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Synthesis, Antimicrobial and Anti-Inflammatory studies of some novel Schiff Base Derivatives

Kumar Abhishek* , Fernandes Jennifer Kumar Pankaj
Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences , Nitte University, Paneer, Deralakatte- 575018, Mangalore, Karnataka.
Corresponding Author: Email: abhi12bunty@gmail.com
Date of Submission: 09-06-2014
Date of Acceptance: 29-06-2014
Conflict of Interest: NIL
Source of Support: NONE
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Abstract

A series of novel substituted 3-acetyl-1-(benzylideneamino) quinolin-2(1H)-one (1-12) have been synthesized by condensing different substituted 3-acetyl-1-aminoquinolin- 2-one and aromatic aldehydes in alcohol medium. 3-acetyl-1-aminoquinolin- 2-one were synthesized from substituted 3-acetyl coumarin upon refluxing with hydrazine hydrate and ethanol. The structures of the final synthesized compounds were confirmed by IR, 1H NMR and mass spectra. The synthesized compounds were screened for their antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans, Aspergillus niger respectively by tube dilution method. Most of the compounds showed good minimum inhibitory concentration compared to the standard drug amoxicillin and fluconazole respectively. Anti-inflammatory studies were carried out by carrageenan induced paw edema method. Anti-inflammatory studies showed statistically significant activity when compared to control.

Keywords

2-Quinolones, schiff base, antimicrobial activity, minimum inhibitory concentration, anti-inflammatory activity.

INTRODUCTION

2-Quinolones (carbostyrils or 1-aza coumarins) are isosteric with coumarins and isomeric to 4- quinolones could become the probable potential candidate for antibacterial activity[1]. 2-Quinolone derivatives were found to be associated with various biological activities such as antitumor[2], anti-inflammatoryl[3], antiplatelet, antiulcer[4], antioxidant[5] and antidepressant activity. Many substituted quinolin-2-one derivatives have recently craned great interest in chemotherapy as antitumor drugs[6]. Compounds containing an azomethine group (-CH=N-) known as Schiff bases are formed by the condensation of a primary amine with a carbonyl compound. Schiff bases of aliphatic aldehydes are relatively unstable and are readily polymerized while those of aromatic aldehydes having an effective conjugation system are more stable. Schiff bases and their complexes are largely studied because they interested and important properties such as their ability to bind reversibly oxygen[7] redox systems in biological systems and oxidation of DNA. Many biological important Schiff bases ligands have been reported which possess antibacterial, antifungal[8], antimicrobial[9], anticonvulsant, antioxidant[10], anti-inflammatory[11] and antitumor activity[12].
By considering the above facts and their increasing importance in pharmaceutical and biological field, it was considered of interest to synthesize some new chemical entities incorporating the two active pharmacophores in a single molecular frame work and to evaluate their biological activities. Hence an attempt was made towards the incorporation of Schiff bases with substituted 3-acetyl-1-amino-quinolin-2-one and to probe how this combination could influence the biological activity. Hence the synthesized compounds were evaluated for their antimicrobial and anti-inflammatory activities and compared with standard drugs.

MATERIALS AND METHODS

All the chemicals were of analytical grade: substituted salicylaldehyde, ethylacetoacetate, absolute ethanol, piperidine, glacial acetic acid, hydrazine hydrate and substituted benzaldehyde. Melting points were determined by open capillary method and are uncorrected. The purity of the compounds was monitored by thin layer chromatography (TLC) using silica gel G plates. The spots were visualized under UV light and by the exposure to iodine vapors. The homogeneity of the compounds were checked on silica gel-G coated plate by using Chloroform: Methanol (8:2) as solvent. All IR spectra were recorded in Alpha Bruker using ATR method. 1H NMR spectra were recorded on Bruker spectrophotometer (400 MHz) in DMSO-d6 solvent using tetra methyl silane (TMS) as an internal standard. Mass spectra was recorded by LCMS method.

General Procedure:

Synthesis of substituted 3-acetyl-1-amino-quinolin- 2-one (AJQ1-AJQ12) [13]

Substituted 3-acetyl coumarin (0.01 mol) with excess hydrazine hydrate 99% (0.1 mol) in 25 ml ethanol was refluxed for 12 hours. It was then cooled and poured into crushed ice with stirring. The solid product formed was filtered and recrystallised from ethanol.

Synthesis of Substituted 3-acetyl-1- (benzylideneamino) quinolin-2(1H)-one (AJS1- AJS12) [14]

A mixture of substituted 3-acetyl-1-amino-quinolin- 2-one (0.01mol) and substituted benzaldehyde (0.01 mol) was refluxed for 4-5 hours with continuous stirring in presence of few drops of glacial acetic acid as catalyst. The reaction mixture was monitored by TLC. It was then cooled and added to ice cold water. The precipitated solid was filtered and recrystallised from ethanol
R: H, 6-NO2, 6-Cl R1: 3-NO2, 3, 4, 5-OCH3, 4-CH3, 4-OH, 2-Cl, 2-NO2

Spectral data

3-acetyl-1-aminoquinolin-2(1H)-one (AJQ1)
IR (cm-1): 1506(Ar C=C str), 829 (Ar C-H bend), 2950(C-H aliphatic str), 1701 (C=O str), 3362, 3398 (N-H str).
1H NMR (400 MHz, DMSO-d6):  7.25-8.27 (m, 5H, Ar-H), 3.73(s, 2H, NH2), 2.59 (s, 3H, COCH3). Mass (m/z): 202 (M+)

3-acetyl-1-(3-nitrobenzylideneamino) quinolin- 2(1H)-one (AJS1)

IR (cm-1): 1511(Ar C=C str), 816 (Ar C-H bend), 3083 (Ar C-H str), 1360 (Ar-NO2), 1701 (C=O str), 1618 (C=N).
1H NMR (400 MHz, DMSO-d6):  7.14-8.52 (m, 9H, Ar-H), 2.57 (s, 3H, COCH3). Mass (m/z): 335 (M+) 3-acetyl-1-(3,4,5-

trimethoxybenzylideneamino)quinolin-2(1H)-one (AJS2)

IR (cm-1): 1504(Ar C=C str), 830 (Ar C-H bend), 3036 (Ar C-H str), 1223 (C-O str), 1698 (C=O str), 1611(C=N).
1H NMR (400 MHz, DMSO-d6):  7.28-8.25 (m, 8H, Ar-H), 2.56 (s, 3H, COCH3), 3.32 (s, 3H, OCH3) Mass (m/z): 380 (M+)

3-acetyl-6-chloro-1-(4- methylbenzylideneamino)quinolin-2(1H)-one (AJS9)

IR (cm-1): 1506(Ar C=C str), 832 (Ar C-H bend), 3030 (Ar C-H str), 1695 (C=O str), 776(C-Cl str), 1379(Ar-CH3 C-H str), 1614(C=N).
1H NMR (400 MHz, DMSO-d6):  7.14-8.27 (m, 7H, Ar-H), 2.57 (s, 3H, COCH3), 2.27 (s, 3H, CH3)
Mass (m/z): 339 (M+1)

Antimicrobial Activity

All the synthesized compounds were evaluated for their minimum inhibitory concentration by tube dilution method[15]. The synthesized test compounds were tested at different concentrations and amoxicillin and fluconazole was used as standard. Serial dilutions of the test compound was made in a liquid medium which was inoculated with a standardized number of organisms and incubated for 24 hrs. The lowest concentration of test compound preventing appearance of turbidity is considered to be the minimal inhibitory concentration (MIC). After preparation of different concentrations of the antimicrobial agent in brain heart infusion broth (by using the broth dilution method), we inoculate them with the tested organism. Then after incubation we can determine the MIC by choosing the lowest concentration in which no growth occurs.

Anti-inflammatory activity

The anti-inflammatory activity of the test compounds was carried out using carrageenaninduced rat paw edema[16] model according to Winter et al.[17] by employing 1% Carrageenan solution as phlogistic agent. Edema was induced in the left hind paw of Wistar rats (150-200 g) of either sex by the sub-plantar injection of 0.1 ml of 1% Carrageenan in distilled water. Each group composed of six animals. The animals which were bred in our laboratory were housed under standard conditions and received a diet of commercial food pellets and water ad libitum during the maintenance but they were entirely fasted during the experiment period. Our studies were conducted in accordance with recognized guidelines on animal experimentation.
The test compounds were given intraperitoneally 30 min after Carrageenan injection. Naproxen was taken as the standard at a dose of 13.5 mg/kg body weight (p.o). The rat paw volume was measured after 1hr, 2hr, 3hr and 4hrs respectively after Carrageenan injection by using Plethysmometer. The difference between the paw volume at 4 hr and 0 hr measurement was calculated and taken as edema volume. Percentage inhibition in the paw edema was calculated by using the formula,
% Edema inhibition= 100(1-Vt/Vc), where Vt represents mean increase in paw volume of test and Vc represents mean increase in paw volume of control.

Statistical analysis

All experimental groups were composed of six animals. Data obtained from animal experiments were expressed as mean ± SEM. The statistical significance of difference between groups were assessed by means of analysis of variance (ANOVA) followed by Dunnet's test.

RESULTS

All values are expressed as mean ± SEM (n = 6). *P < 0.05 significant compared to control. **P < 0.01 significant compared to control

DISCUSSION

Antimicrobial Activity

All the synthesized compounds were evaluated for their minimum inhibitory concentration by tube dilution method. Compounds AJS2, AJS6, AJS7 and AJS12 showed significant antibacterial activity against gram +ve bacteria and compounds AJS3, AJS5 and AJS11 showed significant antibacterial activity against gram-ve bacteria compared to standard drug amoxicillin. Compounds AJS1, AJS4, AJS6, AJS9, AJS10 and AJS12 showed significant antifungal activity against C.albicans and compounds AJS4, AJS5, AJS8, AJS9, AJS10 and AJS12 showed significant antifungal activity against A.niger compared to standard drug fluconazole. The results of the minimum inhibitory concentration are summarized in Table 2.

Anti-inflammatory activity

All the synthesized compounds were tested for their anti-inflammatory activity using Carrageenan induced rat paw edema method at a dose of 200 mg/kg of body weight using Diclofenac sodium as standard drug at the dose level of 13.5 mg/kg body weight. The percentage inhibition of edema volume was calculated by using the formula, % inhibition = 100(1- Vt/Vc), Where Vt and Vc are the relative change in the edema volume of paw after the administration of the test and control respectively. Percentage inhibition shown by tested compounds are given in Table 3. Compounds AJS1, AJS2, AJS4, AJS7, AJS8 and AJS12 showed significant antiinflammatory activity compared with respective control groups but the maximum inhibition of paw edema was shown by compounds AJS7 and AJS8 at 4th hour when compared to the standard drug diclofenac sodium.

CONCLUSIONS

The above results proved that novel schiff bases synthesized from 2-quinolones are found to be interesting lead molecules as antimicrobial and anti-inflammatory agents. The study reports the successful synthesis of schiff bases derivatives with moderate yields. Most of the synthesized compounds showed significant antimicrobial activity and anti-inflammatory activities. It can be concluded that schiff bases containing 2- quinolone moiety certainly holds great promise towards the good activity leads in medicinal chemistry.

ACKNOWLEDGEMENTS

The authors are thankful to Nitte University for providing the necessary facilities to carry out this research. The authors are grateful to Sequent Research Ltd, Mangalore and Central Instrumentation Facility, MIT Manipal for providing spectroscopic data.

Tables at a glance

Table icon Table icon Table icon
Table 1 Table 2 Table 3
 

Figures at a glance

Figure 1
Figure 1
 

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