Current Trends in Pharmacy and Pharmaceutical Chemistry

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Bisht and Bisht: Microwave assested synthesis of phthalimide amino derivatives with their antioxidant potential


Introduction

Imide is the form of amide in which the nitrogen atom is affix to two carbonyl group. Imide mention to any compound which contains the divalent radical. These compounds are obtained from ammonia or primary amine, where two hydrogen atoms are replaced by a bivalent acid group or two monovalent acid groups, resulting in comprising of two carboxylic acid groups.1

Phthalimide possess a structural feature C8H5NO2 and an imide ring which help them to be biologically active and pharmaceutically useful.2 Among bicyclic non-aromatic nitrogen heterocycles, phthalimides are an interesting class of compounds. Phthalimides have served as starting materials and intermediates for the synthesis of many types of alkaloids and pharmacophores.3 The structural diversity and biological importance of nitrogen containing heterocycles have prepared them important targets for synthesis over many years.4 Phthalimide and some of its derivatives proved to have received awareness due to their antibacterial, antifungal, analgesic, antitumour, anxiolytic and anti-HIV-1 activities.When phthalimide is subjected to Mannich condensation, it may yield Mannich bases which may display more potent biological activities. The present research focuses on novel synthesized phthalimides having significant biological activities.3 Amongstheterocyclic scaffolds, phthalimides are of particular biological interest and have been reported as herbicides, insecticides and anti-inflammatory agents. Phthalimide are an important class of drugs exhibiting anxiolytic, antimicrobial, antibacterial, antituberculosis, anticancer, hypolipidemic, analgesic, antiproliferative, acetylcholinesterase inhibitors and inhibitor of human neuronal nitric oxide synthase.4 Chemically, oxidation is the removal of electrons and reduction is the gain of electrons, oxidation is always coupled with reduction. Many biological oxidation can takes place without the participation of molecular oxygen, e.g. dehydration.5 “Antioxidants are reducing agents which are add up to the drug or other pharmaceuticals to avert their oxidation through oxidative process”.6 For convenience, antioxidants have been traditionally divided into two classes, primary or chain breaking antioxidants and secondary or preventative antioxidants. Secondary or preventative antioxidants are compounds that retard the rate of oxidation.7 Many human diseases and degeneration process have been linked in some way to the action of free radicals.6, 7, 8

The aim of the present study is to synthesize Phthalimide derivatives by using microwave assisted synthesis method and compare the activity of the synthesized molecules.

Materials and Methods

Phthalic anhydride, Urea, Glycine, Sulphanilic acid, Aniline, Chloroform & DPPH were received from Central Drug House Ltd. New Delhi, India. Methanol, Ethyl acetate & n-Hexane were received from Himedia Pvt. Ltd.

Method and methodology

Thus, the present communication utilized the technology gracefully for the synthesis, identification and characterization of some novel derivatives by the reaction of Phthalic anhydride with urea, glycine, aniline, sulphanilic acid to yield various Phthalimide derivatives using domestic microwave by getting percentage yield 70.7%, 76.65%, 80.21% and 73.78% of synthesized compound B1,B2,B3 and B4 respectively. All synthesized compound(s) were subjected to melting point determination, TLC analysis, column chromatography (for purification), 1H-NMR and Mass Spectrometry.

Result and Discussion

We developed new synthetic methodologies for the synthesis of Phthalimidederivatives. The starting material phthalic acid was reacted with amino acids to give phthalimide, the addition reaction was takes place:

Mechanism of synthesis(Figure 1)

For phthalimide derivatives

Figure 1

General mechanism of phthalimide

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Percentage yield(Table 1)

Table 1

Percentage yield of phthalimide compounds

S.No.

Compounds

% yield

1.

B1

70.7

2.

B2

76.65

3.

B3

80.21

4.

B4

73.78

Figure 2

Bar diagram of different Phthalimide derivatives

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Physicochemical properties(Table 2)

Table 2

Physicochemical properties of various Phthalimide derivatives (B1-B4)

Compound

Molecular formula

Molecular weight

Appearance

Percentage yield (%)

B1

C9H6O3N2

190.16

White crystals

70.70

B2

C10H7O4N

205.17

Brown powder

76.65

B3

C14H9O2N

223.23

Off White crystals

80.21

B4

C14H9O5NS

303.29

Off White crystals

73.78

Melting point(Table 3)

Table 3

Melting Point of Phthalimide derivatives

S.No.

Compound

Melting Point Range ( 0 C)

1.

1, 3-dioxoisoindoline-2-carboxamide (B1)

210±2

2.

2-(1,3-dioxoisoindoline-2-yl)acetic acid (B2)

146±2

3.

2-phenylisoindoline-1,3-dione (B3)

203±2

4.

4-(1,3-dioxoisoindoline-2-yl)benzenesulfonic acid (B4)

230±2

Solubility(Table 4)

Table 4

Solubility of Phthalimide derivatives

S.No.

Compound

Solubility

1.

1, 3-dioxoisoindoline-2-carboxamide (B1)

Water, Methanol

2.

2-(1,3-dioxoisoindoline-2-yl)acetic acid (B2)

Water, Ethanol

3.

2-phenylisoindoline-1,3-dione (B3)

Water, Chloroform

4.

4-(1,3-dioxoisoindoline-2-yl)benzenesulfonic acid (B4)

Water, Ethanol

PH(Table 5)

Table 5

pH of Phthalimide compounds

S.No.

Compound

Observation

1.

1, 3-dioxoisoindoline-2-carboxamide (B1)

7.88

2.

2-(1,3-dioxoisoindoline-2-yl)acetic acid (B2)

11.53

3.

2-phenylisoindoline-1,3-dione (B3)

8.78

4.

4-(1,3-dioxoisoindoline-2-yl)benzenesulfonic acid (B4)

8.25

Ultraviolet spectroscopy(Table 6)

Table 6

Wavelength of phthalimide derivatives

S.No.

Compound

Solvent

Wavelength(nm)

1.

1, 3-dioxoisoindoline-2-carboxamide (B1)

Water

281nm

2.

2-(1,3-dioxoisoindoline-2-yl)acetic acid (B2)

Water

374nm

3.

2-phenylisoindoline-1,3-dione (B3)

Water

298nm

4.

4-(1,3-dioxoisoindoline-2-yl)benzenesulfonic acid (B4)

Water

245nm

Thin layer chromatography(Figure 3)

Figure 3

Spots of derivatives of phthalimidevisualized in uv

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Table 7

Retention factor of phthalimidecompounds

S.No

Compound

Rf value

1.

1, 3-dioxoisoindoline-2-carboxamide (B1)

0.70

2.

2-(1,3-dioxoisoindoline-2-yl)acetic acid (B2)

0.48

3.

2-phenylisoindoline-1,3-dione (B3)

0.60

4.

4-(1,3-dioxoisoindoline-2-yl)benzenesulfonic acid(B4)

0.52

The characteristic 1H NMR data and interpretation of synthesized compounds

Table 8

1H NMRdata and interpretation of synthesized compounds

Compound No.

δ (ppm)

Group

No. of H

B1

7.55-7.69

Ar-H

4

B2

7.81- 7.94 4.32

Ar-H CH2

4 2

B3

7.41-7.54 7.88-7.97

Ar-H Ar-H

5 4

B4

2.52-2.53 7.55-7.69 11.91

OH (Alcohol) Ar-H CH (Benzene)

1 4 1

Figure 4

Table 8+Compound structure (B1)

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Figure 5

Table 8+Compound structure (B2)

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Figure 6

Table 8+Compound structure (B3)

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Figure 7

Table 8+Compound structure (B4)

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Elemental analysis(Table 9)

Table 9

Elemental analysis of different Phthalimide compounds

Comp.

Mol. Formula

Mol. Weight

Compound- Name

Calculated % found

C%

H%

N%

O%

S

B1

C9H6O3N2

190.16

1, 3-dioxoisoindoline-2-carboxamide (B1)

56.85%

03.18%

14.73%

25.24%

_

B2

C10H7O4N

205.17

2-(1,3-dioxoisoindoline-2-yl)acetic acid (B2)

58.54%

03.44%

06.83%

31.19%

_

B3

C14H9O2N

223.23

2-phenylisoindoline-1,3-dione (B3)

75.33%

04.06%

06.27%

14.33%

_

B4

C14H9O5NS

303.29

4-(1,3-dioxoisoindoline-2-yl)benzenesulfonic acid (B4)

49.52%

13.36%

04.12%

23.56%

09.44%

Antioxidant activity(Table 10)

• In vito antioxidant activity by using DPPH scavenging method

Table 10

DPPH scavenging activity of different Phthalimide derivatives

Concentration (mg/ml)

% inhibition

B1

B2

B3

B4

Ascorbic acid

0

0.0

0.0

0.0

0.0

0.0

0.02

13.35

31.23

16.88

65.72

84.02

0.04

17.51

44.95

21.26

67.43

86.35

0.06

18.88

53.93

24.37

69.09

86.57

0.08

20.92

55.72

24.77

69.52

86.92

0.10

25.22

59.79

25.59

69.56

98.42

Figure 8

Bar diagram of different Phthalimide derivatives

https://s3-us-west-2.amazonaws.com/typeset-prod-media-server/57509918-c67c-447d-b718-493e4ff2e749image9.png

Conclusion

On the basis of the previous results, the study concluded that the synthesis of the designed compound has been successfully achieved. Purity and characterization of the synthesized compounds were confirmed by determination of physical properties (melting point, pH and Rf values), elemental analysis and 1H-NMR spectra. The compound B3 of phthalimide shows higher percentage practical yield. The in-vitro antioxidant activity of all synthesized compound was tested by using DDPH scavenging activity. The compounds were concealed at distinct concentration from 0.02-0.10mg/ml in order to examine the percentage inhibition of compounds. From the result in table (10) compound B4manifest highly significant activity against DPPH. The result shows that as the concentration of compound increase, the compound showed high remarkable activity against DPPH. The other complete tested compound showed low to moderate activity.Thus, the study could be concluded as the compounds have significant antioxidant activity. Thus, it may be concluded that the synthesized compound productively can be further used in the treatment of above-mentioned element.

Acknowledgement

The authors are thankful to the Himalayan Institute of Pharmacy & Research, Dehradun, Uttarakhand, India for helping us to carry out the study. We are thankful to the Uttarakhand technical university for their support in characterization studies. All the teaching staff of Himalayan Institute of Pharmacy & Research, Dehradun for their silent contribution in particular.

Source of Funding

None.

Conflict of Interest

None.

References

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S K Chimatahalli Investigation of Antioxidant Properties of Phthalimide DerivativesBorderless Sci publishing20153219920610.13179/canchemtrans.2015.03.02.0194

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Article type

Original Article


Article page

23-27


Authors Details

Ajay Singh Bisht, Rajat Bisht


Article History

Received : 10-06-2021

Accepted : 14-07-2021

Available online : 31-07-2021


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