023;41:14797-14811. https://doi.org/10.1080/07391102.2023.2194000
[Google Scholar]
Dezhampanah H., Esmaili M., Jampour S.. Spectroscopic and molecular docking studies on interaction of two Schiff base complexes with bovine serum albumin. Journal of Biomolecular Structure & Dynamics. 2020;38:2650-2658. https://doi.org/10.1080/07391102.2019.1639548
[Google Scholar]

Show Sections

[1] Sharma V., Chitranshi N., Agarwal A.K.. Significance and biological importance of pyrimidine in the microbial world. International Journal of Medicinal Chemistry. 2014;2014:202784. https://doi.org/10.1155/2014/202784
[Google Scholar]

[2] Menor-Salván C., ésar, Marín-Yaseli M.R.. Prebiotic chemistry in eutectic solutions at the water–ice matrix. Chemical Society Reviews. 2012;41:5404. https://doi.org/10.1039/c2cs35060b
[Google Scholar]

[3] Quin L.D., Tyrell J.A.. Fundamentals of heterocyclic chemistry: Importance in nature and in the synthesis of pharmaceuticals. John Wiley & Sons; 2010. ISBN: 978-0-470-62653-5

[4] Pozharskii A.F., Soldatenkov A.T., Katritzky A.R.. Heterocycles in life and society: an introduction to heterocyclic chemistry, biochemistry and applications (2nd ed.). John Wiley & Sons; 2011. https://doi.org/10.1002/9781119998372

[5] Kaur S., Kumari P., Singh G., Bhatti R., Singh P.. Design and synthesis of Aza-/Oxa heterocycle-based conjugates as novel anti-inflammatory agents targeting cyclooxygenase-2. ACS Omega. 2018;3:5825-5845. https://doi.org/10.1021/acsomega.8b00445
[Google Scholar]

[6] Zhang Y., Wang B., Zhang X., Huang J., Liu C.. An efficient synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and thiones catalyzed by a novel Brønsted acidic ionic liquid under solvent-free conditions. Molecules (Basel, Switzerland). 2015;20:3811-3820. https://doi.org/10.3390/molecules20033811
[Google Scholar]

[7] Mushtaq A., Munawar A., Parveen B., Javed S., Zahoor A.F., Ali K.G., Mansha A., Irfan A.. Recent advances in the synthesis of dihydropyrimidinones via biginelli reaction. J. Iran. Chem. Soc.. 2024;21:2565-2586. https://doi.org/10.1007/s13738-024-03100-z
[Google Scholar]

[8] Melo M.F.F., Da Silva B.A., Mukherjee R.. Spasmolytic actions of the new indole alkaloid Trinervine from Strychnos trinervis root. Phytomedicine. 1994;1:205-207. https://doi.org/10.1016/S0944-7113(11)80066-8
[Google Scholar]

[9] Diao P.C., Li Q., Hu M.J., Ma Y.F., You W.W., Hong K.H., Zhao P.L.. Synthesis and biological evaluation of novel indole-pyrimidine hybrids bearing morpholine and thiomorpholine moieties. European Journal of Medicinal Chemistry. 2017;134:110-118. https://doi.org/10.1016/j.ejmech.2017.04.011
[Google Scholar]

[10] Wender P.A.. Toward the ideal synthesis and molecular function through synthesis-informed design. Natural Product Reports. 2014;31:433-440. https://doi.org/10.1039/c4np00013g
[Google Scholar]

[11] Zhu J., Bienaymé H., eds. Multicomponent Reactions. John Wiley & Sons; 2005. ISBN: 978-3-527-60511-8

[12] Parveen M., Uzma, Azam M., Azeem M., Aslam A., Bashir M., Alam M.. Catalytic activity of TiO2 nanoparticles in cyclization reactions for pyrazolone formation: DNA binding analysis via spectroscopy, X-ray crystallography, and molecular docking. Journal of Saudi Chemical Society. 2024;28:101881. https://doi.org/10.1016/j.jscs.2024.101881
[Google Scholar]

[13] Zhu Y.‐Lin, Huang S.‐Lin, Pan Y.‐Jiang. Highly chemoselective multicomponent Biginelli‐type condensations of cycloalkanones, urea or thiourea and aldehydes. European Journal of Organic Chemistry. 2005;2005:2354-2367. https://doi.org/10.1002/ejoc.200400845
[Google Scholar]

[14] Marzabadi M.R., Hong X., Nagarathnam D., Miao S.W., Chiu G., Wong W.C., Wetzel J.M., Fang J., Forray C., Chen T.B., O.’Malley S.S., Chang R.S., Gluchowski C.. Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorganic & Medicinal Chemistry Letters. 1999;9:2843-2848. https://doi.org/10.1016/s0960-894x(99)00484-9
[Google Scholar]

[15] Rovnyak G.C., Kimball S.D., Beyer B., Cucinotta G., DiMarco J.D., Gougoutas J., Hedberg A., Malley M., McCarthy J.P., Zhang R.. Calcium entry blockers and activators: Conformational and structural determinants of dihydropyrimidine calcium channel modulators. Journal of Medicinal Chemistry. 1995;38:119-129. https://doi.org/10.1021/jm00001a017
[Google Scholar]

[16] Dallinger D., Stadler A., Kappe C.O.. Solid- and solution-phase synthesis of bioactive dihydropyrimidines. Pure and Applied Chemistry. 2004;76:1017-1024. https://doi.org/10.1351/pac200476051017
[Google Scholar]

[17] Sujatha K., Shanmugam P., Perumal P.T., Muralidharan D., Rajendran M.. Synthesis and cardiac effects of 3,4-dihydropyrimidin-2(1H)-one-5 carboxylates. Bioorganic & Medicinal Chemistry Letters. 2006;16:4893-4897. https://doi.org/10.1016/j.bmcl.2006.06.059
[Google Scholar]

[18] Dondoni A., Massi A., Minghini E., Sabbatini S., Bertolasi V.. Model studies toward the synthesis of dihydropyrimidinyl and pyridyl α-amino acids via three-component biginelli and hantzsch cyclocondensations. The Journal of Organic Chemistry. 2003;68:6172-6183. https://doi.org/10.1021/jo0342830
[Google Scholar]

[19] Xie W., Wang H.. Immobilized polymeric sulfonated ionic liquid on core-shell structured Fe₃O₄/SiO₂ composites: A magnetically recyclable catalyst for simultaneous transesterification and esterifications of low-cost oils to biodiesel. Renewable Energy. 2020;145:1709-1719. https://doi.org/10.1016/j.renene.2019.07.092
[Google Scholar]

[20] Xie W., Wan F.. Basic ionic liquid functionalized magnetically responsive Fe3O4@HKUST-1 composites used for biodiesel production. Fuel. 2018;220:248-256. https://doi.org/10.1016/j.fuel.2018.02.014
[Google Scholar]

[21] Xie W., Wan F.. Immobilization of polyoxometalate-based sulfonated ionic liquids on UiO-66-2COOH metal-organic frameworks for biodiesel production via one-pot transesterification-esterification of acidic vegetable oils. Chemical Engineering Journal. 2019;365:40-50. https://doi.org/10.1016/j.cej.2019.02.016
[Google Scholar]

[22] Chatterjee R., Bhattacharjee S., Bhaumik A.. Bifunctional metal‐free heterogeneous catalyst for the synthesis of methanol and diols from CO2 and epoxide. Asian Journal of Organic Chemistry. 2022;11 https://doi.org/10.1002/ajoc.202200317
[Google Scholar]

[23] Debruyne M., Van Speybroeck V., Van Der Voort P., Stevens C.V.. Porous organic polymers as metal free heterogeneous organocatalysts. Green Chemistry. 2021;23:7361-7434. https://doi.org/10.1039/d1gc02319e
[Google Scholar]

[24] Liu Y., Li S., Chen Y., Hu T., Pudukudy M., Shi L., Shan S., Zhi Y.. Modified melamine-based porous organic polymers with imidazolium ionic liquids as efficient heterogeneous catalysts for CO₂ cycloaddition. Journal of Colloid and Interface Science. 2023;652:737-748. https://doi.org/10.1016/j.jcis.2023.07.127
[Google Scholar]

[25] Migowski P., Lozano P., Dupont J.. Imidazolium based ionic liquid-phase green catalytic reactions. Green Chemistry. 2023;25:1237-1260. https://doi.org/10.1039/d2gc04749g
[Google Scholar]

[26] Wolny A., Chrobok A.. Silica-based supported ionic liquid-like phases as heterogeneous catalysts. Molecules (Basel, Switzerland). 2022;27:5900. https://doi.org/10.3390/molecules27185900
[Google Scholar]

[27] Jadhav C.K., Nipate A.S., Chate A.V., Songire V.D., Patil A.P., Gill C.H.. Efficient rapid access to Biginelli for the multicomponent synthesis of 1,2,3,4-tetrahydropyrimidines in room-temperature Diisopropyl ethyl ammonium acetate. ACS Omega. 2019;4:22313-22324. https://doi.org/10.1021/acsomega.9b02286
[Google Scholar]

[28] Selva M., Perosa A., Guidi S., Cattelan L.. Ionic liquids as transesterification catalysts: Applications for the synthesis of linear and cyclic organic carbonates. Beilstein Journal of Organic Chemistry. 2016;12:1911-1924. https://doi.org/10.3762/bjoc.12.181
[Google Scholar]

[29] Suwito H., Zulianto L., Ul Haq K., Erwanto E., Abdulloh A., Novi Kristanti A., Indriani I.. Ethyl (E)-4-(2,4-Dimethoxyphenyl)-6-(2,4-dimethoxystyryl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. Molbank. 2017;2017:M946. https://doi.org/10.3390/m946
[Google Scholar]

[30] Anvar S., Mohammadpoor-Baltork I., Tangestaninejad S., Moghadam M., Mirkhani V., Khosropour A.R., Landarani Isfahani A., Kia R.. New pyridinium-based ionic liquid as an excellent solvent–catalyst system for the one-pot three-component synthesis of 2,3-disubstituted quinolines. ACS Combinatorial Science. 2014;16:93-100. https://doi.org/10.1021/co400144b
[Google Scholar]

[31] Kumar A., Parveen M., A.A. Nami S., Azam M., Sajid Ansari M., Farooq I., Alam M.. Efficacy of the ionic liquid 1,4-Bis(carboxymethyl)piperazine-1,4-diium chloride as a catalyst for xanthenes/acridines synthesis: Spectral characterization, X-ray structure, and nematicidal activity. Journal of Saudi Chemical Society. 2024;28:101807. https://doi.org/10.1016/j.jscs.2024.101807
[Google Scholar]

[32] Madivalappa Davanagere P., Maiti B.. 1, 3-Bis (carboxymethyl) imidazolium chloride as a sustainable, recyclable, and metal-free ionic catalyst for the Biginelli multicomponent reaction in neat condition. ACS Omega. 2021;6:26035-26047. https://doi.org/10.1021/acsomega.1c02976
[Google Scholar]

[33] Srinuvasu V., Rao N.K.. Solvent free synthesis of derivatives of 4-(indolyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate and bioevluation. World Journal of Pharmaceutical Research. 2024;13:2015-2022. https://doi.org/10.20959/wjpr20249-32272
[Google Scholar]

[34] Kamat V., Reddy D.S., Kumar A.. Catalytic role in Biginelli reaction: synthesis and biological property studies of 2‐oxo/thioxo‐1,2,3,4‐tetrahydropyrimidines. Archiv Der Pharmazie. 2023;356 https://doi.org/10.1002/ardp.202300008
[Google Scholar]

[35] Majellaro M., Jespers W., Crespo A., Núñez M.J., Novio S., Azuaje J., Prieto-Diaz R., Gioe C., Alispahic B., Brea J.. 3,4-Dihydropyrimidin-2 (1 H)-ones as antagonists of the human a2b adenosine receptor: optimization, structure–activity relationship studies, and enantiospecific recognition. Journal of Medicinal Chemistry. 2020;64:458-480. https://doi.org/10.1021/acs.jmedchem.0c01431
[Google Scholar]

[36] Fu Z., Shen T., Du Z., Qiao Z., Song Q.. An efficient one-pot synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones/thiones catalysed by 2-thienylboronic acid. Journal of Chemical Research. 2012;36:200-202. https://doi.org/10.3184/174751912X13318375421
[Google Scholar]

[37] Ali F., Khan K.M., Salar U., Iqbal S., Taha M., Ismail N.H., Perveen S., Wadood A., Ghufran M., Ali B.. Dihydropyrimidones: As novel class of β-glucuronidase inhibitors. Bioorganic & Medicinal Chemistry. 2016;24:3624-3635. https://doi.org/10.1016/j.bmc.2016.06.002
[Google Scholar]

[38] Kaur K., Knaus E. E.. Synthesis of alkyl 6‐methyl‐4‐(2‐pyridyl)‐1, 2, 3, 4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates for evaluation as calcium channel antagonists. Journal of Heterocyclic Chemistry. 2007;44(3):745-747. https://doi.org/10.1002/jhet.5570440339
[Google Scholar]

[39] Fadda A.A., Bondock S.B., Khalil A.M., Tawfik E.H.. Synthesis of some new 1, 2, 3, 4‐tetrahydropyrimidine‐2‐thione and their thiazolo [3, 2‐a] pyrimidine, thiazino and benzothiazepine derivatives. Journal of Heterocyclic Chemistry. 2013;50:838-843. https://doi.org/10.1002/jhet.1573
[Google Scholar]

[40] Mobinikhaledi A., Forughifar N.. Microwave-assisted synthesis of some pyrimidine derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements. 2006;181:2653-2658. https://doi.org/10.1080/10426500600862977
[Google Scholar]

[41] Oliveros J.C.. Venny. An interactive tool for comparing lists with venn diagrams. 2007 http://bioinfogp.cnb.csic.es/tools/venny/index.html
[Google Scholar]

[42] Litvić M., Večenaj I., Ladišić Z.M., Lovrić M., Vinković V., Filipan-Litvić M.. First application of hexaaquaaluminium (III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3, 4-dihydropyrimidinones by Biginelli reaction. Tetrahedron. 2010;66:3463-3471. https://doi.org/10.1016/j.tet.2010.03.024
[Google Scholar]

[43] Sujatha K., Shanthi G., Selvam N. P., Manoharan S., Perumal P. T., Rajendran M.. Synthesis and antiviral activity of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) against peste des petits ruminant virus (PPRV) Bioorganic & Medicinal Chemistry Letters. 2009;19:1 4501-45. https://doi.org/10.1016/j.bmcl.2009.02.113
[Google Scholar]

[44] Atwal K.S., Rovnyak G.C., Schwartz J., Moreland S., Hedberg A., Gougoutas J.Z., Malley M.F., Floyd D.M.. Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. Journal of Medicinal Chemistry. 1990;33:1510-1515. https://doi.org/10.1021/jm00167a035
[Google Scholar]

[45] Kidwai M., Jahan A., Bhatnagar D.. Polyethylene glycol: A recyclable solvent system for the synthesis of benzimidazole derivatives using CAN as catalyst. Journal of Chemical Sciences. 2010;122:607-612. https://doi.org/10.1007/s12039-010-0095-7
[Google Scholar]

[46] More S.V., Sastry M.N.V., Yao C.-F.. Cerium (iv) ammonium nitrate (CAN) as a catalyst in tap water: A simple, proficient and green approach for the synthesis of quinoxalines. Green Chem.. 2006;8:91-95. https://doi.org/10.1039/b510677j
[Google Scholar]

[47] Liang X., Gao S., Gong G., Wang Y., Yang J.-G.. Synthesis of a novel heterogeneous strong acid catalyst from p-Toluenesulfonic acid (PTSA) and its catalytic activities. Catalysis Letters. 2008;124:352-356. https://doi.org/10.1007/s10562-008-9474-9
[Google Scholar]

[48] Thorat B. R., Gurav A., Dalvi B., Sawant A., Lokhande V., Mali S. N.. Green synthesis of substituted dihydropyrimidin-2(1H)-one by using zinc chloride /acetic acid catalytic system. Current Chinese Chemistry. 2021;11:30-46. https://doi.org/10.2174/2665997201999200512110147
[Google Scholar]

[49] Litvić M., Večenaj I., Ladišić Z.M., Lovrić M., Vinković V., Filipan-Litvić M.. First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: A simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli reaction. Tetrahedron. 2010;66:3463-3471. https://doi.org/10.1016/j.tet.2010.03.024
[Google Scholar]

[50] Rovnyak G.C., Kimball S.D., Beyer B., Cucinotta G., DiMarco J.D., Gougoutas J., Hedberg A., Malley M., McCarthy J.P., Zhang R.. Calcium entry blockers and activators: Conformational and structural determinants of dihydropyrimidine calcium channel modulators. Journal of Medicinal Chemistry. 1995;38:119-129. https://doi.org/10.1021/jm00001a017
[Google Scholar]

[51] Kakati P., Singh P., Yadav P., Awasthi S.K.. Aiding the versatility of simple ammonium ionic liquids by the synthesis of bioactive 1,2,3,4-tetrahydropyrimidine, 2-aminothiazole and quinazolinone derivatives. New Journal of Chemistry. 2021;45:6724-6738. https://doi.org/10.1039/d1nj00280e
[Google Scholar]

[52] Masoud N.-E., Hoseini S.J., Mohammadi F.. Fe₃O₄ nanoparticles as an efficient and magnetically recoverable catalyst for the synthesis of 3,4-dihydropyrimidin-2 (1H)-ones under solvent-free conditions. Chinese Journal of Catalysis. 2011;32:1484-1489. https://doi.org/10.1016/S1872-2067(10)60263-X
[Google Scholar]

[53] Geng Z., Zhang H., Yin G., Zhang Y., Zhao J.. A one-pot synthesis of benzimidazoles via aerobic oxidative condensation of benzyl alcohols with o-phenylenediamines catalyzed by [MIMPs]+ Cl-/NaNO2/TEMPO. Journal of Chemical Research. 2020;44:557-565. https://doi.org/10.1177/1747519820912163
[Google Scholar]

[54] Pell A.J., Pintacuda G., Grey C.P.. FT-IR and Raman study of organic ionic liquids: spectral assignments and structure spectroscopy. Chem. Rev.. 2019;119:6821-6905. https://doi.org/10.1021/acs.chemrev.8b00451
[Google Scholar]

[55] Ghasemi Karaj-Abad S., Abbasian M., Hosseinzadeh M., Nasry Saheb S., Esmaeily Shoja Bonab S.. Synthesis and characterization of phenylene diamine and poly (Methyl Methacrylate) coupled with multi-walled carbon nanotubes by in situ oxidation polymerization. Journal of Nanostructures. 2022;12:510-520. https://doi.org/10.22052/JNS.2022.03.004
[Google Scholar]

[56] Zoromba M.S., Al-Hossainy A.F., Mahmoud S.A., Bourezgui A., Shaaban E.R.. Improvement of the thermal stability and optical properties for poly (ortho phenylene diamine) using soft templates. Journal of Molecular Structure. 2020;1221:128792. https://doi.org/10.1016/j.molstruc.2020.128792
[Google Scholar]

[57] Amir M., Javed S.. Elucidation of binding dynamics of tyrosine kinase inhibitor tepotinib, to human serum albumin, using spectroscopic and computational approach. International Journal of Biological Macromolecules. 2023;241:124656. https://doi.org/10.1016/j.ijbiomac.2023.124656
[Google Scholar]

[58] Dahiya V., Anand B.G., Kar K., Pal S.. In vitro interaction of organophosphate metabolites with bovine serum albumin: A comparative 1H NMR, fluorescence and molecular docking analysis. Pesticide Biochemistry and Physiology. 2020;163:39-50. https://doi.org/10.1016/j.pestbp.2019.10.004
[Google Scholar]

[59] Aamir Qureshi M., Javed S.. Structural dynamics studies on the binding of aflatoxin B1 to chicken egg albumin using spectroscopic techniques and molecular docking. Journal of Biomolecular Structure & Dynamics. 2020;38:3144-3155. https://doi.org/10.1080/07391102.2019.1652690
[Google Scholar]

[60] Amir M., Qureshi M.A., Javed S.. Biomolecular interactions and binding dynamics of tyrosine kinase inhibitor erdafitinib, with human serum albumin. Journal of Biomolecular Structure & Dynamics. 2021;39:3934-3947. https://doi.org/10.1080/07391102.2020.1772880
[Google Scholar]

[61] Jahanban-Esfahlan A., Panahi-Azar V.. Interaction of glutathione with bovine serum albumin: Spectroscopy and molecular docking. Food Chemistry. 2016;202:426-431. https://doi.org/10.1016/j.foodchem.2016.02.026
[Google Scholar]

[62] Ravindran A., Singh A., Raichur A.M., Chandrasekaran N., Mukherjee A.. Studies on interaction of colloidal Ag nanoparticles with bovine serum albumin (BSA) Colloids and Surfaces. B, Biointerfaces. 2010;76:32-37. https://doi.org/10.1016/j.colsurfb.2009.10.005
[Google Scholar]

[63] Li X., Sun X., Zhao R., Shao D., Bi S.. Study on the binding of sulfaclozine sodium monohydrate with bovine and human serum albumins using multi-spectroscopy and molecular docking. Journal of Biomolecular Structure & Dynamics. 2021;39:4835-4844. https://doi.org/10.1080/07391102.2020.1780945
[Google Scholar]

[64] Parveen M., Uzma N., Khan A.A., Nami S.A.A., Kataria R., Malik A., Amali N.A.M., Abd Kadir N.H., Alam M.. Isolation, characterization, and single-crystal X-ray analysis of lantabetulic acid from rhus alata: Insights into HSA and BSA binding interactions, with in-silico study. ACS Omega. 2024;9:39484-39502. https://doi.org/10.1021/acsomega.4c03406
[Google Scholar]

[65] Shaghaghi M., Dehghan G., Rashtbari S., Sheibani N., Aghamohammadi A.. Multispectral and computational probing of the interactions between sitagliptin and serum albumin. Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy. 2019;223:117286. https://doi.org/10.1016/j.saa.2019.117286
[Google Scholar]

[66] Qureshi M.A., Amir M., Khan R.H., Musarrat J., Javed S.. Glycation reduces the binding dynamics of aflatoxin B1 to human serum albumin: A comprehensive spectroscopic and computational investigation. Journal of Biomolecular Structure & Dynamics. 2023;41:14797-14811. https://doi.org/10.1080/07391102.2023.2194000
[Google Scholar]

[67] Dezhampanah H., Esmaili M., Jampour S.. Spectroscopic and molecular docking studies on interaction of two Schiff base complexes with bovine serum albumin. Journal of Biomolecular Structure & Dynamics. 2020;38:2650-2658. https://doi.org/10.1080/07391102.2019.1639548
[Google Scholar]


Entry	Catalyst	Solvents	Temperature	Time (min)	Yield	Ref.
1.	No catalyst	EtOH	80	52	Trace amount	-
2.	AlCl₃	EtOH	100	20	64	[40]
3.	[Al(H₂O)₆](BF₄)₃	-	100	20	78	[49]
4.	NiCl₂.6H₂O	EtOH	100	20	73	[50]
5.	ZnCl₂	EtOH	100	20	52	[48]
6.	Mn(OAc)₃.2H₂O	EtOH	100	24	70	[44]
7.	FeCl₃.6H₂O	EtOH	100	24	71	[50]
8.	CAN	EtOH	60	90	85	[43, 44, 46]
9.	[BCMAB][2Cl]	EtOH	60	25	98	-
10.	[BCMIM][Cl]	-	80	24	83	[32]
11.	PTSA	EtOH	60	60	50	[47]


Entry	Catalyst	Reaction time (min)	Yield (%)
1	-	60	20
2	HCl(g)	60	25
3	H₂SO₄	60	27
4	PTSA	60	50
5	[BMIM][BF4]	60	30
6	[CMMIM][BF4]	60	60
7	[BCMAB][2Cl]	25	98
8	[BCMIM][Cl]	60	96

Green synthesis and catalytic efficiency of [BCMAB][2Cl] ionic liquid for the synthesis of bioactive 1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives via Biginelli condensation: BSA binding affinity and molecular docking studies

Abstract

Keywords

BSA binding

Green chemistry

Ionic liquid catalysts

Multicomponent reactions

Molecular docking

Sustainable synthesis

1. Introduction

2. Materials and Methods

2.1. General

2.2. Motivation and outreach strategy

2.3. Experimental section

2.3.1. Preparation of ILs salt, 1,4-bis(carboxymethyl)benzene-1,4-diaminium chloride [BCMAB][2Cl].

2.3.2. Synthesis of modified Biginelli products (4a-k)

2.3.3. Spectral data of synthesized compound

2.4. Biological activity

2.4.1. Reagents

2.4.2. Ultraviolet-visible (UV-vis) absorption spectroscopy

2.4.3. Fluorescence measurement

2.5. Molecular docking

3. Results and Discussion

3.1. Chemistry

3.2. Optimizing reaction conditions

3.3. Catalytic evaluation

3.4. Effect of solvent

3.5. Plausible mechanism of the reaction: Catalytic mechanism

3.6. Sustainability metrics in Biginelli condensation reaction

3.7. Recyclability of ILs catalyst

3.8. Characterization of [BCMAB][2Cl] ILs catalyst.

3.8.1. Fourier transform infrared (FT-IR) analysis

3.8.2. Powder-X-ray diffraction (XRD) analysis

3.8.3. TGA analysis

3.8.4. SEM analysis with EDX

3.9. Biological evaluation of 1,2,3,4 tetrahydropyrimidine-5-carboxylate derivatives

3.9.1. UV–visible (UV-vis) spectroscopic studies

3.9.2. Fluorescence quenching and binding characteristics

3.9.3. Binding parameters

3.10. Molecular docking

4. Conclusions

Acknowledgment

CRediT authorship contribution statement

Declaration of competing interest

Data availability

Declaration of Generative AI and AI-assisted technologies in the writing process

Supplementary data

References

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