SYNTHESIS AND ANTIMICROBIAL EVALUATION OF CERTAIN ARYLAZO IMIDAZOLES
M. Sreedevi Meesaraganda, Raghavendra Guru Prasad Aluru, ..
1. Sri Kirshnadevaraya University, Anantapur, A.P., India. 2. ICFAI Foundation for Higher Education, Hyderabad, A.P., India.
Keywords: Arylazo imidazoles, Elemental analysis, IR spectra, 1H NMR spectra, Antimicrobial screening.
Abstract

Seven novel arylazo imidazoles were synthesized and structures have been elucidated on the basis of elemental analysis, IR and 1H NMR spectral data. Antibacterial activity studies was done against two gram positive bacteria (S. aureus, P.aeruginosa,) and two gram negative bacteria (E.coli and B.subtili), while antifungal activity studies was done against C.albicans and A.nigerz. Minimum inhibitory concentration was found out by Serial dilution method. Antibacterial and antifungal activity studies of the title compounds (IIIa-IIIe) was compared with standards namely Furacin and Flucanazole. All the synthesized arylazo imidazoles have shown significant activity against the tested microbes. The compounds IIIb, IIIc and IIId exhibit relatively higher activity than the standards.

Article Information

Identifiers and Pagination:
Year:2013
Volume:5
First Page:100
Last Page:106
Publisher Id:JAppPharm (2013 ). 5. 100-106
Article History:
Received:June 2, 2013
Accepted:June 19, 2013
Collection year:2013
First Published:July 1, 2013

INTRODUCTION

Amino alkylation of an acidic proton next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine is called Mannich reaction. The final product ß-amino carbonyl compound is known as a Mannich base [1]. Mannich bases and their derivatives have applications in many areas. They have been used in paint and polymer chemistry as hardeners, cross linkers, reaction accelerators [2,3].  However, the most important applications are in the field of pharmaceutical products [4,5]. Mannich bases can either directly be employed or used as intermediates in the synthesis of compounds of pharmaceutical importance.

A series of novel Mannich bases derived from secondary amines and cinchophen amide have been found to exhibit  antimicrobial activity [6]. Pandeya et al.[7-9] have reported the synthesis and anti-HIV activity of Mannich bases of isatin.  Sridhar et al.[10] have described the synthesis, antibacterial, antifungal and anti-HIV activities of norflaxacin Mannich bases. Koksal et al.[11] synthesised novel series Mannich bases of 5-nitro-3-substituted piperazino-methyl-2-benzoxazolinones that were found to demonstrate analgesic activities and  anti inflammatory activities.Gahane et al.[12]  have described the synthesis and anticonvulsant activity of 3-aryIidene-2-phenylimino-4-thiazolidinones. The newly synthesized Mannich bases were tested for their anti-inflammatory and ulcerogenic activity.  Barlin and Ireland [13] prepared di-Mannich bases which were found to be active antimalarials especially against chloroquine resistant isolate (K-I) of Plasmodium falciparum. Mannich bases are found to exhibit antihelmintic activity [14], CNS activity [15], anti-inflammatory activity [16], analgesic activity [16], antitumor activity [17], cytotoxicity [18] etc. Prompted by above observations, the authors have synthesized a series of Mannich derivatives carrying imidazole moiety and evaluated for their antimicrobial activity.  The details are presented in the following lines.

EXPERIMENTAL

All the chemicals and reagents used were procured from Merck (India) Limited. The melting points of the newly synthesized compounds were determined in open capillaries and were uncorrected.  The IR spectra were recorded on a Perkin-Elmer 983 IR spectrometer. The 1H-NMR spectra were recorded on a Bruker AC 300F (200 MHz) NMR spectrometer using DMSO – d6 or CDCl3 as solvent and TMS as an internal standard.  Mass spectra of the compounds were recorded on a Jeol JMS-D300 mass spectrometer operating at 70 eV.  The purity of all the compounds was confirmed by TLC.   

Synthetic procedure employed in the present studies

(2-methyl-5-nitro-4-phenyl azo-imidazol-1-yl)- aceticacid hydrazide I is synthesized by the procedure mentioned in the literature [19].

A mixture of (2-methyl-5-nitro-4-phenyl azo-imidazole-1-yl)-acetic acid hydrazide I (30.3gm, 0.1 mol), KOH (5.5 gm, 0.1 mol), ethanol (100 mL) and carbondisulphide (6.00 mL, 0.1 mol) taken in a round bottomed flask fitted with a water condenser was refluxed on a water bath till the evolution of hydrogen sulphide ceased.  The excess of alcohol was removed by distillation.  The reaction mixture was cooled to room temperature and the contents were poured into ice cold water and neutralized with dilute hydrochloric acid.  The solid precipitated was filtered, washed with water and dried.  The product so obtained was purified by recrystallization from ethanol-dioxane mixture to give 5-(2-methyl-5-nitro-4-phynylazo-imidazole-1-yl-methyl)-3H-{1,3,4} oxadiazole-2-thione II. (Scheme I).

A solution of 5-(2-methyl-5-nitro-4-phynylazo-imidazole-1-yl-methyl)-3H-{1,3,4} oxadiazole-2-thione II (0.01 mol) in absolute ethanol-dioxane mixture (1:1, 20 mL) was treated with formaldehyde 40% (1.5 mL).  To this, appropriate amine (0.01 mol) in ethanol (10 mL) was added and reaction mixture was stirred over night.  The precipitated Mannich base was collected by filtration, dried and recrystallization using ethanol-DMF mixture (1:1).  The other compounds III b-g were obtained by similar procedure using the appropriate amine. Characterization data of these compounds are given in table 3.4. (Scheme I)



R1=H, R2=Phenyl, p-anisyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, morpholinyl.

Scheme 1: Synthesis of Mannich bases III.

RESULTS AND DISCUSSION

The compound II and compounds of III series are characterized by elemental analysis, IR and 1H NMR spectral data.

Characterization of 5-(2-methyl-5-nitro-4-phynylazo-imidazole-1-yl-methyl)-3H-{1,3,4} oxadiazole-2-thione II

The IR(KBr) spectrum of 5-(2-methyl -5-nitro-4-phenylazo-imidazol-1-yl methyl)-3H-[1,3,4]-oxadiazol-2-thione II exhibited characteristic band at around 3136 cm-1 (NH, str), 2873 cm-1 (CH, str), 1134 cm-1 (C=S), 1546 cm-1(asymmetric str, nitro group), 1325 cm-1 (NO2, symmetric str), 1615 cm-1 (N=N, str), and 3058  cm-1 (C6H5, str).  The IR spectral data is furnished in Table1. 

The 1HNMR spectrum (200 MHz) of II was recorded in CDCl3 + DMSO-d6.  The formation of  5-(2-methyl -5-nitro-4-phenyl azo-imidazol -1-yl methyl)-3H-[1,3,4]-oxadiazol-2-thione  II was further confirmed by 1HNMR spectral assignments. A broad signal due to thiol-thione tautomeric proton was observed at around d 14.7.  A sharp singlet was observed at 2.30  integrating for three protons of the methyl group while the CH2 protons connecting the oxadiazole and imidazole moiety appeared as a singlet at 5.45 integrating for two protons.  The aromatic protons appeared as a singlet at 6.60-7.20 integrating for five proton. The 1HNMR data of II is compiled in Table1.

Table 1: Characterization data of 5-(2-methyl -5-nitro-4-phenylazo-imidazol-1-yl methyl)-3H-[1,3,4]oxadiazol-2-thione II

Elemental analysis data

Molecular

Formula

Yield %

m.p(OC)

Elemental analysis found

(Calculated)

C

H

N

O

S

C13H11N7O3S

74

213-214

44.72

(45.21)

3.01

(3.21)

27.89

(28.39)

14.01

(13.90)

9.42

(9.29)

IR spectral data(? max in cm-1)

NH

CH3

C=S

NO2

N=N

C6H5

3136

2873

1134

1546

1325

1615

 

3058

 

1HNMR spectral data (200 MHz)(solvent..CDCl3+DMSO-d6)(d ppm)

d 2.30 (s, 3H, CH3), 5.45 (s, 2H, NCH2), 14.70 (s, thiol-thione tautomeric proton), 7.0 (m, 5H, C6H5).

 

Characterization of 5-(2-methyl -5-nitro-4-phenylazo-imidazol-1-yl methyl)-3-phenyl amino methyl -3H-[1,3,4]oxadiazol-2-thione III a-g

The characterization data in particular elemental analysis data is given in Table 2.

The structures of these compounds III a-g were determined by IR, and 1HNMR spectra.

The IR ( KBr) spectra of  5-(2-methyl -5-nitro-4-phenyl azo-imidazol-1-yl methyl)-3-phenyl amino methyl -3H-[1,3,4]oxadiazol-2-thione IIIa exhibited characteristic bands around 1610; 1546, 1325; 2940; 1113; 3142; 1597 cm-1 due to N=N, asymmetric NO2 stretching, symmetric NO2 stretching, CH stretching, C=S,  NH and C=N groups respectively.  The IR spectral data is furnished in Table 3.

Table 2: Characterization data of 5-(2-methyl -5-nitro-4-phenyl azo-imidazol-1-yl methyl)-3-phenyl amino methyl -3H-[1,3,4]oxadiazol-2-thione III

Compd

-R1

-R2

Molecular

Formula

Yield %

m.p(0C)

Elemental analysis found

(Calculated)

C

H

N

S

Halogen

 

IIIa

H

phenyl

C20H18N8O3S

54

162

52.80

(53.32)

3.83

(4.03)

24.37

(24.87)

6.83

(7.12)

----

 

IIIb

H

p-anisyl

C21H20N8O4S

62

181

51.90

(52.49)

4.00

(4.20)

22.82

(23.32)

6.90

(6.67)

----

 

IIIc

H

p-fluorophenyl

C20H17FN8O3S

65

156

50.78

(51.28)

3.46

(3.66)

23.52

23.92)

6.96

(6.84)

4.16

(4.06)

 

IIId

H

p-chlorophenyl

C20H17ClN8O3S

46

143

49.04

(49.54)

3.33

(3.53)

22.61

(23.11)

6.91

(6.61)

7.21

(7.31)

 

IIIe

H

p-bromophenyl

C20H17BrN8O3S

52

173

44.88

(45.38)

3.04

(3.24)

20.63

(21.17)

6.12

(6.06)

15.16

(15.09)

 

IIIf

H

p-nitrophenyl

C20H17N9O5S

59

169

47.98

(48.48

3.26

(3.46

24.94

(25.44

6.55

(6.47)

----

 

IIIg

-

Morpholinyl

C18H20N8O4S

56

174

48.14

(48.64)

4.32

(4.54)

24.81

(25.21)

7.15

(6.86)

----

 

 

Table 3: IR spectral data of Mannich bases

compd

R1

R2

? max in cm-1

NO2

CH

(str)

C=S

N=N

C=N

NH

IIIa

H

C6H5

2945

1113

1610

1599

3147

IIIb

H

p-Anisyl

2950

1113

1610

1601

3152

 

IIIc

H

p-fluorophenyl

2955

1113

1610

1603

3157

IIId

H

p-chlorophenyl

2960

1113

1610

1601

3162

IIIe

H

p-bromophenyl

 

2965

1113

1610

1605

3167

IIIf

H

p-nitrophenyl

2948

1113

1610

1609

3172

IIIg

--

morpholinyl

2956

1113

1610

1602

3177

 

The 1HNMR spectra (200 MHz) of III a-g were recorded in CDCl3+DMSO-d6.  The data is shown in the Table 4. The formation of Mannich base is indicated by the signal at around d 11-13 due to thiole-thione tautomeric proton.  The 1HNMR spectrum of IIIb showed a sharp signal at d 2.40 integrating for three protons of the methyl group.  The N-CH2-N protons appeared at d 5.60 as a singlet was integrating for two protons, while the CH2 protons connecting the oxadiazole and imidazole moiety appeared as a singlet at d 4.95 integrating for two protons.  The signal due to NH proton appeared as broad singlet at d 11.10 integrating for one proton. The phenyl group attached to azo group has appeared as a singlet at d 7.25 integrating for five protons.  The 4-methoxyphenyl group in the Mannich base was noticed as two doublets at d 6.97 and d 7.47 and each doublet corresponds to two protons.  The 1HNMR data of typical compounds of IIIa-g is compiled in Table 4.

Table 4: 1HNMR data of Mannich bases III

compd

R1

R2

1HNMR(200 MHz)(solvent..CDCl3+DMSO-d6)

(d ppm)

IIIa

H

C6H5

d 2.50 (s, 3H, CH3), 5.50 (s, 2H, N-CH2-N), 4.96 (s, 2H,N-CH2), 10.23 (s, 1H, NH), 7.50 (m, 5H, C6H5), 7.25 (s, 5H, C6H5). 

IIIb

H

p-anisyl

d 2.40 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.62 (s, 2H, N-CH2-N), 5.06 (s, 2H, N-CH2), 11.10 (s, 1H, NH) 6.97 (d, 2H, Aromatic protons), 7.47 (d, 2H, Aromatic protons), 7.25 (m, 5H, C6H5).

IIIc

H

p-fluoroanisyl

d 2.49 (s, 3H, CH3), 5.47 (s, 2H, N-CH2-N), 4.95 (s, 2H, N-CH2), 11.22 (s, 1H, NH), 7.26 (m, 5H, C6H5), 7.4 (d, 2H, Aromatic protons),7.50 (d, 2H, Aromatic protons). 

IIIf

H

p-nitrophenyl

d 2.55 (s, 3H, CH3), 5.55 (s, 2H, N-CH2-N), 4.98 (s, 2H, N-CH2), 11.25 (s, 1H, NH), 7.29 (m, 5H, C6H5), 7.48 (d, 2H, Aromatic protons),7.60 (d, 2H, Aromatic protons). 

IIIg

-

morpholinyl

d 2.50 (s, 3H, CH3),5.49 (s, 2H, N-CH2-N), 4.95 (s, 2H, N-CH2), 11.19 (s, 1H, NH), 7.24  (m, 5H, C6H5), 2.62 (t, 4H, -CH2-N-CH2), 3.70 (t, 4H, -CH2-O-CH2).

 

Evaluation of antimicrobial activity

The antibacterial activity of the newly synthesized Mannich bases was carried out against four different pathogenic organisms, namely  Staphylococcus aureus and Bacillus subtilis(Gram positive) and Escherichia coli and Pseudomonas aeruginosa (Gram negative). Antifungal activity study was carried out against the fungi namely, Candida albicans and A. niger The MIC values of the compounds in the present investigation have been assessed by serial dilution method [20].

Determination of Minimum Inhibitory Concentration

The test compound is dissolved in dimethylformamide (5 mL) to prepare a stock solution of concentration 1000 µg/mL.  One loop full of an 18 hour broth culture was inoculated into 5 mL of nutrient broth and was incubated at 37°C for 4 hours. An assay was prepared by diluting with labeled test tubes numbered 1-11. An aliquot of 0.5 mL stock solution of test compound was added to the first tube. The solution was mixed well and 0.5 mL of this solution was transferred into second tube. This process was repeated serially to obtain the quantities indicated in each of the test tubes. The eleventh tube was taken as growth control. Drops of diluted broth culture of the test organism (approximately 0.5 mL) were added into all tubes using a sterilized pasteur pipette. The solutions were mixed gently and the incubation was carried out at 37°C for 16-18 hours. The concentration at which there was no turbidity was taken as minimum inhibitory concentration. The results of antimicrobial studies are also given in Table 5.

Table 5: Antibacterial and Antifungal activity data of compounds III

Compound

Antibacterial activity (MIC in mg/mL)

Antifungal activity data

S. aureus

P.aeruginosa

E.coli

B.subtilis

C. albicans

A.

niger

IIIa

--

--

--

--

--

--

IIIb

0.25

0.25

0.50

0.25

0.25

0.25

IIIc

0.25

0.25

0.50

0.25

0.125

0.125

IIId

0.25

0.25

0.125

0.25

0.125

0.125

IIIe

 

 

 

 

 

 

IIIf

0.25

0.25

0.25

0.25

0.25

0.25

IIIg

0.25

0.25

0.25

0.25

0.25

0.25

Furacin (Std)

0.25

0.25

0.25

0.5

-----

----

Flucanazole (Std)

---

---

----

----

0.25

0.25

Solvent control (DMF)

----

----

----

----

----

----

 

Among the compounds tested for antibacterial activity, all the compounds showed significant activity comparable with that of standard and in the case of compound III d, the activity was much higher against E. coli. Similarly, all the compounds showed activity comparable to that of the standard drug furacin. Compounds IIIb and IIIc showed the activity at a much lower concentration than that of the standard drug flucanazole. 

 

CONCLUSION

Antibacterial (against S. aureus, P.aeruginosa, E.coli and B.subtili ) and antifungal (against C.albicans and A.nigerz) activity studies of the  synthesized Mannich bases (IIIa-IIIe) was compared with  Furacin and Flucanazole to reveal the potency of  the synthesized compounds.  Antimicrobial screening revealed that compounds exhibit moderate activity when compared to standard. The compounds IIIb, IIIc and IIId exhibit relatively higher activity against than the standards.

 

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Prof. Dr. Cornelia M. Keck (Philipps-Universität Marburg)
Marburg, Germany

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Welcome to the research group of Prof. Dr. Cornelia M. Keck in Marburg. Cornelia M. Keck is a pharmacist and obtained her PhD in 2006 from the Freie Universität (FU) in Berlin. In 2009 she was appointed as Adjunct Professor for Pharmaceutical and Nutritional Nanotechnology at the University Putra Malaysia (UPM) and in 2011 she obtained her Venia legendi (Habilitation) at the Freie Universität Berlin and was appointed as a Professor for Pharmacology and Pharmaceutics at the University of Applied Sciences Kaiserslautern. Since 2016 she is Professor of Pharmaceutics and Biopharmaceutics at the Philipps-Universität Marburg. Her field of research is the development and characterization of innovative nanocarriers for improved delivery of poorly soluble actives for healthcare and cosmetics. Prof. Keck is executive board member of the German Association of Nanotechnology (Deutscher Verband Nanotechnologie), Vize-chairman of the unit „Dermocosmetics“ at the German Society of Dermopharmacy, active member in many pharmaceutical societies and member of the BfR Committee for Cosmetics at the Federal Institute for Risk Assessment (BfR).

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