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Antimicrobial Activity and Synthesis of Quinoline-Based Chalcones

Muhammad Azad, Munawar Ali Munawar and Hamid Latif Siddiqui
 
ABSTRACT
A series of quinoline-based chalcones have been prepared by the condensation of quinoline-3-carbaldehydes with acetophenone and N-substituted-3-acetyl-4-hydroxy-2-quinolones with heterocyclic carbaldehydes. The prepared chalcones have been screened for antimicrobial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtiles, Klebsiellea erogeues, Staphylococcus albus, Aspergillus flavus, Aspergillus niger, Rhodolorula rubera, Lipomyces lopofera and Candida albicans. All the prepared chalcones have shown significant antimicrobial activities.
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  How to cite this article:

Muhammad Azad, Munawar Ali Munawar and Hamid Latif Siddiqui , 2007. Antimicrobial Activity and Synthesis of Quinoline-Based Chalcones. Journal of Applied Sciences, 7: 2485-2489.

DOI: 10.3923/jas.2007.2485.2489

URL: http://scialert.net/abstract/?doi=jas.2007.2485.2489

INTRODUCTION

Quinolines are important compounds because of their bioactive properties and medicinal uses such as antimalarial (Larsen et al., 1996), anti-inflammatory (Chen et al., 2001), antiasthmatic (Roma et al., 2000), antibacterial (Dube et al., 1998) and tyrosine kinase inhibiting agents (Billker et al., 1998).

Chalcones and their derivatives are also medicinally important. Many chalcone derivatives have been reported to possess antimalarial, antibacterial and antifungal properties (Katritzky, 1984). Anticancer properties of some simple chalcone derivatives have also been reported in literature (Rezig et al., 2000; Ducki et al., 1996). The synthesis of quinolinyl chalcones is scarcely reported in literature. Sayed et al. (1976) and Ibrahim et al. (1996) have synthesized a few quinolinyl chalcone derivatives by Claisen-Schmidt condensation. Dominguez et al. (2001) have reported the synthesis of some quinolinyl chalcones and claimed their antimalarial activity. Moussaoui et al. (2002) have also described the synthesis of quinolinyl chalcones and claimed their cytotoxicity in K 562 human leukaemia cell lines. The present study was aimed to prepare quinolinyl chalcones and study of their antimicrobial activities.

MATERIALS AND METHODS

All the required chemicals were purchased from Merck Company and were used as such. 2-chloro-3-formylquinolines and N-substituted-3-acetyl-4-hydroxyquinolin-2(1H)-ones were synthesized by using the methods reported in literature (Meth-Cohn and Narine, 1978) and modified by Kappe et al. (1994). IR spectra were recorded on Perkin Elmer spectrum-1X. 1H-NMR and 13C-NMR spectra were recorded on Bruker DPX-400 instrument at 400 and 100 MHZ, respectively. Chemical shifts are reported in ppm referenced to the residual solvent signal. FAB+-MS spectra were recorded on JEOL SX-102. Using Perkin-Elmer 2400-CHN Analyzer performed elemental analyses. Melting points were recorded on Gallen-kemp apparatus and were uncorrected. Aluminum coated TLC plates were purchased from Merck for monitoring of reaction and purity of compounds.

(2E)-3-(2-chloroquinolin-3-yl)-1-phenyl-2-propen-1-one (1-a): Aqueous sodium hydroxide (2 mL, 25%) was added to a mixture of 2-chloro-3-formylquinoline (1.0 g, 5.2 mmol,), acetophenone (0.6 g, 5.2 mmol) and 25 mL ethanol (95%). The reaction mixture was stirred for 90 min at room temperature and the reaction was monitored by TLC. The pH of the reaction mixture was adjusted to 6.0 by adding 10% hydrochloric acid. The organic mass was extracted with chloroform (3χ25). The chloroform layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography (n-hexane/ethyl acetate 7:3). The title compound was obtained yield (1.16 g, 76%), mp 180-181°C; IR (Kbr, vmax in cm‾1): 1665 (C = O); 1H-NMR (400 MHZ, CDCl3) δ: 8.5 (s, 1H, H4), 8.23 (d, J = 15.72 Hz, 1H, Hβ), 8.04 (br m, 5H, H5, H6, H7, H8, Hα), 7.65 (m, 5H, 5H of phenyl ring) 13C-NMR (100 MHZ, CDCl3) δ: 189.8, 147.9, 139.3, 137.5 136.2, 133.4, 131.7, 130.4, 128.9, 128.8, 128.7, 128.1, 128.0 and 126.3 mass spectrum (FAB), m/z 295 (M+2, 50%), 297 (M+2+2 17%), 258 (M-Cl, 25%), 216 (M- Ph, 10%), 176 (M-Ph-CO-CH, 15%), 105 (Ph-CO, 60%), 77 (Ph, 45%). Anal. C18H12ClNO: (293.5): Calcd; C, 73.6; H, 4.12; N, 4.77; found: C, 73.45; H, 4.04; N, 4.65%.

(2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-phenyl-2-propen-1-one (1-b): The title compound (1-b) was prepared from 2-chloro-3-formyl-6-methylquinoline and acetophenone as described for 1-a, yield (1.26 g, 79%), mp 147°C, IR (KBr, vmax in cm‾1): 1630 (C = O); 1H-NMR (400 MHZ, CDCl3) δ: 8.34 (s, 1H, H4), 8.16 (d, 1H, J = 15.76 Hz, Hβ), 8.06 (m, 2H, H5, H7), 7.8, (d, J = 8.5Hz, 1H, H8) 7.59 (br m, 6H, Hα and 5H of phenyl ring), 2.53 (s, 3H CH3). 13C-NMR (100 MHZ, CDCl3) δ: 189.8, 149.4, 146.4, 139.0, 137.8, 137.6, 135.5, 133.9, 133.2, 128.9, 128.8, 128.7, 128.6, 128.0, 126.9, 126.8, 125.9, 122.3 and 22.38 Mass spectrum (FAB), m/z 309, (M+2, 70%), 311, (M+2+2 30%), 273, (M+2- HCl 25%), 231, (M+2- Ph 5%). Anal. C19H14ClNO: (307.5): Calcd; C, 74.15; H, 4.58; N, 4.55; found: C, 74.05; H, 4.10; N, 4.05%.

(2E)-3-(2,7-Dichloroquinolin-3-yl)-1-phenyl-2-propen-1-one (1-c): The title compound (1-c) was prepared from 2,7-dichloro-3-formylquinoline and acetophenone as described for 1-a and purified by column chromatography with mixture of solvents (n-hexane/ethyl acetate 2:3), yield (1.24 g, 73%), mp 167-8°C; IR (Kbr, vmax in cm‾1): 1670 (C = O); 1H-NMR (400 MHZ, CDCl3) δ: 8.5(s, 1H, H4), 8.23 (d, 1H, J = 15.6Hz, Hβ), 8.07 (m, 3H, H5, H6, H8), 7.87 (d, J = 15.6 Hz, 1H, Hα), 7.66 (br m, 5H, 5H of phenyl ring), 7.28 (s, 1H, H8) 13C-NMR (100 MHZ, CDCl3) δ: 197.8, 159.9, 146.6, 135.5, 135.3, 128.8, 128.7, 128.6, 128.5, 127.2 and 125.6 mass spectrum (FAB), m/z 329 (M+2 90%), 331 (M+2+2 30%), 292 (M- Cl 45%), 250 (M-Ph 24%), 105 (Ph-CO, 54%), 77 (Ph, 40%). Anal. C18H11Cl2NO: (327.5): Calcd; C, 65.87; H, 3.38; N, 4.27; found: C, 65.76; H, 3.42; N, 4.25%.

(2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-phenyl-2-propen-1-one (1-d): The title compound (1-d) was prepared from 2-chloro-3-formyl-6-methoxyquinoline and acetophenone as described for 1-a, yield (1.13 g, 77%), m p 228°C; IR (KBr, vmax in cm‾1): 1620 (C = O); 1H-NMR (400 MHZ, CDCl3) δ: 8.36 (s, 1H, H4), 8.16 (d, 1H, J = 16.00Hz, Hβ), 8.05 (m, 2H,H5, H7), 7.85(d, 9.2 Hz 1H, H8), 7.57 (m, 4H, H2, H4, H6 and Hα), 7.41(m, 2H, H3, H5), 3.94 (s, 3H, OCH3) 13C-NMR (100 MHZ, CDCl3) δ: 189.8, 158.5, 147.8, 139.6, 138.6, 137.6, 134.9, 133.2, 129.9, 128.9, 128.8, 128.7, 126.1, 124.4, 105.3 and 55.7 mass Spectrum (FAB), m/z 325 (M+2, 100%), 327 (M+2+2, 33%), 290 (M+2-Cl 30%), 289 (M+2-HCl 90%), 245 (M-1-Ph 20%), 105 (Ph-CO 80%), 77 (Ph 43%). Anal. C19H14ClNO2: (323.5): Calcd; C, 70.48; H, 4.36; N, 4.33; found: C, 70.46; H, 4.32; N, 4.30%.

(2E)-3-(6-Bromo-2-chloroquinolin-3-yl)-1-phenyl-2-propen-1-one (1-e): The title compound (1-e) was prepared from 6-bromo-2-chloro-3-formylquinoline and acetophenone as described for 1-a and purified by silica gel column chromatography (n-hexane/ethyl acetate (6:1)), yield (1.39 g, 72%), mp 186-7°C; IR (KBr, vmax in cm‾1): 1675 (C = O); 1H-NMR (400 MHZ, CDCl3) δ: 8.4 (s, 1H, H4), 8.2 (d, J = 15.7 Hz, 1H, Hβ), 8.06 (m, 2H, H5, H7) 7.85 (br m, 2H, H8, Hα), 7.65 (br m, 5H, 5H of phenyl ring). 13C-NMR (100 MHZ, CDCl3) δ: 189.6, 150.8, 145.7, 138.8, 137.4, 135.0, 134.9, 133.4, 130.1, 129.9, 129.1, 128.1, 127.9 and 121.1, mass spectrum (FAB), m/z 372 (M+1 10%), 374 (M+1+2, 10%), 336, (M-Cl 8%), 338 (M+2-Cl, 8%), 176 (M-Ph-CO-CH, 20%), 105 (Ph-CO, 45%), 77 (Ph, 34%). Anal. C18H11BrClNO: (372.5): Calcd; C, 58.02; H, 2.98; N, 3.76; found: C, 57.98; H, 2.91; N, 3.69%.

3-{(E)-3-(Furan-2-yl)acryloyl}-4-hydroxy-1-methylquinolin-2(1H)-one (2-a): A mixture of 3-acetyl-4-hydroxy-1-metylquinolin-2(1H)-one (2.17 g, 0.01 mol), furfral (0.96 g, 0.01 mol), piperidine (1-2 drops) and 1-butanol (25 mL) was refluxed for 6 h. The reaction mixture was cooled and allowed to settle the precipitates. Precipitates were filtered under suction and washed with cold 1-butanol. The crude product was purified by column (chloroform/n-hexane 2:1), yield (2.00 g, 68%), mp 160-162°C (Lit. mp 106°C, Ibrahim et al. (1996)), IR (KBr, vmax): 1610 cm‾1 (C = O); 1H-NMR(300 MHZ, CDCl3) δ: 8.5 (d, J = 15.6 Hz, 1H, Hβ), 8.2 (d, J = 8.1 Hz, 1H, H5), 7.45 (d, 1H, J = 15.6 Hz, Hα) 7.68 (m, 1H, H6), 7.56 (m, 1H, H7), 7.28 (d, J = 7.5Hz, 1H, H8), 7.25 (m, 1H, H3) 6.78 (d, J = 3.6 Hz, 1H, H5), 6.53 (d, J = 8.7Hz, 1H, H4), 3.41, (s, 3H, N-CH3). 13C-NMR (75MHz, CDCl3) δ: 194, 176.12, 161.61, 152.19, 145.56, 141.66, 134.81, 130.9, 126.15, 122.78, 122.00, 116.59, 116.12, 114.20, 112.8, 105.56 and 29.16. Anal. C17H13NO4: (295): Calcd; C, 69.15; H, 4.44; N, 4.74; found: C, 68.87; H, 4.38; N, 4.69%.

1-Ethyl-4-hydroxy-{(E)-3-(thiophen-2-yl) acryloyl} quinolin-2(1H)-one (2-b): The title compound (2-b) was prepared from 3-acetyl-1-ethyl-4-hydroxyquinolin-2(1H)-one and 2-formylthiophene as described for 2-a and purified by column chromatography (ethyl acetate/n-hexane 3:2), yield (2.21, 67%), mp 162-4°C, IR (KBr, vmax): 1607.9 cm‾1 (C = O); 1H-NMR(300 MHZ, CDCl3) δ: 8.52 (d, 1H, J = 15.6 Hz, 1H, Hβ), 8.24 (dd, J = 1.8, 8.1 Hz, 1H, H5), 8.11 (d, J = 15.6 Hz, 1H, Hα) 7.68 (m, 1H, H6), 7.47 (d, 4.8Hz 1H, H6), 7.41 (d, J = 3.3 Hz, 1H, H8), 7.29 (d, J = 8.4 Hz, 1H H3) 7.21 (m, 1H, H5), 7.1 (dd, J = 1.5, 3.6Hz, 1H, H4), 4.33 (q, J = 7.2Hz, 2H, N-CH2CH3), 1.41 (t, J = 7.2Hz, 3H, NCH2CH3), 13C-NMR (75 MHZ, CDCl3) δ: 193.6, 176.02, 161.22, 141.04, 140.72, 137.56, 130.83, 132.2, 129.87, 128.32, 126.4, 124.32, 121.84, 116.29, 114.09, 37.14 and 12.84. Anal. Calcd; C18H15NO3S: (325): C, 66.44; H, 4.65; N, 4.30; found: C, 66.23; H, 4.54; N, 4.26%

1-ethyl-4-hydroxy-3-{3-(thiophen-3-yl)acryloyl}quinolin-2(1H)-one (2-c): The title compound (2-c) was prepared from 3-acetyl-1-ethyl-4-hydroxyquinolin-2(1H)-one and 3-formylthiophene as described for 2-a and purified by column chromatography (ethyl acetate/n-hexane 3:1), yield (2.01 g, 62%), mp 140°C, IR (KBr, vmax): 1612.9 cm‾1 (C = O); 1H-NMR (300 MHZ, CDCl3) δ: 8.54 (d, 1H, J = 15.6 Hz, Hβ), 8.28 (dd, 1H, J = 1.8, 8.1 Hz, H5), 8.01 (d, J = 15.6 Hz, 1H, Hα) 7.68 (m, 1H, H6), 7.74 (br m, 2H, H6, H7), 7.55 (dd, J = 0.9, 5.1Hz,1H, H8), 7.37 (br-m, 3H, H2, H4, H5), 4.35 (q, J = 7.2Hz, 2H, N-CH2-CH3), 1.39 (t, J = 7.2Hz, 3H, N-CH2-CH3), 13C-NMR (75 MHZ, CDCl3) δ: 194.54, 176.05, 161.35, 140.75, 138.81, 138.51, 133.77, 129.94, 128.00, 126.94, 123.69, 124.32, 121.89, 116.37, 114.43, 105.54, 37.18 and 12.83. Anal. C18H15NO3S: (325): Calcd; C, 66.44; H, 4.65; N, 4.30; O, 14.75; S, 9.85; found: C, 66.05; H, 4.54; N, 4.21%.

RESULTS AND DISCUSSION

During the present study a series of chalcones were prepared by condensing 3-formylquinolines with acetophenone and 3-acetyl-4-hydroxyquinolin-2(1H)-one with different heterocyclic aldehydes. For this purpose a series of substituted 2-chloro-3-formylquinolines were prepared from acetanilide derivatives using Meth-Cohn and Narine (1978) procedures (Scheme 1). The required acetanilides were prepared by direct condensation of anilines with acetic acid in the presence of orthophosphoric acid (Munawar et al., 2005).

The prepared quinolines were condensed with acetophenone in the presence of ethanolic sodium hydroxide to give a series of chalcone derivatives in good yield (Scheme 2).

N-Substituted-3-acetyl-4-hydroxyquinolin-2(1H)-one derivatives were prepared by a modified Kappe et al. (1994) method and condensed with thiophen-2-carbaldehyde, thiophen-3-carbaldehyde and furfural in the presence of piperidine in 1-butanol to obtain α,β-unsaturated carbonyl compounds (Scheme 3).

In 1HNMR spectra of these compounds, the protons of α, β unsaturated carbonyl compounds have given two doublets in the range 7.5 ppm for Hα and 8.5 ppm for Hβ with coupling constant in the range (15-16 Hz). It is inferred that they are trans isomers. The rest of signals for protons have appeared in the expected regions. Additional structure elucidation is supported by 13CNMR spectra. A signal in the range δ (194-189) ppm in 13CNMR of all the compounds that indicates carbonyl group is present. Interestingly the mass spectra of the prepared chalcones have shown the most intense signal (M+2)+ in 1(a-d) compounds and not in 1-e. Probably this is due to the hydrogenation of α,β unsaturated chalcones in glycerol matrix in the ionization chamber followed by ionization of the saturated chalcones. Meili and Seibi (1984) have reported similar hydrogenation by glycerol in FAB-spectra of several compounds.

Antimicrobial activity: The newly synthesized compounds were screened for their antibacterial and antifungal activities against the organisms: Escherichia coli, Pseudomonas aeruginosa, Bacillus subtiles, Klebsiellea erogeues, Staphylococcus albus, Aspergillus flavus, Aspergillus niger, Rhodolorula rubera, Lipomyces lopofera and Candida albicans.

Scheme 1: Synthesis of quinoline carbaldehydes

Scheme 2: Synthesis of chalcones

Scheme 3: Chalcones with five membered heterocyclic compounds

Table 1:

In vitro antimicrobial activity (bacteria) of newly prepared chalcones (1a-e and 2a-c) (μg disc‾1) by disc-diffusion assay and diameter of zone of inhibition (mm)

-: No inhibition

Table 2: ANOVA for the effect of different compounds for their antibacterial activity against five bacterial species
***: Significant at p≤0.001, df: degree of freedom, SS: Sum of Squares, MS: Mean Squares

Using the disc-diffusion method (Karaman et al., 2003) carried out the antimicrobial tests. Suspension of (100 μL) containing 108cfu mL‾1 of bacteria, 106cfu mL‾1 of fungi was spread on Mueller-Hinton agar (MHA) medium and Sabouraud’s Dextrose Agar (SDA) medium, respectively. The discs (6mm in diameter), impregnated with 10μL of the test compounds (1000μg disc‾1) at the concentration of 100mg mL‾1 were placed on the inoculated agar. Negative controls were prepared using the same solvent (DMF), which was employed to dissolve the test compounds. Ofloxacin (5μg disc‾1) and Clotrimazole (10μg disc‾1) were used as positive reference standards to determine the sensitivity of each microbial species tested. The inoculated plates were incubated at 37°C for 24 h and 27°C for 72 h for bacterial and fungal strains, respectively. Antimicrobial activities were evaluated by measuring the diameter of zone of inhibition against test organisms and results were given in Table 1, 3 and 4.

Table 3: Antimicrobial activities of prepared compounds
In a column values with different values show a significant difference (p≤0.05) as determined by Duncan’s Multiple Range Test

Table 4: In vitro antimicrobial activities (fungi) of newly prepared chalcones (1a-e and 2a-c) (μg disc‾1) by disc-diffusion assay and diameter of zone of inhibition (mm)

On the basis of the observed zone of inhibition values, it can be concluded that there is a significant differences in the antibacterial and antifungal potentials of prepared quinolinyl chalcones. The difference among the responses of different prepared compounds is also significant (Table 2 and 5).

Among the prepared compounds 2a, 2b and 2c have shown more antibacterial and antifungal activities against the tested microbes than rest of the compounds. This is might be because of structural features. Probably quinolones rapidly inhibit DNA synthesis by promoting the DNA gyrase cleavage resulting in bacterial deaths. The responses of the prepared compounds are less than standard; a fourth generation agent with improved gram-positive coverage. The relative responses of different compounds against each microbial species are shown (Table 3 and 6).

Table 5: ANOVA for the effect of 9 different compounds for their antifungal activity against five fungal species
***: Significant at p≤0.001, df: degree of freedom, SS: Sum of Squares, MS: Mean Squares

Table 6: Antifungal activity of prepared compounds
In a column values with different values show a significant difference (p≤0.05) as determined by Duncan’s Multiple Range Test

ACKNOWLEDGMENTS

The authors acknowledge the enabling role of the Higher Education Commission Islamabad, Pakistan and appreciate its financial support through Development of S and T Manpower through Indigenous Ph.D programme and we are also thankful to Mr. John Kershaw for the spectral measurements and elemental analyses, Department of Chemistry, Loughborough University, Loughborough, Leicestershire UK.

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