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Fe3O4@PmPDA@UiO–66-NH2 multi-functional nanocatalyst for the synthesis of biologically active Pyrazolopyranopyrimidines: Antimicrobial, antioxidant and anticancer Behavior Studies

Shefa Mirani Nezhad1, Seied Ali Pourmousavi1*, Ehsan Nazarzadeh Zare1*

1 School of Chemistry, Damghan University, Damghan, 36716–45667, Iran

*Corresponding authors-Email: pourmousavi@du.ac.ir (S. A.P); ehsan.nazarzadehzare@gmail.com, e.nazarzadeh@du.ac.ir (E. N. Z.)

Image1.jpeg

Abstract

Metal-organic frameworks are crystalline materials composed of metal ions or clusters coordinated to often rigid organic molecules, forming three-dimensional porous structures. This combination of inorganic and organic building blocks opens up almost unlimited chemical and structural possibilities. This potential has led to metal-organic frameworks for catalytic applications attracting great interest. In this context, polymer coated UiO–66-NH2 nanocomposite as a multifunctional magnetic catalyst has been synthesized in three steps including (1) synthesis of Fe3O4 nanoparticles by co-precipitation technique (2) preparation of UiO–66-NH2 through a solvothermal method, (3) preparation of nanoparticles-polymer-MOF hybrid nanocomposite using Fe3O4, poly meta-phenylenediamine (PmPDA), and UiO–66-NH2. The prepared catalyst was fully characterized by XRD, FTIR, EDX, FESEM, TGA and VSM analyses. The nanocomposite Fe3O4@PmPDA@UiO–66-NH2 was used as catalyst for the synthesis of pyrazolopyranopyrimidines. Various pyrazolopyranopyrimidine products were synthesized in remarkable yields (90–96 %) in a short reaction time (10–80 min). The biological activity of pyrazolopyranopyrimidines was studied. The anticancer evaluation of some pyrazolopyranopyrimidines was studied on the survival rate of HepG2 cancer cells and NIH/3T3 fibroblast cells by using an MTT assay. Furthermore, these compounds have an antioxidant activity between 85.3 and 98.3 %. and their antimicrobial activity against S. aureus and E. coli has been studied.

Keywords: UiO–66-NH2, pyrazolopyranopyrimidines, Nanocomposites, multi-functional catalyst.

1. Introduction

Metal-organic frameworks (MOFs), also known as porous coordination polymers (PCPs), are porous crystals linked by metal ions/clusters and multidentate organic ligands via coordination bonds. Because of their tunable functionality, specific surface structures, and diverse synthesis methods, MOFs are extensively applied in drug delivery [1,2] adsorption [3,4], sensing [5,6], catalysis [7,8], gas capture, storage and separation [9] and several other scientific research fields. MOFs have a three-dimensional network structure formed by coordination bonds between metal ions and multidentate organic ligands, and most of them show low thermal stability and poor water stability. [10] An octahedral structure was first described for the material UiO–66 (Zr). Compared to other MOFs, the biggest advantage is that UiO–66 has excellent thermal, chemical, anti-mechanical, and water stability [11].

Homogeneous catalysts offer high activity and selectivity due to their dissolved nature in the reaction medium. Due to the difficult separation, however, their recycling is complex and expensive. techniques such as thermal or chemical recovery, membrane processes and multiphase transfers improve separation and recycling.

Classical heterogeneous catalysts in industry often have lower activities and selectivities due to steric and diffusion factors. In order to improve catalyst activity and selectivity, nanoscale metal based catalysts and support have been proposed. Nanometer-sized supports increase surface area and form homogenous emulsions. Magnetic nanoparticles are widely used as catalyst supports due to their high surface area, stability, high loading capacity, and easy recycling. Magnetic separation simplifies catalyst recovery and tolerates most chemical environments except highly acidic or corrosive environments. Magnetic nanocomposites of various materials and compositions are used in a wide range of applications from engineering to biomedical fields [12,13]. Pyrazolopyranopyrimidines are polycyclic heterocycles composed of pyrazole, pyrimidine, and pyran units. The pyranopyrazole segment is important in the pharmaceutical field and is responsible for a variety of biological activities of molecules containing this segment. Such compounds may act as anticancer agents [14], Analgesic and Anti-inflammatory [15], antimicrobial [16], Antiplatelet [17], and antioxidant activity [18]. The pyranopyrimidine moiety, found in natural products is known for its biological activities such as antidiabetic [19], antimicrobial [20], anticancer agents [21], and antifungal activity [22].

Numerous protocols developing derivatives of pyrazolopyranopyrimidines have been reported in recent years. For example, the use of Merrifield resin [MerDABCOSO3H]Cl [23], using Triazole Bonded Silica Heterogeneous [24], Using Fe3O4@THAM-Piperazine [25], choline chloride:urea Deep Eutectic Solvent [26], UltrasoundAssisted [27], Tetramethylguanidin functionalized nanosize γAl2O3 [28], CoFe2O4@SiO2-PA-CC-Guanidine [29], DBUbased nanomagnetic [30], Yttrium-Metal–Organic Framework [31], and ZnFe2O4/ glutamic acid [32].

The development of the magnetic nanocomposite Fe3O4@PmPDA@UiO–66-NH2 and its use in the environmentally friendly and gentle synthesis of bioactive pyrazolopyranopyrimidines are the goals of the current work. Further investigations are carried out on the reusability of the catalysts and on the antioxidant and antibacterial properties of the end products. Benefits of the present study we can mention the efficiency and conversion of average product to higher and faster reaction time.

2. Experimental

2.1. Materials

Zirconium chloride, 2-aminoterephthalic acid, ferric chloride (FeCl3·6H2O), ferrous chloride (FeCl2·4H2O), HCl, m-Phenylenediamine, ammonium persulfate (APS), sodium hydroxide and solvents were purchased from Merck Company. Also, ethyl acetoacetate, ethyl benzoylacetate barbituric acid, phenylhydrazine and other reagents were purchased from Merck Company.

2.2. Synthesis of UiO–66-NH2

A mixture of 125 mg ZrCl4, 1 mL concentrated HCl and 5 mL DMF was added to a 100 mL vial. The contents of the vial were sonicated for 20 minutes to completely dissolve. Then 134 mg of BDC-NH2 (2-aminoterephthalic acid) in 10 mL DMF was added to the vial. The reaction mixture was sonicated for another 20 min and was heated at 80 °C overnight. At the end, the nanoparticles were collected through a centrifuge, the supernatant was removed and the nanoparticles were resuspended in DMF and centrifuged (wash twice), then suspended in EtOH and centrifuged again (Figure 1)..

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Figure 1. The synthesis procedure of UiO–66-NH2

2–3. Syntheis of Fe3O4 nanoparticles

FeCl2·4H2O (2.1 mmol) and FeCl3·6H2O (4.9 mmol) were dissolved in deionized water, The mixture was mechanically stirred at 80 °C for 15 min and NaOH solution (10%) was added to the mixture until the pH reached 10. After 30 minutes the black precipitate had been separated by magnetic and washed several times with deionised water and twice with ethanol (Figure 2)..

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Figure 2. The synthesis procedure of Fe3O4 nanoparticles

2–4. Syntheis of Fe3O4@PmPDA@UiO–66-NH2

In a 250 mL flask, 0.3 g of Fe3O4 nanoparticles and 0.35 g of UiO–66-NH2 were sonicated in 20 mL of distilled water for 30 min, then 1 g of mPDA monomer was dissolved in 100 mL of HCl solution (0.1 M) and was added to the reaction mixture. The reaction mixture was sonicated for another 30 min until the solid monomer was completely dissolved. Polymerization was initiated upon adding 10 mL of the APS in the HCl solution (0.1 mol/L). This addition was carried out within 1 h under magnetic stirring at room temperature. The reaction mixture was kept under continuous stirring using a magnetic stirrer in N2 atmosphere for 24 hours. In the end, the precipitated nanocomposite was separated with an external magnet and washed water and methanol several times. The resulting powder was dried in a vacuum oven at 50 °C for 1 h (Figure 3).

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Figure 3. The synthesis procedure of Fe3O4@PmPDA@UiO–66-NH2

2–5.General Procedure for the Synthesis of 3-subtituted 1-phenyl–1H-pyrazol–5-ol

The synthesis of 3-subtituted–1-phenyl–5-pyrazolone was performed by combining ethyl acetoacetate or ethyl benzoylacetate with phenylhydrazine (molar ratio of 1:1 in EtOH). Then acetic acid was added as a catalyst, followed by stirring for 2 h at reflux condition. After allowing the reaction mixture to cool, the crude solid product was filtered and further purified using ethanol recrystallization (Figure 4A)..

2.6. General route for the prepration of Pyrazolopyranopyrimidines

A mixture of 3-subtituted–1-phenyl–1H-pyrazol–5-ol (1.0 mmol), an aldehyde (1.0 mmol), barbituric acid (1.0 mmol), and Fe3O4@PmPDA@UiO–66-NH2 (0.05 g) in 5 mL EtOH was stirred at room temperature and monitored via thin-layer chromatography (ethyl acetate /hexane 5:1) until the reaction was complete. The catalyst was separated with an external magnet. The crude solid product was filtered and purified by crystallization in ethanol (Figure 4B)....

.

Broken image

Figure 4. Preparation of 3-subtituted–1-phenyl–1H-pyrazol–5-ol (A),, Synthesis of pyrazolopyranopyrimidines (B).

2.7. In Vitro Cell Viability Assay

To investigate the cytotoxicity of the synthesized compounds, the colorimetric 3-(4,5 dimethylthiazol–2-yl)–2, 5-diphenyl tetrazolium bromide (MTT) assay was performed as previously described [33]. Briefly, HepG2 cancer cells and NIH/3T3 fibroblast cells were seeded at a density of 5 × 103 cells per well in 96-well plates and incubated overnight at 37°C in a humidified 5% CO2 environment. Subsequently, the cells were treated with different concentrations of the synthesized compounds (150, 75, 37.5, 18.75, 9.375, and 0 μg/mL) for 24 and 48 h. After the predetermined periods, MTT solution (5 mg/mL) was added to each well, and the plates were further incubated at 37°C for 4 h. The medium was then removed, and DMSO (200 μL) was added to each well to dissolve the formazan crystals. The absorbance of the solubilized purple formazan was measured using a microplate spectrophotometer (BioTek, USA) at 540 nm. The cell viability percentage was calculated as follows:

Cell Viability percentage = (Absorbance of treated cells) / (Absorbance of untreated cells) × 100

3. Results and discussions

3.1. Characterization of of catalyst

FTIR: Figure 5A shows FT-IR spectra of PmPDA, UiO–66 and Fe3O4@PmPDA@UiO–66-NH2. In the FTIR spectrum of UiO–66-NH2, the peaks related to the symmetric and asymmetric stretching of the carboxyl functional groups UiO–66-NH2 appeared at 1300–1700 cm–1. The peak at 1457 cm–1 related to the result of the stretching of the aromatic C-C rings, the broad absorption peak at 3460 cm−1 related to the -NH2 groups in the 2-aminoterephthalic acid structure of UiO–66-NH2.

In the FT-IR spectrum of PmPDA, The two characteristic peaks at 1529 and 1510 cm−1 correspond to the stretching of the amine quinoid and amine benzenoid units. the peaks around 3200 and 3490 cm−1 correspond to the stretching vibration of the NH2 and N-H groups. After modifying UiO–66-NH2 with Fe3O4 and PmPDA, the FTIR spectrum of the composite shows that the intensity of the peaks assigned to PmPDA becomes more prominent and the peaks corresponding to UiO–66-NH2 are greatly reduced.

TGA: The TGA was used to check the thermal stability of PmPDA, UiO–66-NH2, and Fe3O4@PmPDA@UiO–66-NH2. The UiO–66-NH2 thermogram in Figure 5B shows weight loss in three main stages. The first weight loss associated with loss of surface moisture and solvent occurs at about 100 °C. The second weight loss, which occurs at around 200 –250 °C, is related to the loss of DMF (solvent) from the pores of the MOFs as well as the loss of coordinated water molecules within the cage in the MOF structure. The third weight loss at around 400–500 °C is due to the destruction of organic bonds and structural degradation of MOFs [34,35]. The degradation of PmPDA occurs in three steps. The first weight loss at around 100 °C is related to the removal of moisture, HCl and solvent trapped in the copolymer backbone. The second weight loss is related to the removal of low molecular weight oligomers and the third weight loss (40%), which occurs at about 400 to 600 °C, is due to the destruction of the main chains of the copolymer. Comparing the thermograms of UiO–66-NH2, PmPDA and Fe3O4@PmPDA@UiO–66-NH2 showed that the stability of Fe3O4@PmPDA@UiO–66-NH2 was higher than other samples, which is related to the strong bonding interaction between the hydroxyl group of Fe3O4 nanoparticles and amine groups on the PmPDA and UiO–66-NH2 [36].

Image6.tiff

Figure 5. FTIR spectra (A) and TGA curves of PmPDA, UiO–66-NH2, and Fe3O4@PmPDA@UiO–66-NH2 (B).

FESEM: The surface morphology of the prepared compounds was examined by FESEM. Based on the results of FESEM, UiO–66-NH2 was synthesized with the morphology of semi-cubic. FESEM images in Figure 6 showed regularly shaped particles in the range of 150 to 250 nm. After addition of Fe3O4 and PmPDA to UiO–66-NH2, morphology it was changed; and aggregations observed due to the addition of an organic structure and nanoparticles.

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Figure 6. FESEM micrographs of UiO–66-NH2 and Fe3O4@PmPDA@UiO–66-NH2

EDX: The chemical composition of UiO–66-NH2 and Fe3O4@PmPDA@UiO–66-NH2 was analyzed by the EDX (Figure 7). The presence of Zr, O, and C in the UiO–66-NH2, and O, Zr, C, Fe and N in the Fe3O4@PmPDA@UiO–66-NH2 confirmed the formation of MOF and nanocomposite. Furthermore, Figure 8 shows the EDX mapping of Fe3O4@PmPDA@UiO–66-NH2 which approved the presence of Zr, C, O, Fe and N in the nanocomposite.

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Figure 7. EDX spectra and tabulated data of UiO–66-NH2 and Fe3O4@PmPDA@UiO–66-NH2

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Figure 8. EDX mapping of Fe3O4@PmPDA@UiO–66-NH2

VSM: The magnetic properties of Fe3O4 nanoparticles and Fe3O4@PmPDA@UiO–66-NH2 were studied by VSM analysis and are shown in Figure. 9A

The magnetization saturation value of Fe3O4 and Fe3O4@PmPDA@UiO–66-NH2 were 60.29 and 27.94 emu/g, respectively. The decrease in magnetic saturation of Fe3O4@PmPDA@UiO–66-NH2 compared to Fe3O4 is proportional to the amount of nonmagnetic coating layers integrated with Fe3O4 into magnetic nanocomposites.

XRD: Based on the XRD pattern, the characteristic diffraction peaks of UiO–66-NH2 appeared at 2θ = 7.4, 8.6, and 25.8 in the XRD pattern, indicating the successful synthesis of NH2-UiO–66 (Figure 9b) [37]. XRD patterns of Fe3O4@PmPDA@UiO–66-NH2 nanocomposite showed semi-crystalline nature. The peak appearing in 7.5 corresponds to UiO–66-NH2.

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Figure 9. VSM curve of Fe3O4 nanoparticles and Fe3O4@PmPDA@UiO–66-NH2 nanocomposite (A), XRD patterns of UiO–66-NH2

3.2. Catalytic potential study of the Fe3O4@PmPDA@UiO–66-NH2

The synthesis of pyrazolopyranopyrimidines was investigated using the catalyst Fe3O4@PmPDA@UiO–66-NH2. The one-pot reaction between benzaldehyde, barbituric acid and 3-methyl–1-phenyl–1H-pyrazol–5-ol was studied to optimize the reaction conditions in the presence of nanocomposite (Table 1). First, the reaction was examined at room temperature and in various solvents and without solvent (Entries 1–11).. The highest yields and shortest reaction times were obtained in the solvents ethanol and methanol. Given the increasing importance of environmentally friendly reaction media in organic synthesis, ethanol was chosen as the optimal solvent. Our next attempt was to investigate the effect of temperature on the progress of the reaction. The results showed that with increasing temperature, the efficient performance of the reaction decreases (Entries 11–13).. The effect of catalyst amount was also investigated, the results showed that the reaction requires a catalyst and no product was formed even after 6 hours in the absence of a catalyst (Entry 15).. The catalytic activity of Fe3O4, PmPDA, and UiO–66-NH2 was also studied using the typical reaction. The results showed that compared to other samples, when the reaction was carried out in the presence of the catalyst, the products were obtained in a short time and with the highest efficiency (Entries 18–20).

Table 1. Optimization of the 3-methyl–1-phenyl–1H-pyrazol–5-ol, benzaldehyde, and barbituric acid reaction a.

Yield %b

Time (Min)

Temp /°C

Catalyst (g)

Solvent

Entry

30

360

r.t

0.03

Solvent-free

1

45

360

r.t

0.03

H2O

2

90

75

r.t

0.03

Methanol

3

90

80

r.t

0.03

Ethanol

4

50

360

r.t

0.03

H2O/EtOH

5

80

360

r.t

0.03

CH3CN

6

65

360

r.t

0.03

THF

7

60

360

r.t

0.03

CH2Cl2

8

20

360

r.t

0.03

Hexane

9

65

360

r.t

0.03

Ethyl acetate

10

85

120

r.t

0.03

DMF

11

85

80

40

0.03

EtOH

12

70

80

60

0.03

EtOH

13

Trace

80

Reflux

0.03

EtOH

14

Trace

360

r.t

-

EtOH

15

90

60

r.t

0.05

EtOH

16

91

60

r.t

0.06

EtOH

17

55

60

r.t

Fe3O4 (0.05)

EtOH

18

82

60

r.t

PmPDA(0.05)

EtOH

19

80

60

r.t

UiO–66-NH2(0.05)

EtOH

20

a Reaction conditions: 3-methyl–1-phenyl–1H-pyrazol–5-ol (1.0 mmol), benzaldehyde (1.0 mmol), barbituric acid (1.0 mmol), b isolated yield.

Various aromatic aldehydes were investigated for the synthesis of pyrazolopyranopyrimidines using the optimal amount of (0.05 g Fe3O4@PmPDA@UiO–66-NH2 (Table 2).. The obtained products were purified by crystallization in ethanol and identified using spectroscopic techniques (1H-NMR and 13C-NMR).

Table 2. Synthesis of pyrazolopyranopyrimidines by Fe3O4@PmPDA@UiO–66-NH2 and aldehydes a.

Ref.

M. P. (°C)

Yieldb

(%)

Time

(min.)

Code

Product

Entry

Reported

Observed

[38]

210–211

208–210

90%

60

4a

Broken image

1

[39]

201–204

200–202

94%

45

4b

Broken image

2

NR

172–174

90%

55

4c

Broken image

3

[40]

234–235

232–2235

96%

30

4d

Broken image

4

NR

218–220

90%

70

4e

Broken image

5

[40]

230–232

222–225

95%

40

4f

Broken image

6

NR

181–183

92%

60

4g

Broken image

7

NR

180–182

94%

25

4h

Broken image

8

[39]

207–209

207–209

96%

30

4i

Broken image

9

NR

274–276

98%

10

4j

Broken image

10

[38]

170–171

178–180

90%

15

4k

Broken image

11

NR

NR

180–182

90%

60

4l

Broken image

12

[38]

207–209

207–210

92%

80

4m

Broken image

13

[39]

158–159

184–186

95%

35

4n

Broken image

14

NR

310–312

90%

80

4o

Broken image

15

NR

200–202

90%

60

4p

Broken image

16

NR

283–285

94%

15

4q

Broken image

17

NR

164–166

92%

35

4r

Broken image

18

NR

206–208

95%

35

4s

Broken image

19

NR

198–200

94%

30

4t

Broken image

20

NR

208–211

95%

25

4u

Broken image

21

NR

219–221

90%

50

4v

Broken image

22

NR

153–155

90%

80

4w

Broken image

23

NR

158–160

94%

30

4x

Broken image

24

NR

228–230

95%

25

4y

Broken image

25

a Reaction conditions: barbituric acid (1 mmol), aldehyde (1 mmol), 3-subtituted –5- pyrazolone (1 mmol), (5 mL) EtOH and catalyst (0.05 g) at r.t; b isolated yield. NR: not reported.

3.2.1. Proposed mechanism

Figure 10 shows the proposed reaction mechanism for the synthesis of pyrazolopyranopyrimidines in the presence of Fe3O4@PmPDA@UiO–66-NH2. In this mechanism, first, by activating barbituric acid in the presence of the nanocatalyst, Knoevenagel condensation between benzaldehyde and barbituric acid is performed and intermediate (III) is formed. Then 3-subtituted–1-phenyl–1H-pyrazol–5-ol deprotonation is performed by the catalyst. The reaction is followed by Michael’s addition of 3- subtituted –1-phenyl–1H-pyrazole–5-ol to intermediate (II) affords (III). intermediate (III) was converted into (IV) by tautomerization. Subsequently, intramolecular cyclization produces the product after by removing H2O from the intermediate (V).

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Figure 10. The proposed mechanism for the synthesis of pyrazolopyranopyrimidines by Fe3O4@PmPDA@UiO–66-NH2.

3.3. Heterogeneity studies

Hot filtration test: To check the stability of the nanocomposite Fe3O4@PmPDA@UiO–66-NH2, the hot filtration method was used. The typical reaction was performed under optimized conditions. After 30 minutes (i.e., just over half the reaction time), the Fe3O4@PmPDA@UiO–66-NH2 nanocomposite was isolated from the hot mixture by a magnet and the reaction mixture was held in it for 6 hours. The same reaction conditions were maintained. It was found that the product yield remained the same (50%) after isolation of the nanocomposite catalyst. This indicates that the reaction stops upon isolation of the Fe3O4@PmPDA@UiO–66-NH2 nanocomposite catalyst [41,42].

The analysis of catalytic recyclability and reusability is also more significant in synthetic chemistry from a greener and sustainable perspective. The recovery capability of Fe3O4@PmPDA@UiO–66-NH2 was considered for the reaction of 3-methyl–1-phenyl–1H-pyrazol–5-ol, benzaldehyde, and barbituric acid to produce 4a. Recycling the nanocatalyst was obtained by the stated method in the experimental section; After completion of the reaction, the reaction mixture was diluted with ethanol to isolate the nanocatalyst, and then the nanocatalyst was washed with EtOH. Afterward, the nanocatalyst was reused for the next reaction. it was reusable remains fairly unchanged after 5 consecutive runs. with insignificant loss of its activity (Figure 11)..

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Figure 11. Fe3O4@PmPDA@UiO–66-NH2. reusability in the synthesis 4a.

3.4. In-vitro Anti-cancer effects

Using the MTT test, we evaluated the cytotoxic effects of the synthesized compounds on cancerous and normal cell lines. To this aim, The HepG2 and NIH/3T3 fibroblast cells were treated with serial concentrations (150, 75, 37.5, 18.75, 9.375 μg/mL) of each sample for 24 and 48 h. Figure 12 indicates that the viability of HepG2 cells was affected dose- and time-dependent, showing a decrease in the percentage of viable cells when treated with samples 1- 4 compared to untreated cells (p < 0.001). Based on our results, a greater inhibition of cell viability was obtained after 48 h of incubation with higher concentrations of synthesized compounds, demonstrating the anti-proliferative effects of these agents.

Additionally, in most cases, the viability of fibroblast cells exhibited a comparatively minor decline when incubated with samples 1- 4 as opposed to HepG2 cells. As a result, synthesized compounds hold the capability to eradicate cancerous cells while imposing minimal detrimental effects on healthy cells.

Image40.jpeg

Figure 12. Cellular toxicity assessment of samples 1–4 using MTT assay in HepG2 and fibroblast cells after 24 and 48 h of incubation. Data are represented as mean +- SD (n = 3). * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001 compared with control group.

The 50% inhibition concentrations (IC50) of samples 1- 4 were also calculated and reported in Table 3. Our findings demonstrate that the treatment with samples 1 and 3 accompanied the highest cytotoxic effects on HepG2 cells, while they imposed significantly lower cytotoxic effects on fibroblast cells after 24h and 48h. Based on estimated IC50 values, sample 2 and sample 4 cells showed less preferential antiproliferative activities against cancer cells and provided a narrower therapeutic window for the treatments of malignant cells.

Table 3. In vitro cytotoxicity effect (IC50) of samples 1–4 against HEPG2 and fibroblast cells after 24h and 48h of treatment.

Sample

Code

Cell

Time(h)

24

48

1

4c

HepG2

361.7

137.5

Fibroblast

1848

216.3

2

4g

HepG2

175.2

141.2

Fibroblast

71754

151.2

3

4l

HepG2

162.5

118.2

Fibroblast

6886

167.0

4

4t

HepG2

175.4

164.9

Fibroblast

169.1

372.4

3.5. Antioxidant activity

Having antioxidant properties of organic compounds can increase the potential of their use in pharmaceutical compounds, food and packaging industries. Consequently, the antioxidant activity of pyrazolopyranopyrimidines in the DPPH solution was evaluated (Figure 13).. The results show that most of the derivatives have antioxidant properties in the range of 85.3 to 98.3 %.

Image41.png

Figure 14. The photographs and the histograms of the antioxidant activity of synthesized

of pyrazolopyranopyrimidines.

3.6. Antibacterial activity

The in vitro antibacterial activities of the pyrazolopyranopyrimidines (4a, 4b, 4c, 4g, 4i, 4j, 4l, and 4m) were investigated against Staphylococcus aureus and Escherichia coli. Figure 14 and Table 4 display the results. All samples showed the good antibacterial activity against Staphylococcus aureus (gram-positive), while samples 4j and 4b had no effect on the gram-negative bacterium Escherichia coli.

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Figure 14. Antibacterial activities of some pyrazolopyranopyrimidines against Escherichia coli and Staphylococcus aureus via Kirby–Bauer disk diffusion technique.

Table 4. Antibacterial activities of some pyrazolopyranopyrimidines via Kirby–Bauer disk diffusion technique.

Compound

Inhibition Zone (mm)

Staphylococcus aureus

Gram-Positive (+)

Escherichia coli

Gram-Negative (-)

4a

13 ± 5.0

10 ± 1.5

4b

15 ± 4.5

NEa

4c

18 ± 5.0

6 ± 1.5

4g

13±1.2

7 ± 0.5

4j

10± 0.7

NE

4l

16 ± 5.0

10 ± 1.1

4m

19 ± 2.0

10 ± 0.5

4t

12 ± 4.5

10 ± 1.1

Gentamicin

26 ± 1.2

19.6 ± 0.7

Chloramphenicol

22.3 ± 1.7

20.7 ± 1.0

a No effect

4. Conclusion

The Fe3O4@PmPDA@UiO–66-NH2 nanocomposite acting as an efficient catalyst for the synthesis of pyrazolopyranopyrimidines. The nanoparticles-polymer-MOF hybrid nanocomposite was prepared using Fe3O4 nanoparticles, poly meta-phenylenediamine (PmPDA), and UiO–66-NH2. The FESEM images of catalyst surface morphology showed that the surface of MOF cages was coated with polymers and nanoparticles. Furthermore, the TG analysis showed high thermal stability of the catalyst. Pyrazolopyranopyrimidines were synthesized through one-pot three-component condensation in the presence of 0.05 g of multifunctional catalyst, and the desired products were prepared under optimal reaction conditions in a short time (15–80 minutes) and with a yield of more than 90%. The advantages of this reaction are simple handling and work-up procedures, high yields and the reusability of the catalyst. The MTT assay of some pyrazolopyranopyrimidines on the survival rate of HepG2 cells and normal cells showed that the synthesized compounds are capable of eradicating cancer cells while causing minimal harmful effects on healthy cells. antioxidant activity ranging from 85.3 % to 98.3 %. In addition, Pyrazolopyranopyrimidines were effective against Escherichia coli and Staphylococcus aureus.

Spectroscopic Data

4a (Figure S1, S2): white solid, m.p.: 208–210 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.34 (s, 3H, CH3), 5.55 (s, 1H, benzylic), 7.15 (t, 3H, J = 8 Hz, aromatic), 7.25 (t, 2H, J = 8 Hz,aromatic), 7.36 (t, 1H, J = 8 Hz, aromatic), 7.52 (t, 2H, J = 8 Hz, aromatic), 7.67–7.69 (d, 2H, J = 8 Hz, aromatic), 10.66 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 19.03, 65.50, 92.87, 106.97, 118.84, 121.66, 126.16, 127.19, 127.40, 128.52, 129.75, 129.75, 135.48, 141.67, 146.75, 150.63, 161.92.

4b (Figure S3, S4): white solid, m.p.: 200–202 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.34 (s, 3H, CH3), 5.52 (s, 1H, benzylic), 7.15–7.16 (d, 2H, J = 7.2 Hz, aromatic), 7.90–7.32 (t, 2H, J = 8 Hz,aromatic), 7.36 (t, 1H, J = 8 Hz, aromatic), 7.53 (t, 2H, J = 8 Hz, aromatic), 7.66–7.68 (d, 2H, J = 8 Hz, aromatic), 10.70 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 10.88, 30.77, 92.72, 106.55, 121.74, 127.50, 128.42, 129.18, 129.75, 130.78, 135.38, 140.77, 146.66, 150.63, 161.68.

4c (Figure S5, S6): white solid, m.p.: 172–174 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.33 (s, 3H, CH3), 5.60 (s, 1H, benzylic), 7.20–7.29 (m, 2H aromatic), 7.35–7.37 (d, 2H, J = 8 Hz,aromatic), 7.50–7.53 (m, 3H, J = 7.2 Hz, aromatic), 7.66–7.68 (d, 2H, J = 8 Hz, aromatic), 10.67 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 11.16, 30.62, 92.65, 105.69, 121.71, 126.94, 127.38, 128.36, 129.71, 130.12, 130.45, 133.05, 135.41, 139.20, 146.40, 150.66, 162.24.

4d (Figure S7, S8): white solid, m.p.: 232–235 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.35 (s, 3H, CH3), 5.55 (s, 1H, benzylic), 7.35–7.35 (m, 2H aromatic), 7.50–7.53 (m, 4H, aromatic), 7.66–7.68 (d, 2H, J = 8 Hz, aromatic), 10.69 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 11.14, 30.49, 92.29, 105.16, 121.74, 127.02, 129.44, 129.72, 131.95, 133.92, 138.48, 146.40, 150.68, 162.96.

4h (Figure S9): white solid, m.p.: 180–182 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.37 (s, 3H, CH3), 5.64 (s, 1H, benzylic), 7.38 (t, 1H, J = 7.2 Hz, aromatic), 7.52–7.69 (m, 6H aromatic), 7.94(br, 1H, aromatic), 8.05–8.07 (d, 1H, J = 8 Hz, aromatic), 10.75 (s, 2H, NH).

4i (Figure S10,11): white solid, m.p.: 207–209 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.34 (s, 3H, CH3), 5.52 (s, 1H, benzylic), 7.07 (t, 2H, J = 8 Hz, aromatic), 7.16 (m, 1H, aromatic), 7.36 (t, 1H, J = 8 Hz, aromatic), 7.53 (t, 2H, J = 8 Hz, aromatic), 7.67–7.69 (d, 2H, J = 8 Hz, aromatic), 10.69 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 10.89, 30.58, 92.94, 106.83, 115.03, 121.73, 127.46, 129.03, 135.41, 137.64, 137.67, 146.65, 150.63, 159.82, 161.76, 162.22.

4o (Figure S12, 13): white solid, m.p.: 310–312 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.30 (s, 3H, CH3), 4.89 (s, 1H, benzylic), 7.18–8.12 (m, 3H, aromatic), 7.42 (t, 2H, J = 8 Hz, aromatic), 7.68–7.69 (d, 2H, J = 8 Hz, aromatic), 10.29 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 12.09, 33.23, 90.99, 117.35, 121.12, 121.43, 126.07, 126.46, 129.35, 133.87, 134.48, 140.44, 146.70, 150.67, 151.13, 155.82, 162.38, 154.28, 168.27.

4l (Figure S14, S15): white solid, m.p.: 180–182 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 2.33 (s, 3H, CH3), 5.47 (s, 1H, benzylic), 6.56 (t, 3H, J = 8 Hz, aromatic), 7.04 (t, 1H, J = 8 Hz, aromatic), 7.36 (t, 1H, J = 8 Hz, aromatic), 7.53 (t, 2H, J = 8 Hz, aromatic), 7.67–7.69 (d, 2H, J = 8 Hz, aromatic), 9.20 (br, 1H, OH), 10.69 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 10.86, 30.98, 92.88, 107.11, 113.17, 114.18, 117.90, 121.61, 127.41, 129.43, 129.78, 135.48, 143.20, 146.77, 150.65, 157.63, 162.02, 166.12.

4p (Figure S16, S17): white solid, m.p.: 200–202 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 5.82 (s, 1H, benzylic), 7.07–7.14 (m, 3H, aromatic), 7.23 (t, 2H, J = 7.2 Hz, aromatic), 7.40 (t, 1H, J = 8 Hz, aromatic), 7.54–7.58 (m, 5H, aromatic), 7.82–7.84 (t, 2H, J = 8 Hz, aromatic), 7.92–7.93 (m, 2H, aromatic), 10.80 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm)14.56, 31.69, 91.99, 106.16, 121.61, 122.48, 125.58, 126.21, 127.00, 127.76, 128.38, 128.64, 129.04, 129.35, 129.57, 129.70, 130.75, 133.59, 135.55, 141.89, 149.11, 150.71, 161.90, 163.11, 166.20, 170.84.

4w (Figure S18, S19): white solid, m.p.: 153–155 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 6.37 (s, 1H, benzylic), 7.36–7.45 (m, 4H, aromatic), 7.51–7.61 (m, 6H, aromatic), 7.73–7.75 (d, 1H, J = 8 Hz, aromatic), 7.86–7.88 (m, 6H, aromatic), 10.67 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm) 141.55, 30.13, 94.25, 106.21, 122.73, 124.02, 125.49, 125.73, 126.19, 126.34, 127.32, 129.05, 129.23, 129.41, 129.68, 130.67, 131.28, 134.14, 135.65, 137.99, 148.18,150.58, 162.37, 170.83.

4x (Figure S20, S21): white solid, m.p.: 158–160 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 6.06 (s, 1H, benzylic), 7.39 (t, 3H, J = 8 Hz, aromatic), 7.59–7.60 (m, 7H, aromatic), 7.76–7.78 (d, 2H, J = 8 Hz, aromatic), 7.89 (br, 2H, aromatic), 10.70 (s, 2H, NH). 13C-NMR (100 MHz, DMSO-d6): δ (ppm)14.55, 29.52, 91.59, 103.90, 122.61, 124.31, 127.74, 127.94, 129.24, 129.32, 129.65, 129.99, 130.31, 130.54, 131.91, 134.80, 135.72, 148.82, 150.14, 150.71, 161.23.

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2021-08-20