Research Articles

2019  |  Vol: 5(6)  |  Issue: 6 (November-December)  |  https://doi.org/10.31024/ajpp.2019.5.6.24
Synthesis of novel 5-Bromoisatin based pyrimidine derivatives and their antimicrobial evaluation

Ramesh Kumar*, Mahesh Kumar

Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001 (Haryana) India

*Corresponding author

Ramesh Kumar

Department of Pharmaceutical Sciences,

Maharshi Dayanand University, Rohtak- 124001 (Haryana) India

 

Abstract

Objective: In this study, a new series of 5-bromoisatin derivative clubbed with pyrimidine i.e. 3-[4-(2-Amino-6-substituted-phenyl-pyrimidine-4-yl)-phenylamino]-5-bromo-1, 3-dihydro-indol-2-one derivative were synthesized. Material and Methods: The reaction of 5-bromoisatin and 4-aminoacetophenone in ethanol yielded Schiff bases (1). These on further reaction with different aromatic aldehyde resulted in synthesis of chalcones (2a-2o) derivatives of 5-bromoisatin. In the subsequent step reaction of chalcones with guanidine hydrochloride yielded pyrimidine derivatives (3a-3o) of 5-bromoisatin derivative. The structures of compounds were confirmed by their physicochemical and spectral means (IR and 1HNMR). The synthesized compounds were evaluated in vitro for antimicrobial activity by tube dilution method. Minimum inhibitory concentration (MIC) of compounds were determined against S. aureusB. subtilis (Gram positive), and P. aeruginosaE. coli (Gram negative) bacteria and C. albican and A. niger fungal strain. Results: Although several compounds showed antimicrobial activity, moreover, compound 3g, 3h and 3i showed significant activity. Conclusion: Compound substituted with - NO2, -Cl and -Br showed significant antimicrobial activity.

Keywords: 5-Bromoisatin, pyrimidine, antimicrobial, antifungal


Introduction

Microbial resistance is worldwide threat in contemporary medicine and poses a threat to mankind. As per the report of WHO, in 2016, 490 000 people developed multi-drug resistant TB globally, and drug resistance is starting to complicate the fight against HIV and malaria, as well. Resistance to first-line drugs to treat infections caused by Staphlylococcus aureus-a common cause of severe infections in health facilities and the community is widespread. People with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection. Designing newer antimicrobial agent to counter this resistance is need of hour and has compelled the researcher to develop a new scaffold which can be further optimized as antimicrobial agents. Isatin/substituted isatin is nitrogen containing heterocyclic chemical moiety. In nature, the presence of isatin is reported in plants of the genus Isatis, in Calanthe discolor LINDL and in Couroupita guianensis Aubl. It has also been found in the secretion from the parotid gland of Bufo frogs, and in humans, it is a metabolic derivative of adrenaline (da Silva et al., 2001). In literature, isatin is documented to have a variety of pharmacological action such as antimicrobial (Kumar and Kumar, 2018), anticancer (Ismail et al., 2017), anticonvulsant (Saravanan et al., 2014), antiviral (Abbas et al., 2017), anti HIV (Pawar et al., 2011), antitubercular (Vintonyak et al., 2011) etc. On the other hand, pyrimidine is also nitrogen containing hetrocyclic moiety possessing versatile biological activity and is also a component of deoxyribonucleic acid (DNA) bases; cytosine, thymine, and uracil.  The basic skeleton of pyrimidine is also present in vitamin B1 and barbiturates. Pyrimidine derivatives also used as hypnotics, such as veranal (Jubeen et al., 2018). It is reported to have anticancer (Al-Issa., 2013), antimicrobial activity (Holla et al., 2006), antioxidant (Chandrashekaraiah et al., 2014), anti-inflammatory (Rashad et al., 2005), diuretic (Majeed and Shaharyar, 2011), anti-HIV (Kim et al., 1992), antiviral (Hisaki et al., 1999), and antidiabetic (Lee et al., 2005) activities. In view of these facts and in continuation of our previous work, we envisaged to synthesize 5-bromoisatin derivative clubbed with pyrimidine unit to get an active motif.

Material and methods

Chemicals and solvents used in synthesis were of laboratory grade and used as received. Melting points were estimated with melting point apparatus in open capillaries and are uncorrected. The purity of the compounds was ascertained by TLC and the structures of the synthesized compounds were confirmed by IR, 1H NMR. Iodine vapours and UV lamp were used for visuliasation of spot. IR spectra were recorded in KBr pellets on FT IR spectrometer. H1NMR were recorded on spectrometer in DMSO using tetramethylsilane as an internal standard. The chemical shifts of the compounds were reported in ppm.

Synthesis of 3-(4-acetylphenylimino)-5- bromo-1, 3-dihydro indol-2-one (Schiff bases) (Kumar and Kumar, 2018; Chinnaswamy et al., 2013; Gangarapu et al., 2013)

Equimolar quantity of 5-bromoisatin (0.01mol) and 4-aminoacetophenone (0.01mol) were dissolved in 50 ml ethanol. The content was refluxed in the presence of catalytical amount of glacial acetic acid. The content was put undisturbed overnight. The precipitates of Schiff base- (3-(4-acetylphenylimino)-5- bromo-1, 3-dihydro indol-2-one; 1) obtained were filtered, dried and recrystallized using ethanol.

Synthesis of 5-Bromo-3-[4-(3-Substituted-phenyl-acryloyl)-phenylimino]-1, 3-dihydro-indol-2-one (chalcone derivatives of 5- bromoisatin ) (a-o) (Furniss et al., 2004; Tomma et al., 2014):

In this step, 0.01 mol of Schiff base (compound 1) and different substituted aromatic aldehydes (0.01mol) were dissolved in 50 ml ethanol. To this 10 ml solution of 10% w/v NaOH was added drop wise. The mixture was then stirred for 2-3 hr till it become thick. The chalcones (5-Bromo-3-[4-(3-substituted-phenyl-acryloyl)-phenylamino]-1, 3-dihydro-indol-2-one) were then filtered and re-crystallized using ethanol. The progress of reaction was monitored using TLC.

Synthesis of 3-[4-(2-Amino-6-substituted-phenyl-pyrimidin-4-yl)-phenyl imino]-5-bromo-1, 3-dihydro-indol-2-one (Pyrimidine derivatives of 5-Bromoisatin) (3a-3o) (Kachroo et al., 2014; Trivedi et al. 2008):

A solution of chalcones (a-o) (0.01mol) and guanidine hydrochloride (0.01mol) was prepared in 50 ml ethanol. To this a solution of KOH was added. The content was then refluxed for 10 h on water bath, cooled and then poured in crushed ice. The precipitate obtained were filtered, washed and recrystallized from ethanol.

Figure 1.  Scheme shows preparation of Schiff base, chalcone and pyrimidine derivative of 5-bromoisatin

 

 

 

Characterization data of synthesized derivatives (5-Bromoisatin derivatives):

3a.   3-[4-(2-Amino-6-phenyl-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3416.38 (N-H str, amine), 2949.54 (C-H str, aromatic), 1692 (C=O str.), 1657 (C=N str.). 1H NMR (DMSO) (δ-ppm):  8.256 (1H, s, N-H), 6.612-7.774 (8H, m, Ar-H), 4.36 (2H, s, -NH)

3b. 3-[4-(2-Amino-6-(2-methoxy-phenyl)-pyrimidin-4yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3421.30 (N-H str, amine), 2927.24 (C-H str, aromatic), 1709 (C=O str.), 1662 (C=N str.), 1110.8 (-C-O-CH3, ether). 1H NMR (DMSO) δ; 8.012 (1H, s, N-H), 6.74-7.46 (8H, m, Ar-H), 4.21 (2H, s, -NH), 3.87 (3H, s,-OCH3).

3c. 3-[4-(2-Amino-6-(4-methoxy-phenyl)-pyrimidin-4yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1 ): 3418.70 (N-H str , amine), 2915.14 (C-H str, aromatic),1712 (C=O str.), 1660(C=N str.), 1107.4 (-C-O-CH3, ether).1H NMR (DMSO) δ; 7.82(1H, s, N-H), 6.44-7.6 (8H, m, Ar-H), 4.13 (2H, s, -NH), 3.60 (3H, s,-OCH3).

3d.  3-[4-(2-Amino-6-(4-hydroxy-phenyl)-pyrimidin-4yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1 ): 3430.40 (N-H str, amine), 3235.2(O-H str), 2906.7 (C-H str, aromatic), 1715 (C=O str.), 1666(C=N str. aromatic), 1104.5 (-C-O-CH3, ether).1H NMR (DMSO) δ; 8.251(1H, s, N-H), 6.61-7.83 (8H, m, Ar-H), 5.21(1H, s, -OH), 4.211 (2H, s,-NH2).

3e. 3-[4-(2-Amino-6-(4-chlorophenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one  IR (KBr) (cm-1): 3441.45 (N-H str, amine), 2932.47 (C-H str, aromatic), 1716.8 (C=O str.), 1658 (C=N str.). 1H NMR (DMSO) δ; 7.68(1H, s, N-H), 6.55-7.78(8H, m, Ar-H), 3.93(2H, s, -NH).

3f.  3-[4-(2-Amino-6-(4-bromo phenyl)-pyrimidin-4yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3418.60 (N-H str, amine), 2925.24 (C-H str, aromatic), 1708 (C=O str.), 1661 (C=N str.), 1107.8 (-C-O-CH3, ether). 1H NMR (DMSO) δ; 7.80(1H, s, N-H), 6.47-7.28 (8H, m, Ar-H), 4.16 (2H, s, -NH), 3.71 (3H, s,-OCH3).

3g. 3-[4-(2-Amino-6-(2-nitrophenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3392.1 (N-H str, amine), 2881.15 (C-H str, aromatic), 1715.4 (C=O str.), 1635 (C=N str.). 1H NMR (DMSO) δ; 7.95(1H, s, N-H), 6.53-7.78 (8H, m, Ar-H), 4.11(2H, s, -NH2).

3h. 3-[4-(2-Amino-6-(4-nitro-phenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1,3-dihydro-indol-2-one IR (KBr) (cm-1): 3389.7 (N-H str , amine), 2877.4 (C-H str, aromatic),1712.5 (C=O str.), 1658 (C=N str.).1H NMR (DMSO) δ; 7.88(1H, s, N-H), 6.59-7.90 (8H, m, ArH), 4.12 (2H, s, -NH2).

3i.   3-[4-(2-Amino-6-(2, 6-dichloro-phenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3381.2(N-H str, amine), 2877.5(C-H str, aromatic), 1707.2(C=O str.), 1644.3(C=N str.). 1H NMR (DMSO) δ; 7.90(1H, s, N-H), 6.59-7.85(8H, m, Ar-H), 4.18 (2H, s, -NH2).

3j.        3-[4-(2-Amino-6-(4-dimethylamino-phenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3428.6 (N-H str, amine), 2911.5 (C-H str, aromatic), 1726.6 (C=O str.), 1635.6(C=N str.). 1H NMR (DMSO) δ; 7.79(1H, s, N-H), 6.69-7.78 (8H, m, Ar-H), 2.86(2H, s, -NH2).

3k. 3-[4-(2-Amino-6-(2-chlorophenyl)-pyrimidin-4-yl)-phenyl-imino]-5-bromo-1, 3-dihydro-indol-2-one  IR (KBr) (cm-1): 3390.1 (N-H str , amine), 2878.15 (C-H str, aromatic),1719.8(C=O str.), 1642.5 (C=N str.1H NMR (DMSO) δ; 7.92(1H, s, N-H), 6.54-7.76 (8H, m, Ar-H), 3.95 (2H, s, -NH).

3l. 3-[4-(2-Amino-6-(2-bromophenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one  IR (KBr) (cm-1 ): 3429.4 (N-H str , amine), 2906.7 (C-H str, aromatic),1716.3 (C=O str.), 1644.2 (C=N str.) 1H NMR (DMSO) δ; 7.88(1H, s, N-H), 6.58-7.81(8H, m, Ar-H), 4.01 (2H, s, -NH2).

3m. 3-[4-(2-Amino-6-(3-nitrophenyl)-pyrimidin-4-yl)-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3388.00 (N-H str , amine), 2886.4 (C-H str, aromatic),1714.12 (C=O str.), 1645.5(C=N str.). 1H NMR (DMSO) δ; 7.96(1H, s, N-H), 6.51-7.73 (8H, m, Ar-H), 4.21(2H, s, -s, NH2).

3n. 3-[4-(2-Amino-6-(3, 4-dimethoxyphenyl)-pyrimidin-4-yl]-phenylimino)-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3408.11 (N-H str , amine), 2874.2 (C-H str, aromatic),1718.0 (C=O str.), 1661 (C=N str.), 1116.7(-C-O-CH3, ether). 1H NMR (DMSO) δ; 7.82(1H, s, N-H), 6.38-7.51 (8H, m, Ar-H), 4.05 (2H, s, -NH), 3.68(6H, s,-OCH3)

3o. 3-[4-[2-Amino-6-(4-hydroxy-3-methoxy-phenyl)-pyrimidin-4-yl]-phenylimino]-5-bromo-1, 3-dihydro-indol-2-one IR (KBr) (cm-1): 3411.2 (N-H str , amine), 3241.0 (O-H str), 2880.8 (C-H str, aromatic),1713.0 (C=O str.), 1652.2 (C=N str.), 1123. 2(-C-O-CH3, str, ether). 1H NMR (DMSO) δ; 7.92(1H, s, N-H), 6.48-7.35 (8H, m, Ar-H), 4.14 (2H, s, -NH), 3.76 (6H, s,-OCH3).

Table 1. Physicochemical data of synthesized compounds

Compounds

Molecular Formula

Mol. Wt.

Melting Point (oC)

Rf value

% Yield

3a

C24H16BrN5O

470.32

190-193

0.68

70.0

3b

C25H18BrN5O2

500.35

212-214

0.71

68.0

3c

C25H18BrN5O2

500.35

206-209

0.76

65.0

3d

C24H16BrN5O2

485.05

196-199

0.65

71.0

3e

C24H15BrClN5O

504.77

230-233

0.69

76.0

3f

C24H15 Br2N5O

549.2

224-226

0.73

71.0

3g

C24H15BrN6O3

515.32

228-230

0.77

64.0

3h

C24H15BrN6O3

515.32

226-228

0.75

69.0

3i

C24H14BrCl2N5O

539.21

218-221

0.65

61.0

3j

C26H21BrN6O

513.39

202-205

0.78

74.0

3k

C24H15BrClN5O

504.77

226-229

0.67

70.0

3l

C24H15Br2N5O

549.22

228-230

0.72

75.0

3m

C24H15BrN6O4

515.32

222-224

0.74

68.0

3n

C26H20BrN5O3

530.37

237-239

0.60

78.0

3o

C25H18BrN5O3

516.35

234-236

0.64

80.0

(Solvent front: chloroform: benzene: acetic acid)

Antimicrobial activity

The antimicrobial activity was performed against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis); the Gram-negative bacteria (Escherichia coli and P. aeuroginos) and fungal strains Candida albicans and Aspergillus niger using the tube dilution method (Cappucino and Sherman, 1999). Double strength nutrient broth- I.P. (bacteria) and sabourand’s glucose broth- I.P. (fungi) media were used respectively for the growth of bacteria and fungi. The samples were incubated at 37°C for 24 h (bacteria), at 25°C for 7 d (A. niger) and at 37°C for 48 h (C. albicans). Ciprofloxacin and fluconazole were standard drugs for antibacterial activity and antifungal activity, respectively. The results were recorded in terms of minimum inhibitory concentration (MIC).

Determination of MIC

Minimum inhibitory concentration (MIC) of compounds was determined by two fold serial dilution method. A stock solution (100μg/ml) of the synthesized compounds and standard drugs was prepared in dimethylsulfoxide. Further dilution of each test compound and standard drugs were made in test medium to provide final concentration of 50, 25, 12.5, 6.25, 3.125 and 1.56μg/ml. To all the test tubes 0.1ml of suspension of bacteria in saline was added and tubes were incubated at required temperatures. MIC was that lowest concentration of sample that inhibited the development of turbidity. The observed MIC is presented in table 2.

Table 2. Antimicrobial activity (µM/ml) of synthesized 5-Bromooisatin derivatives

Compo-

unds

 

Minimum Inhibitory Concentration (MIC)

Bacterial strains

Fungal Strains

Gram Positive

Gram Negative

S. aureus

B. subtilis

P. aeruginosa

E. coli

C. albicans

A. niger

3a

1.58

1.58

1.58

1.58

1.58

1.58

3b

1.47

1.47

1.47

1.47

1.47

1.47

3c

1.47

1.47

1.47

1.47

1.47

1.47

3d

1.52

1.52

1.52

1.52

1.52

1.52

3e

0.758

0.758

0.758

0.758

1.628

1.628

3f

0.329

0.329

0.329

0.329

1.460

1.460

3g

0.355

0.355

0.355

0.355

0.355

0.355

3h

0.355

0.355

0.355

0.355

0.355

0.355

3i

0.336

0.336

0.336

0.336

0.336

0.336

3j

1.429

1.429

1.429

1.429

1.429

1.429

3k

0.729

0.729

1.458

1.458

0.729

1.458

3l

0.660

0.660

1.321

1.321

1.321

1.321

3m

1.372

1.372

1.372

1.372

1.372

1.372

3n

1.375

1.375

1.375

1.375

1.375

1.375

3o

1.419

1.419

1.419

1.419

1.419

1.419

Std

0.471

0.471

0.471

0.471

0.510

0.510

Standard drugs: Ciprofloxacin (antimicrobial) and Fluconazole (antifungal)

Results and discussion

The title compounds were prepared according to the previously reported procedure. In the first step the reaction of 5-bromoisatin and 4-aminoacetophenone in ethanol yielded Schiff bases (1). These on further reaction with different aromatic aldehyde resulted in synthesis of chalcones (2a-2o) derivatives of 5-bromoisatin. In the subsequent step reaction of chalcones with guanidine hydrochloride yielded pyrimidine derivatives (3a-3o) of 5-bromoisatin derivative. The prepared compounds were characterized by their physicochemical (Table 1) and spectral means as discussed in experimental.

The antimicrobial activity of the synthesized compounds was determined by tube dilution method (Cappucino and Sherman, 1999) and the results are given in Table 2. Ciprofloxacin and fluconazole were taken as standard for antibacterial and antifungal activity respectively. The result of antimicrobial activity demonstrate that compound 3f (MICsa = 0.329 µM, MICbs 0.329 µM, MICpa 0.329 µM and MICec 0.329 µM) and compound 3g (MICsa = 0.355 µM, MICbs 0.355µM, MICpa 0.355 µM and MICec 0.355 µM ), compound 3h (MICsa = 0.355 µM, MICbs 0.355µM, MICpa 0.355 µM and MICec 0.355 µM), compound 3i (MICsa = 0.336µM, MICbs 0. 0.336 µM, MICpa 0.336 µM and MICec 0.336 µM)  are active against both gram positive and gram negative strain. Compound 3j (MICsa = 0.791µM, MICbs 0.791 µM) and compound 3l (MICsa = 0.728µM, MICbs = 0.728µM) are active against S. aureus and B. subtilis. In case of antifungal activity compound 3j (MICca = 0.355 µM, MICan = 0.355 µM), compound 3h (MICca = 0.355 µM, MICan = 0.355 µM) and compound 3i (MICca = 0.336µM, MICna = 0.355 µM) are active against both C. albican and A. niger, while compound 3k (MICca = 0.856µM)  are active against A. niger only.

Conclusion

In summary we, have synthesized a new series of derivatives of 5-Bromoisatin clubbed with pyrimidine i.e. 3-[4-(2-Amino-6-substituted-phenyl-pyrimidine-4-yl)-phenylamino]-5-bromo-1, 3-dihydro-indol-2-one. Amongst the synthesized compounds several shows antimicrobial activity. Compound 3g (3-[2-Amino-6-(2-nitrophenyl)-pyrimidin-4-ylimino]-5-bromo-1,3-dihydroindol-2-one), 3h (3-[2-Amino-6-(4-nitro-phenyl)-pyrimidin-4-ylimino]-5-bromo-1,3-dihydro-indol-2-one) and 3i (3-[2-amino-6-(2, 6-dichlorophenyl)-pyrimidin-4-ylimino)-5-bromo-1, 3-dihydro-indol-2-one) showed both antibacterial and antifungal activity while compound 3f  (3-[2-Amino-6-(4-bromo phenyl)-pyrimidin-4ylimino]-5-bromo-1, 3-dihydro-indol-2-one) showed only antibacterial activity. Although there could not be established a direct correlation between structure and activity, moreover compound substituted with - NO2, -Cl and -Br showed significant antimicrobial activity.

Conflicts of Interest

The author declares that there is no conflict of interest.

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