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. 2020 Nov 5;5(45):29055–29067. doi: 10.1021/acsomega.0c03575

Rapid Construction of Substituted Dihydrothiophene Ureidoformamides at Room Temperature Using Diisopropyl Ethyl Ammonium Acetate: A Green Perspective

Chetan K Jadhav †, Amol S Nipate †, Asha V Chate †, Vidya S Dofe ‡, Jaiprakash N Sangshetti §, Vijay M Khedkar £, Charansingh H Gill †,*
PMCID: PMC7675536  PMID: 33225136

Abstract

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An economic, sustainable, and straightforward environmentally friendly synthesis of highly diversified polyfunctional dihydrothiophenes is successfully achieved via diisopropyl ethyl ammonium acetate as a room-temperature ionic liquid. Multicomponent synthesis contains domino processes; the benefit of this present protocol is highlighted by its readily available starting materials, superior functional group tolerance, purity of synthesized compounds was checked by high-performance liquid chromatography results in up to 99.7% purity for the synthesized compounds, reaction mass efficiency, effective mass yield, and excellent atom economy. In addition, a series of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene analogs were synthesized, and selected samples were chosen for testing their in vitro antibacterial and antifungal activities. Furthermore, a molecular docking study against sterol 14α-demethylase could provide valuable insight into the mechanism of antifungal action providing an opportunity for structure-based lead optimization.

Introduction

Over the last few decades, ionic liquids (ILs) have received an excessive deal of attention in an extensive range of different areas, attainment from material synthesis to an alternative reaction as well as separation science media.1−6 ILs can be considered as green substitutes for organic solvents. They differ from molecular solvents by their “structure and organization” and their idiomatic ionic character, which can lead to precise effects, building them multipurpose and tunable materials.7−11 Also, ILs have been successfully used in many multicomponent reactions.12−17Therefore, ILs may be an ideal medium of multicomponent domino-type reactions without pressure-tight equipment and organic solvents.

Multicomponent reactions (MCRs) offer a chance for the combination of three or more flexible and straightforward building blocks in a one-pot operation, constructing complex structures by the continuous formation of two or more bonds, according to the domino principle.18−21Environmentally friendly processes via decreasing the waste production, number of synthetic steps, and energy depletion are among the benefits of MCRs.22−30

Among heterocyclic compounds, thiophene and its substituted derivatives are a vital category of organic compounds (Figure 1) with regard to their numerous pharmacological and biological activities such as anti-allergic, anticancer, antidiabetic, antibacterial, and anti-HIV.31−37 Therefore, it will be remarkable and substantial to apply 1,3-thiazolidinedione in cascade transformation for the development of innovative and valuable organic compounds.38−40

Figure 1.

Figure 1

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Chemical structures of some biologically active dihydrothiophenes.

In the past few decades, the careful study of the previously closely reported literature discloses pioneering work for the one-pot reaction of 1,3-thiazolidinedione, malononitrile, aldehyde, and aniline. In 2009, Sun et al. have reported the synthesis of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophenes by domino reactions of 1,3-thiazolidinedione in acetonitrile using organic amines as a catalyst.41 In 2011, Shi et al. reported an improved synthesis of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene derivatives under ultrasound irradiation.42 Again in 2011, Lu et al. reported an efficient synthesis of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene derivatives by domino reactions of 1,3-thiazolidinedione under catalyst-free conditions.43 Whereas, in 2019, Kordnezhadian et al. carried out DBU-functionalized MCM-41-coated nanosized hematite (DBU-F-MCM-41-CNSH): a new magnetically separable basic nanocatalyst for the diastereoselective one-pot four-component synthesis of dihydrothiophene ureidoformamides.44 Each of these reported procedures has its own merit, but all suffer from limitation of the synthesis to only a narrow range of dihydrothiophene ureidoformamides, a difficulty to isolate products or long reaction time, and harsh reaction conditions.

Thus, we wished to explore a more “eco-friendly” and expeditious protocol for the construction of dihydrothiophene ureidoformamides from aldehydes, malononitrile, 1,3-thiazolidinedione, and aromatic amines in DIPEAc at room temperature under solvent-free conditions (Scheme 1).

Scheme 1. One-Pot Four-Component Synthesis of 2-(N-Carbamoyl acetamide)-Substituted 2,3-Dihydrothiophenes (5aa–5aaj) in the Presence of DIPEAc as a New Room-Temperature Ionic Liquid.

Scheme 1

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Results and Discussion

Chemistry

Nowadays, the selection of a suitable reaction medium is of crucial importance for the successful organic synthesis. Ionic liquids (ILs) have become quite a popular solvent and accelerant in the chemical community due to their new generations, which contain catalytic functional groups, especially acidic3,45 and basic groups.46−49 Among the ILs, room-temperature ionic liquids (RTILs) have been the prominence of multiple current scientific surveys because of the properties being non-explosive, non-volatile, easy to handle, thermally robust, and nearly-zero vapor pressures.50 Our group has elaborated on the applications and syntheses of the ILs,51 and we have wished to utilize them as a reaction media and a homogeneous catalyst support for a high-yield, rapid, and recyclable process for the synthesis of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene.

Just following our goal to determine an innovative, sustainable, green, and synthetic path to choose the superior experimental conditions for the production of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene, a model reaction was started with an equimolar (1:1:1:1) involving the four-component domino reaction between 4-chlorobenzaldehyde (1a) (1.0 mmol), malononitrile (2) (1.0 mmol), 1,3-thiazolidinedione (3) (1.0 mmol), and aniline (4a) (1.0 mmol). Scheme 2 is selected to elevate catalysts and conditions, reaction media, and catalyst dosage. As shown in Table 1, it was seen that when the reaction was performed in the absence of a catalyst in water, acetonitrile, and ethanol, the desired product was obtained in yields of only 15 and 20%, even after 9 h (Table 1, entries 1–3). We tried the reaction using changed catalysts such as CTAB, p-TSA, Et3N, Cs2CO3, β-CD, [Et3NH][HSO4], [DBUH][OAc], PEG-400, ChCl/2ZnCl2, ChCl/2 urea, pyrrolidine ammonium acetate, piperidine ammonium acetate, triethyl ethyl ammonium acetate, DIPEAc, [bmim]Br, PEG-400/H2O, DABCO, and dicationic ionic liquid (Table 1, entries 4–26). During the screened catalysts, surprisingly, among all the catalyst at room temperature, DIPEAc showed an excellent yield (94%) with a low E-factor (0.25) (Table 1, entry 26). To accomplish a successful reaction transformation, we did a couple of temperature screening experiments and found the optimal reaction temperature (room temperature) (Table 1, entries 14–16, 18–22, and 28–38). In the presence of DIPEAc, this time, we have been seeing a new spot on the thin-layer chromatographic plate along with some unreacted 4-chlorobenzaldehyde (1a) and malononitrile (2) (Table 1, entries 13–22). Structural elucidation from 1H NMR, 13C NMR, and liquid chromatography–mass spectrometry (LC–MS) analysis of the isolated product gave an uncompleted Knoevenagel adduct because of the hygroscopic nature of malononitrile; then, we changed the equimolar ratio of malononitrile and optimized the model reaction, and we observed that the respective molar proportion for the model reaction between 4-chloro-benzaldehyde (1a) and malononitrile (2) changed from 1:1:1:1 to 1:1.2:1:1. This means that during the reaction, the molar proportion of malononitrile (2, 1.2 mmol) required was some more that of 4-chlorobenzaldehyde (1, 1 mmol), thiazolidinedione (3, 1 mmol), and aniline (4, 1 mmol). Employing this aspect, compound 5a was isolated in 94% yield after only 30 min at room temperature. The model reaction in water using phase transfer catalysts was found to form the desired 5a in less yields. Therefore, it can be thought that DIPEAc (Scheme 3) is a superior and green catalyst and solvent compared to the others shown in Table 1.

Scheme 2. One-Pot Four-Component Reaction of 4-Chlorobenzaldehyde (1a, 1 mmol), Malononitrile (2, 1 mmol), 1,3-Thiazolidinedione (3, 1 mmol) and Aniline (4a, 1 mmol) under Different Conditions.

Scheme 2

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Table 1. Efficiency Comparative Study of Various Catalysts for the Synthesis of 5-Amino-4-cyano-3-phenyl-N-(phenyl carbamoyl)-2,3-dihydrothiophene-2-carboxamide (5a)a.

entry catalyst representative molar ratio of reactants 1–4 medium time yieldb (%)/time (h) E-factor (without catalyst) E-factor (with catalyst)
1   (1:1:1:1) H2O 9 h trace    
2   (1:1:1:1) EtOH 9 h trace    
3   (1:1:1:1) CHCN 9 h 25    
4 Cs2CO3 (1:1:1:1) EtOH 7 h 41 2.02 2.19
5 p-TSA (1:1:1:1) H2O 7 h 52 1.57 1.63
6 β-CD (1:1:1:1) H2O 6 h 40 1.63 1.70
7 CTAB (1:1:1:1) H2O 6 h 51 1.41 1.49
8 Et3N (1:1:1:1) EtOH 6 h 56 3.29 3.50
9 [Et3NH][HSO4] (1:1:1:1) [Et3NH][HSO4] 6 h 60 1.83 2.07
10 [DBUH][OAc] (1:1:1:1) [DBUH][OAc] 6 h 62 1.49 1.87
11 ChCl:2urea (1:1:1:1) ChCl:2urea 2 h 68 1.73 2.09
12 ChCl:2ZnCl2 (1:1:1:1) ChCl:2ZnCl2 3 h 65 1.02 1.23
13 PEG-400 (1:1:1:1) PEG-400 6 h 52 1.22 1.49
14 PEG-400 (1:1:1:1) H2O 6 h 78 1.82 2.07
15 pyrrolidine ammonium acetate (1:1:1:1) pyrrolidine ammonium acetate 5 h 62 1.68 1.68
16 piperidine ammonium acetate (1:1:1:1) piperidine ammonium acetate 5 h 65 0.32 0.40
17 triethyl ethylammonium acetate (1:1:1:1) triethyl ethylammonium acetate 5 h 68 0.82 0.65
18 [bmim]Br (1:1:1:1) [bmim]Br 4 h 62 0.79 0.91
19 DABCO (1:1:1:1) H2O 6 h 63 0.77 0.95
20 dicationic ionic liquid (1:1:1:1) dicationic ionic liquid 6 h 73 0.82 0.93
21 DIPEAc (1:1:1:1) H2O 3 h 70 0.72 0.72
22 DIPEAc (1:1:1:1) EtOH 1 h 72 0.62 0.36
23 DIPEAc (1:1:1:1) DIPEAc 45 min 82 0.19 0.30
24 DIPEAc (1:1.2:1:1) H2O 3 h 75 0.72 0.72
25 DIPEAc (1:1.2:1:1) EtOH 1 h 73 0.62 0.36
26 DIPEAc (1:1.2:1:1) DIPEAc 30 min 94 0.20 0.25
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a

Reaction conditions: 4-chloro benzaldehyde (1.0 mmol), malononitrile (1.2 mmol), 1,3-thiazolidinedione (1.0 mmol), and aniline (1.0 mmol) in a medium (4 mL) stirred at room temperature.

b

Isolated yields b: no condensation. Bold values are for highlighting the good result.

Scheme 3. Synthesis of Diisopropyl Ethyl Ammonium Acetate (DIPEAc).

Scheme 3

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From this optimization of catalysts, we can conclude that DIPEAc gives a better yield of the desired product. After the effective optimization of the catalyst, we also investigated the catalyst loading in the model reaction DIPEAc for the synthesis of 5a. To assure the volume of the DIPEAc, the model reaction was investigated by a number of trials by changing the catalyst loading from 1 to 5 mL; as the amount of DIPEAc rises progressively, there is a steady growth noticed in the product yield. Then, 4 mL of DIPEAc furnished the 5a in 94% yield at room temperature (Table 2, entry 1) and completed an excellent renovation of the reactants into the product in room-temperature DIPEAc at room temperature for 30 min (HPLC = 98.81%). Further, an increase in the amount of DIPEAc showed no significant difference in reaction time and product yield. The model reaction was performed without any solvent and catalyst. The very small amount of the product was obtained after a prolonged period (Table 2, entry 1).

Table 2. Solvent Impact on the Reaction for Synthesis of 2-(N-Carbamoyl Acetamide)-Substituted 2,3dihydrothiophene Derivatives in Room Temperature DIPEAca.

entry DIPEAc temp. (°C) solvent time (min) yield (%)b
1 0 room temp.   24 h Trace
2 1 mL room temp.   30 60
3 2 mL room temp.   30 75
4 3 mL room temp.   30 80
5 4 mL room temp.   30 94
6 5 mL room temp.   45 95
7 20 mol % reflux EtOH 320 80
8 20 mol % reflux H2O 320 75
9 20 mol % reflux CH3CN 320 55
10 20 mol % reflux MeOH 320 75
11 20 mol % reflux DMF 320 52
12 20 mol % reflux CH2Cl2 320 50
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a

Reaction conditions: 4-chloro benzaldehyde (1.0 mmol), malononitrile (1.2 mmol), 1,3-thiazolidinedione (1.0 mmol), and aniline (1.0 mmol) in a medium (4 mL) stirred at room temperature.

b

Isolated yields b: no condensation. Bold values are for highlighting the good result.

Moreover, the performance of DIPEAc was examined by using 20 mol % DIPEAc in different solvents (Table 2, entries 7–12). In ethanol, we detect a preferred reaction medium, and no sticky reaction mass was formed. Still, the isolated reaction yield (73%, E-factor = 0.62) was not satisfactory than that of DIPEAc (94%, E-factor = 0.25), the reaction conversion with a readily superior yield. Meanwhile, in acetonitrile, water, methanol, CH2Cl2, DMF, and DCM reaction, output had lesser yields at reflux temperature. Not any of the solvents persist the superiority of yield and time over the non-solvent condition. Hence, the solventless condition was considered as excellent for the environmental suitability and cost.

As far as sustainable development is concerned, the fastest reaction time and highest efficiency for the formation of dihydrothiophene ureidoformamides were found at room temperature by using 4 mL of DIPEAc. Having excellent conditions in hand, the flexibility of the procedure was investigated for the synthesis of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophenes (5aa–5aam). We afterward examined the substrate scope by the reaction of different substituted aromatic/heteroaromatic aldehyde and aniline-subsumed methoxy, cyano, methyl, halogen (−Cl, −F, and −Br), hydroxyl, and nitro groups were used. The outcomes of all transformations carried out under these conditions are shown in Table 3. Aniline- and aldehyde-containing electron-withdrawing group like −NO2 and electron-donating groups like −OMe and −Me on the aromatic ring was suited with this transformation, and comparable 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophenes (5aa–5aam) were achieved in good to high yields. To our enchantment, halogen-substituted 2-benzylidene malononitrile gave the products with high yields (5ab, 5ak, and 5ao). Furthermore, sterically crowded di- and trisubstituted benzaldehyde gave the desired outcomes in high yields (5ah, 5aai, and 5aae). The aliphatic aldehydes and heteroaryl aldehydes also remained under the current reaction medium without any trouble (5ay, 5aad, and 5aah).

Table 3. Substrate Scope for Synthesis of 2-(N-Carbamoyl acetamide)-Substituted 2,3-Dihydrothiophene Derivatives in Room-Temperature DIPEAca.

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a

Reaction conditions: 4-chloro benzaldehyde (1.0 mmol), malononitrile (1.2 mmol), 1,3-thiazolidinedione (1.0 mmol), and aniline (1.0 mmol) in a medium (4 mL) stirred at room temperature. Isolated yields in parentheses: no condensation.

To describe the mechanism of this one-pot multicomponent reaction of aryl aldehyde (1), malononitrile (2), 1,3-thiazolidinedione (3), amines (4), and formation of 2- (N-carbamoyl acetamide)-substituted 2,3-dihydrothiophenes (5aa–5aam) in the presence of room-temperature DIPEAc (12), we suggest a plausible reaction mechanism, which is demonstrated in Scheme 4.

Scheme 4. Plausible Mechanism for the Formation of 2-(N-Carbamoyl acetamide)-Substituted 2,3-Dihydrothiophenes.

Scheme 4

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The first step is the DIPEAc (12) catalyzing the synthesis of arylidene malononitrile (13) derived from the Knoevenagel condensation of the aromatic aldehyde (1) with malononitrile (2) after removing one molecule of water. In the next stage, 1,3-thiazolidinedione (3) in the existence of DIPEAc (12) transforms to its corresponding enolate (3a) and adds to the arylidene malononitrile (13) by Michael addition of the carbanion of 1,3-thiazolidinedione to arylidene cyanoacetamide (14). Then, the cyclic secondary amine (4) attacks the carbonyl group of 1,3-thiazolidinedione to open its ring and cause the formation of a sulfide anion (15) and the intramolecular addition of a sulfide anion to the cyano group in the intermediate (16). After this, at last thiophene (5) is produced by a dehydrogenation process in air. The DIPEAc medium was the best promoter for the preparation of dihydrothiophene derivatives; reasons for this could be explained as follows: (1) the use of DIPEAc raises the solubility of reagents, which results to a higher interfacial area and lower mass transfer resistance.52 (2) The promoting impact of DIPEAc to the reaction could be credited to its hydrophobic, polarity, and hydrogen-bonding effects53,54 (Scheme 4), making it easy to develop related products. It was revealed that only polar protic solvents could give the expected outcome, and the hydrogen-bonding effect is the main difference between other solvents and polar protic solvents, so the hydrogen-bonding effect may be the key factor to facilitate the reaction.

It is noteworthy that there is sometimes one or more feasible reaction pathway for MCRs.55 To verify the reliability of the proposed mechanistic way for the one-pot four-component reaction of aryl aldehydes, malononitrile, 1,3-thiazolidinedione, and amines in the presence of DIPEAc (4 mL) at room temperature (Scheme 5), some individual trials were designed and carried out. Primarily, 4-chlorobenzaldehyde (1a, 1 mmol) was reacted with malononitrile (2, 1.2 mmol) in the presence of DIPEAc (4 mL) as a catalyst and solvent at room temperature, and the 2-(4-chlorobenzylidene)malononitrile (13b) was achieved in 98% yield after 5 min (Scheme 5a). In the next stage, the possibility of the Michael addition of 1,3-thiazolidinedione (3) to the arylidene malononitrile (13b) in the presence of DIPEAc was verified. Therefore, the newly synthesized 2-(4-chlorobenzylidene) malononitrile (1 mmol) was treated with 1,3-thiazolidinedione (3, 1 mmol) in the presence of DIPEAc (4 mL) at room temperature and as expected, 2-((4-chlorophenyl) (2,4-dioxothiazolidin-5-yl) methyl) malononitrile (14a) was achieved in 95% yield after 20 min (Scheme 5b). Eventually, the synthesized 2-((4-chlorophenyl)-(2,4-dioxothiazolidin-5-yl) methyl) malononitrile (14a, 1 mmol) was treated with aniline (4a, 1 mmol) under the ideal reaction conditions, and the desired product (5aa) was achieved in 94% isolated yield after 30 min. (Scheme 5c)

Scheme 5. Study of the Reliability of the Proposed Reaction Pathway for the Synthesis of 5-Amino-4-cyano-3-phenyl-N-(phenyl carbamoyl)-2,3-dihydrothiophene-2-carboxamide in the Presence of DIPEAc at Room Temperature.

Scheme 5

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As far as sustainability is concerned, it is required to confirm the existing procedure with well-established “green metrics” such as the atom economy, reaction mass efficiency, E-factor, optimum efficiency, and practical mass yield.56−59

The E-factor is an extensively used green metric for chemical reactions. The lesser the value of the E-factor is, the more eco-compatible the reaction is. The E-factor ranging from 0.13 to 0.5 highlighted the greenness of the protocol shown in Figure 2.

Figure 2.

Figure 2

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Radar chart of measured green metrics for the synthesis of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophenes (5aa–5aam).

Later, we measure the green chemistry metrics for both model reactions to afford 5aa and 5ab under optimized reaction conditions, as demonstrated in Table 4. The outcome revealed that the values of green chemistry metrics such as atom economy (AE), E-factor, optimum efficiency (OP), reaction mass efficiency (RME), and effective mass yield (EY) are nearly as close to their ideal values as demonstrated here (see the Supporting Information for detailed calculations).

Table 4. Quantitative Evaluation of Green Chemistry Metrics for 5aa and 5ab.

sr. no. green chemistry merits ideal value product (5aa) product (5ab)
1 E-factor 0 0.20 0.18
2 atom economy (AE) 100% 95.67 96.02
3 reaction mass efficiency (RME) 100% 84.50 84.09
4 optimum efficiency 100% 88.32 87.57
5 effective mass yield 100% 84.50 84.09
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To verify the catalytic performance of the catalyst, DIPEAc (diisopropyl ethyl ammonium acetate), shown in Figure 3, the IR spectra of the recovered DIPEAc (after four cycles) were observed to correspond with those of the fresh sample. As authenticated in Figure 4, the IR spectra shown by the recovered catalyst were proven to be almost identical to the fresh one.

Figure 3.

Figure 3

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Recyclability of the catalyst.

Figure 4.

Figure 4

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IR spectra of reuse and recovery of DIPEAc (green spectrum: fresh; orange spectrum: after IV recycles).

Antimicrobial Screening

In the route of identifying several novel antimicrobial agents, we are especially curious about the present work with novel 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene derivatives. In this paper, the antimicrobial screening of 39 newly synthesized compounds was screened against four bacteria and four fungi using the agar well diffusion method. Zone of inhibition (μg/mL) values are displayed in Table 5.60,61 The outcomes showed that majority of the synthesized compounds demonstrated antimicrobial activities against four bacteria Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Bacillus subtilis (B. subtilis), and Staphylococcus aureus (S. aureus) and four fungal strains Aspergillus niger (A. niger), Aspergillus flavus (A. flavus), Fusarium oxysporum (F. oxysporum), and Candida albicans (C. albicans). The standard drugs ampicillin, ciprofloxacin, miconazole, and fluconazole were used as standards for antibacterial and antifungal activities, respectively. The achieved results revealed that most of the compounds have demonstrated satisfactory to superb inhibitory activity against the four tested bacteria and fungi. The electronic property of the compounds has an adjacent correlation with their biological activity as illustrated in Figure 5. A stepwise molecular optimization to the scaffold of most potent compounds 5al, 5ao, 5as, 5az, 5ae, 5af, and 5ai and the molecular area highlighted in Figure 5 explored the SAR.

Table 5. Antimicrobial Screening of 2-(N-Carbamoyl acetamide)-Substituted 2,3-Dihydrothiophenes (5aa–5aam).

    antibacterial activitya
 antifungal activitya
sr. no. structure code E. coli P. aeruginosa S. aureus B. subtilis C. albicans F. oxysporum A. flavus A. niger
1 5aa 76 ± 0.22 60 ± 0.34 31 ± 0.09 95 ± 0.75 100 ± 2.79 125 ± 0.577 100 ± 2.886 125 ± 2.886
2 5ab 39 ± 0.46 92.4 ± 0.28 98.3 ± 0.20 51.3 ± 0.81 55 ± 2.785 50 ± 1.443 45 ± 0.577 40 ± 2.886
3 5ac 71 ± 0.38 96 ± 0.40 71.7 ± 0.61 66.1 ± 0.64 80 ± 1.442 75 ± 1.443 85 ± 1.154 66.1 ± 0.64
4 5ad 95 ± 0.38 130.7 ± 0.87 100 ± 0.25 76 ± 0.39 70 ± 2.786 80 ± 1.443 90 ± 1.443 100 ± 1.154
5 5ae 97.7 ± 0.65 65.7 ± 0.87 24.6 ± 0.95 97.2 ± 0.81 30 ± 1.443 25 ± 2.500 20 ± 1.443 25 ± 1.443
6 5af 66.8 ± 0.34 68.6 ± 0.54 74.2 ± 0.19 88.9 ± 0.37 30 ± 2.886 35 ± 2.500 20 ± 1.154 20 ± 2.500
7 5ag 92.1 ± 0.74 57.1 ± 0.34 75.2 ± 0.37 93.7 ± 0.64 *b 100 ± 2.500 150 ± 1.154 175 ± 1.443
8 5ah 52.0 ± 0.63 88.1 ± 0.35 90.4 ± 0.76 55.8 ± 0.19 150 ± 2.889 90 ± 2.500 90 ± 2.500 100 ± 1.154
9 5ai 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 35 ± 1.443 35 ± 1.154 20 ± .154 20 ± 2.500
10 5aj 77.38 ± 0.67 44.3 ± 0.34 64.2 ± 0.75 109.2 ± 0.44 60 ± 2.886 65 ± 1.443 50 ± 2.886 70 ± 2.500
11 5ak 59.3 ± 0.33 82.3 ± 0.57 35.3 ± 0.63 84.5 ± 0.71 55 ± 1.287 50 ± 1.154 50 ± 1.443 70 ± 2.886
12 5al 88.4 ± 0.31 92.3 ± 0.44 80 ± 0.17 122.3 ± 0.34 35 ± 1.156 40 ± 0.2886 20 ± 1.154 25 ± 1.154
13 5am 71.9 ± 0.30 102.5 ± 0.94 66.8 ± 0.90 48.3 ± 0.84 70 ± 2.886 70 ± 1.443 60 ± 0.577 80 ± 1.443
14 5an 98.3. ± 0.74 104.6 ± 0 .09 83.0 ± 0.22 52.8 ± 0.10 2500 ± 1.111 25 ± 1.443 15 ± 1.443 20 ± 0.10
15 5ao 41.6 ± 0.90 79.3 ± 0.4 101.3 ± 0.62 88.1 ± 0.22 40 ± 1.154 35 ± 2.500 25 ± 1.443 88.1 ± 1.443
16 5ap 168.1 ± 0.64 195.1 ± 0.37 108.5 ± 0.61 156.6 ± 0.78 60 ± 1.154 65 ± 1.443 50 ± 2.886 70 ± 2.500
17 5aq 151.0 ± 0.64 188.7 ± 0.74 164.1 ± 0.31 139.7 ± 0.47 30 ± 1.443 25 ± 2.500 25 ± 2.886 50 ± 1.154
18 5ar 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 50 ± 1.154 60 ± 1.443 40 ± 1.443 45 ± 2.500
19 5as 32 ± 0.46 90.01 ± 0.28 98.3 ± 0.20 50.3 ± 0.81 50 ± 1.154 55 ± 2.500 50 ± 2.886 26 ± 1.653
20 5at 98.7 ± 0.77 104.6 ± 0.06 84.0 ± 0.46 88.1 ± 0.71 100 ± 2.852 125 ± 2.886 100 ± 1.443 100 ± 1.500
21 5au 167.1 ± 0.64 193.1 ± 0.37 105.5 ± 0.61 152.6 ± 0.78 60 ± 2.886 65 ± 1.443 50 ± 2.886 70 ± 2.500
22 5av 61 ± 0.38 86 ± 0.40 61.7 ± 0.61 56.1 ± 0.64 50 ± 1.154 55 ± 1.154 50 ± 1.443 50 ± 2.500
23 5aw 95.3. ± 0.74 108.6 ± 0 .09 73.0 ± 0.22 62.8 ± 0.10 40 ± 1.154 35 ± 2.500 25 ± 1.443 30 ± 1.154
24 5ax 53.0 ± 0.73 98.1 ± 0.35 91.4 ± 0.77 56.8 ± 0.19 45 ± 1.154 40 ± 1.154 35 ± 2.500 40 ± 1.443
25 5ay 72.9 ± 0.40 103.5 ± 0.94 56.8 ± 0.90 58.3 ± 0.84 60 ± 2.886 65 ± 1.443 50 ± 2.886 70 ± 2.500
26 5az 76.8 ± 0.34 58.6 ± 0.54 84.2 ± 0.19 * 25 ± 1.154 30 ± 1.443 20 ± 1.154 *
27 5aaa 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 100 ± 2.79 125 ± 0.577 100 ± 2.886 125 ± 2.886
28 5aab 52.0 ± 0.63 88.1 ± 0.35 90.4 ± 0.76 55.8 ± 0.19 50 ± 1.154 55 ± 2.500 50 ± 2.886 26 ± 1.653
29 5aac 59.3 ± 0.33 82.3 ± 0.57 35.3 ± 0.63 84.5 ± 0.71 150 ± 2.889 90 ± 2.500 90 ± 2.500 100 ± 1.154
30 5aad 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 80 ± 1.442 75 ± 1.443 85 ± 1.154 66.1 ± 0.64
31 5aae 71 ± 0.38 96 ± 0.40 71.7 ± 0.61 66.1 ± 0.64 60 ± 2.886 65 ± 1.443 50 ± 2.886 70 ± 2.500
32 5aaf 98.7 ± 0.77 104.6 ± 0.06 84.0 ± 0.46 88.1 ± 0.71 50 ± 1.154 60 ± 1.443 40 ± 1.443 45 ± 2.500
33 5aag 98.7 ± 0.77 104.6 ± 0.06 84.0 ± 0.46 88.1 ± 0.71 25. ± 1.111 25 ± 1.443 15 ± 1.443 20 ± 0.10
34 5aah 167.1 ± 0.64 193.1 ± 0.37 105.5 ± 0.61 152.6 ± 0.78 150 ± 2.889 90 ± 2.500 90 ± 2.500 100 ± 1.154
35 5aai 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 70 ± 2.886 70 ± 1.443 60 ± 0.577 80 ± 1.443
36 5aaj 71 ± 0.38 96 ± 0.40 71.7 ± 0.61 66.1 ± 0.64 50 ± 1.154 60 ± 1.443 40 ± 1.443 45 ± 2.500
37 5aak 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 100 ± 2.500 * 150 ± 1.154 175 ± 1.443
38 5aal 61 ± 0.38 86 ± 0.40 61.7 ± 0.61 56.1 ± 0.64 60 ± 2.886 65 ± 1.443 50 ± 2.886 70 ± 2.500
39 5aam 165.7 ± 0.54 166.7 ± 0.34 204.7 ± 0.33 191.5 ± 0.82 100 ± 2.852 125 ± 2.886 100 ± 1.443 100 ± 1.500
std ampicillin 100 ± 1.24 100 ± 2.14 250 ± 2.99 250 ± 0.88        
std ciprofloxacin 25 ± 1.00 25 ± 1.15 50 ± 1.44 50 ± 0.96        
std miconazole         25 ± 2.886 25 ± 1.443 12.5 ± 1.443 12.5 ± 0.88
std fluconazole         5 ± 2.500 5 ± 1.154 50 ± 1.154 10 ± 2.500
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a

Values are the average of three readings.

b

All asterisks denote that no activity was observed up to 200 μg/mL.

Figure 5.

Figure 5

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Structure–activity relationship (SAR) of hybrid compounds.

The compounds 5ae, 5af, 5al, 5ao, and 5as revealed good antibacterial activity against all four bacterial pathogens. The compounds 5ae, 5af, 5ai, 5az, 5aai, and 5aag showed excellent activity against all four fungal strains because of the presence of electron-withdrawing substituents (−NO2, −Br, and −Cl) and electron-donating substituents (−CH3 and −OCH3) in the molecule. Compounds 5ae, 5af, and 5ai showed good antibacterial and antifungal activity against the Gram-positive strains E. coli,P. aeruginosa,S. aureus,B. subtilis,C. albicans,F. oxysporum,A. flavus, and A. niger. We imagine that the presence of a 2,3-dihydrothiophene ring, −NO2, −CH3, and −OCH3 moieties in the molecule contributes significantly to the antibacterial and antifungal activity.

Molecular Docking

To clarify the possible mechanism by which the dihydrothiophene ureidoformamides investigated herein can induce antifungal activity, and to further guide the SAR, an in silico binding study through molecular docking was performed against an important fungal target-sterol 14α-demethylase (CYP51), inhibition of which could prevent the conversion of lanosterol to ergosterol, causing the accumulation of 14α-methyl sterols in the cell and leading to impaired cell growth in fungi. This in silico molecular docking approach has now become an integral part of the drug discovery protocol, especially in the absence of available resources to perform the enzymatic assays, imparting knowledge on binding modes, affinities, and the associated thermodynamic interactions with the target enzyme that govern the inhibition of the causative pathogen. The Glide (grid-based ligand docking with energetics) module integrated into the Schrödinger molecular modeling package (Schrödinger, LLC, New York, NY, 2015) was used to predict the binding modes of dihydrothiophene ureidoformamides into the active site of the sterol 14α-demethylase (CYP51) enzyme.62 The 3D crystal structure of sterol 14α-demethylase (CYP51) complexed with its inhibitor fluconazole (PDB code: 3KHM) was retrieved from the RCSB Protein Data Bank (PDB) (https://www.rcsb.org/pdb) and preprocessed using the protein preparation wizard applying the OPLS-2005 force field, which includes the elimination of all crystallographically observed water molecules (as there is no conserved interaction with the enzyme), appending the missing hydrogen/side-chain atoms corresponding to pH 7.0 considering the appropriate ionization states for the acidic and basic amino acid residues, identification of atom/residue overlaps, creating the disulfide bonds, assignment of reasonable charge and protonation state to the obtained structure, and finally energy minimization of the obtained structure until the average r.m.s.d. of non-hydrogen atoms converged to 0.3 Å. Next, the shape and properties of the active site of the enzyme for docking were defined using the receptor grid generation panel for which a grid box of 10 × 10 × 10Å dimensions around the co-crystallized ligand (serving as the reference coordinate to signify the active site for the inhibitor) was generated, which was large enough to explore the 3D space of the enzyme cavity. The 2D structure of dihydrothiophene ureidoformamides was sketched with the build panel of Maestro and converted to an energy-minimized 3D structure for docking using the ligand preparation tool. Flexible docking was carried out using this setup to gauze the binding affinities of the title compounds against the active site of sterol 14α-demethylase using the extra precision (XP) Glide scoring function.

The enzyme–inhibitor complexation predicted by molecular docking showed that all these dihydrothiophene ureidoformamides could bind to CYP51 with a significant binding affinity adopting a similar orientation, and their complexes were stabilized by the formation of several bonded and non-bonded interactions. Their binding energies, which signify the binding relationship, were observed to be negative (−59.484 to −38.094 kcal/mol), while the average docking score was seen to be −7.841 kcal/mol. Furthermore, analysis of the per-residue interaction between these molecules and the active site residues of the enzyme was carried out to identify the most significantly interacting residues and their type of thermodynamic interactions, which is critical in lead optimization. This analysis is discussed for one of the most active analog 5aag and is summarized in Table S1 (see in the Supporting Information) for the remaining molecules in the series.

The lowest energy-docked conformation of 5aag (Figure 6) showed that it is deeply embedded into the active pocket of CYP51 with significant binding affinity, producing a Glide docking score of −9.702 and Glide binding energy of −59.484 kcal/mol. It could occupy the same coordinates as the native ligand engaging in a close network of bonded and non-bonded interactions with the residues forming the active site. It was found to be stabilized into the active site through a series of significant van der Waals interactions observed with Val461 (−2.854 kcal/mol), Met460 (−2.482 kcal/mol), Thr459 (−1.137 kcal/mol), Thr295 (−1.33 kcal/mol), His294 (−1.317 kcal/mol), Ala291 (−3.078 kcal/mol), Leu208 (−2.718 kcal/mol), Glu205 (−1.264 kcal/mol), Met106 (−3.171 kcal/mol), and Tyr103 (−3.504 kcal/mol) through the N-(5-amino-4-cyano-3-(4-flurophenyl)-2,3-dihydrothiophene core group, while the pyridine-linked carboxamide side chain showed a similar network of interactions with Cys422 (−1.111 kcal/mol), Leu356 (−2.936 kcal/mol), Ala287 (−1.553 kcal/mol), Leu127 (−1.254 kcal/mol), Tyr116 (−4.448 kcal/mol), Phe110 (−1.011 kcal/mol), and Ile105 (−1.124 kcal/mol) residues lining the active site. Furthermore, the enhanced binding affinity of 5aag is also attributed to significantly favorable electrostatic interactions observed with Ala291 (−1.297 kcal/mol), Phe290 (−1.312 kcal/mol), Tyr 116 (−1.361 kcal/mol), and Glu101 (−1.015 kcal/mol) residues. Being a metalloprotein, CYP51 was expected to engage in a significant interaction with the ligand through the prosthetic Hem moiety, which was observed for 5aag also wherein the compound showed significant van der Waals (−4.963 kcal/mol) and electrostatic (−3.696 kcal/mol) interactions with them contributing significantly to binding affinity. While the non-bonded (steric and electrostatic) interactions were observed to be the major driving force for the mechanical interlocking of 5aag, the higher binding affinity is also supported by a prominent hydrogen-bonding interaction observed through Ala291 (2.419 Å), Phe290 (2.214 Å), and Tyr116 (2.679 Å).

Figure 6.

Figure 6

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Binding mode of 5aag into the active site of sterol 14α-demethylase (CYP51) (on the right side: the pink lines represent the hydrogen bonding, while the green lines signify π–π stacking interactions).

Furthermore, a very close π–π stacking interaction was also observed with Tyr116 (2.68 Å). Such hydrogen-bonding and π-stacking interactions serve as an “anchor” guiding the orientation of the ligand into the 3D space of the enzyme active site and facilitate the steric and electrostatic interactions therein. A similar network of bonded and non-bonded interactions was observed for other molecules in the series, guiding their binding to CYP51 (see the Supporting Information, S1–S25). The inference derived from this in silico binding studies is now fruitfully utilized for the structure-based lead optimization to arrive at potent molecules with this scaffold.

Conclusions

In conclusion, we have designed a very facile, simple, conveniently practical, and energy-efficient method for easy access of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene derivatives in the presence of DIPEAc (diisopropyl ethyl ammonium acetate) as a reusable catalyst and reaction medium via a one-pot four-component domino reaction at room temperature. Operational simplicity, clean reaction profiles, mild reaction conditions, absence of tedious separation procedures, high atom economy, energy efficiency, excellent yields, and the use of a low-cost and environmentally sustainable ionic liquid are the main advantages of the present method. Likewise, recycling of the reaction media is an added superiority to this protocol. Keeping in mind that the synthetic significance of such pharmacologically relevant 2,3-dihydrothiophene scaffolds directly relates to medicinal chemistry, the present methodology with mild operational simplicity and reaction conditions offers the possibility of its use with cost-effective and environmentally friendlier ways for Gram-scale industrial syntheses as well. Also, a series of 2-(N-carbamoyl acetamide)-substituted 2,3-dihydrothiophene analogs were screened for their in vitro antibacterial and antifungal activities. Molecular docking studies of all new derivatives showed a high binding affinity toward sterol 14α-demethylase (CYP51). They provided clues for further modification of the scaffold to improve the activity and selectivity toward the target.

Experimental Section

General Information

All solvents and reagents were purchased from Merck, Fluka, and Sigma Aldrich chemical companies. TLC accomplished the reaction monitoring on silica gel F254 (Merck, Germany) plates. The eluent solvents were ethyl acetate, petroleum ether, or a mixture of them. Their spectral data analysis characterized the products. Melting points were determined in open capillary tubes with a Buchi B-545 melting point apparatus. 13C NMR (100 MHz) and 1H NMR (250 MHz) spectra were run on a Bruker Avance DRX-250 and Bruker Avance DRX-400, respectively, in pure DMSO-d6 or CDCl3 solvents. IR spectroscopy (Shimadzu FT-IR 8300), in cm–1, was employed for the characterization of the compounds. The HPLC analysis of all compounds was performed on an MS-Agilent 6120 quadrupole system.

General Procedure for the Synthesis of Diisopropyl Ethyl Ammonium Acetate (DIPEAc)

A mixture of anhydrous acetic acid (1 mmol) and N,N-diisopropylethylamine (1 mmol) was stirred at 0–10 °C for 20 min. The viscous liquid, diisopropyl ethyl ammonium acetate, was achieved.16,26

General Procedure for the One-Pot Four-Component Synthesis of 2-(N-Carbamoyl acetamide)-Substituted 2,3-Dihydrothiophenes (5aa–5aaj) in the Presence of DIPEAc

A mixture of appropriate aldehyde (1.0 mmol) and malononitrile (1.2 mmol, 0.06 g) was added to a 25 mL round-bottom flask containing a suspension of DIPEAc (4 mL), and the resulting mixture was stirred at room temperature for 2 min. Then, 1,3-thiazolidinedione (1.0 mmol, 0.11 g) and the amine (1.0 mmol) were added, and the reaction mixture was stirred at the same temperature, and use of the TLC followed the progress of the reaction. At the end of the reaction (indicated by thin-layer chromatography), the solvent was recovered, and 5 mL of distilled water was added to the crude product and allowed to stir at room temperature to make the catalyst soluble and for complete solidification of the final product. The precipitates were washed thoroughly twice with 5 mL of distilled water to afford the desired products in pure form. All synthesized compounds were fully characterized based on analytical and spectral studies such as IR, 1H NMR, 13C NMR, and HPLC analysis (for representative compounds 5aa and 5ab).

Acknowledgments

The author C.K.J. is very much thankful to the Council for Scientific and Industrial Research (CSIR), New Delhi, for the award senior research fellowship. The author is also grateful to the Authority of Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad- 431004, India, for providing the laboratory facility. We are also thankful to SAIF, CSIR-CDRI, Lucknow, and BITS-Pilani, India for providing spectral analysis data.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c03575.

  • Analytical and spectroscopic data, a copy of 1H NMR and 13C NMR spectra, HPLC reports (5aa-5ab), and calculation of green metrics for compound 5aa as a representative entry (PDF)

Author Contributions

The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript.

The authors declare no competing financial interest.

Notes

This work is dedicated to my beloved parents.

Supplementary Material

ao0c03575_si_001.pdf (8.5MB, pdf)

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