Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole

Saudi Pharmaceutical Journal (2011) 19, 75–83

King Saud University

Saudi Pharmaceutical Journal www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole Nilesh J. Thumar, Manish P. Patel

*

Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120 Gujarat, India Received 15 September 2010; accepted 7 January 2011 Available online 3 February 2011

KEYWORDS Carbostyril; Multicomponent reaction; 1H-Pyrazole-4-carbaldehyde; Antimicrobial activity; Minimum inhibitory concentration

Abstract A new series of 12 derivatives of 4-pyrazolyl-N-arylquinoline-2,5-dione (4a–l) were synthesized by one pot base catalyzed cyclocondensation reaction of 1-aryl-5-chloro-3-methyl1H-pyrazole-4-carbaldehyde (1a–c), Meldrum’s acid (2) and 3-arylamino-5,5-disubstitutedcyclohex-2-enone (3a–d). All the compounds were characterized by elemental analysis, FT-IR, 1H NMR and 13C NMR spectral data and were screened, against six bacterial pathogens, namely Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae, Salmonella typhi, Vibrio cholerae, Escherichia coli and antifungal activity, against two fungal pathogens Aspergillus fumigatus and Candida albicans, using broth microdilution MIC (minimum inhibitory concentration) method. Some of the compounds were found to be equipotent or more potent than commercial drugs, against most of the employed strains, as evident from the screening data. ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction The incidence of fungal and bacterial infections has increased dramatically in recent years (Peara and Patterson, 2002). The widespread use of antifungal and antibacterial drugs and their * Corresponding author. Tel.: +91 2692 226856; mobile: +91 9825257948. E-mail address: [email protected] (M.P. Patel). 1319-0164 ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of King Saud University. doi:10.1016/j.jsps.2011.01.005

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resistance against fungal and bacterial infections has led to serious health hazards. The resistance of wide spectrum antifungal and antibacterial agents has initiated discovery and modification of the new antifungal and antibacterial drugs (Biot et al., 2000). The carbostyril (2-quinolone) skeleton is a fertile source of biologically important molecules possessing a wide spectrum of biological and pharmacological activities, such as antimicrobial (Jayashree et al., 2009; Creaven et al., 2010), antiproliferative (Chen et al., 2007), antithrombotic (Buchanan et al., 1989), anti-hepatitis B (Cheng et al., 2008), anti-HIV (Zhang et al., 2003), anti-tumor (Joseph et al., 2002), antioxidative activity (Chung and Woo, 2001) and cytotoxicity against human tumor cell lines (He et al., 2005). Several carbostyril derivatives are also nitric oxide production inhibitors (Ito et al., 2004), 5-HT1B/5-HT2A receptor antagonists (McCort et al., 2001), Rho-kinase inhibitors (Letellier et al., 2008), androgen receptors (Oeveren et al., 2007), p38aMAP kinase inhibitors

76 (Peifer et al., 2008) and induce mitochondrial dysfunction (Chilin et al., 2005). Therefore, the synthesis of 2-quinolone derivatives has kindled a strong interest in us. In recent years, several 4-functionally substituted N-arylpyrazole derivatives, which have been identified as antimicrobial (Damljanovic et al., 2009), anti-inflammatory (Bekhit et al., 2008), antitubercular (Chovatia et al., 2007), antitumor (Joksovic et al., 2009), antiangiogenesis (Abadi et al., 2003), antiparasitic (Rathelot et al., 2002), antiviral (Hashem et al., 2007) also possess analgesic and anxiolytic activities. (Shetty and Bhagat, 2008). The classic multicomponent reaction approach for Nsubstituted-2-quinolones involves base-catalyzed cyclization of aldehyde, Meldrum’s acid and b-enaminone. Literature survey (Wang et al., 2007; Tu et al., 2001, 2006; Suarez et al., 1999) revealed few studies concerning N-substituted quinolin2-one derivatives of aromatic aldehyde, wherein not a single reference where 1H-pyrazole-4-carbaldehydes are used and evaluated for their biological profile. In view of these particulars and by taking into account a modification on the quinolone nucleus can bring significant changes in pharmacological activities and can afford new classes of therapeutically active compounds for biomedical screening containing therapeutically active moieties pyrazole and quinolin-2-one and as part of our current studies in developing new antimicrobial agents containing quinoline (Ladani et al., 2009a,b, 2010; Mungra et al., 2009, 2010; Nirmal et al., 2009; Shah et al., 2009; Thakor et al., 2008) and 1H-pyrazole-4-carbaldehyde (Thumar and Patel, 2009a, 2011; Shah et al., 2009) derivatives, we report herein the synthesis of some new derivatives of 4-pyrazolyl-N-arylquinoline-2,5-dione (4a– l) via multicomponent reaction approach. The constitution of all the products was characterized using elemental analysis, FT-IR, 1H NMR, 13C NMR and mass spectrometry. All compounds were screened for in vitro antimicrobial activity against eight human pathogens, of which three were Gram-positive bacterial pathogens Streptococcus pneumoniae, Clostridium tetani, Bacillus subtilis, three were Gram-negative bacterial pathogens Salmonella typhi, Vibrio cholerae, Escherichia coli and two were fungal pathogens Aspergillus fumigatus and Candida albicans, using broth microdilution MIC method (NCCLS, 2002; Zanatta et al., 2007).

2. Material and methods 2.1. General Required acetic anhydride, substituted anilines, malonic acid and phosphorous oxychloride were obtained from S.D. Fine Chem Ltd., Vadodara, Gujarat, India. Cyclohexanedione and dimedone were obtained from Sigma–Aldrich. Moreover, 1aryl-3-methyl-1H-pyrazol-5(4H)-ones were obtained from Meghmani Organics Ltd., Ahmedabad, Gujarat, India and were used without further purification. Solvents were purified and dried before being used. The microwave assisted reactions are conducted in a ‘‘RAGA’s Modified Electromagnetic Microwave System’’ whereby microwaves are generated by magnetron at a frequency of 2450 MHz having an adjustable output power levels, i.e., 10 levels from 140 to 700 W and with an individual sensor for temperature control (fiber optic is used as a

N.J. Thumar, M.P. Patel individual sensor for temperature control) with attachment of reflux condenser with constant stirring (thus avoiding the risk of high pressure development). All the melting points were determined in open glass capillary tubes using an electrical melting point apparatus (IEI Instrumentation Pvt. Ltd., Ahmedabad, India) and are uncorrected. Thin-layer chromatography (TLC), was performed on aluminum plates (precoated with silica gel, 60F254, 0.25 mm thickness, Merck, Darmstadt, Germany) for monitoring the progress of all reactions, purity and homogeneity of the synthesized compounds; the solvent system toluene:ethyl acetate (7:3) was used UV radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H, N) was carried out by Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer, USA) and all compounds are within ±0.4% of the calculated value. The IR spectra were recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer, USA) and only the characteristic peaks are reported in cm1. 1H NMR and 13C NMR spectra were recorded in DMSO-d6 on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific Corporation Ltd., Switzerland) using solvent peak as internal standard at 400 and 100 MHz, respectively. Chemical shifts are reported in parts per million (ppm). Splitting patterns were designated as follows: s, singlet; d, doublet; dd, doublet of doublet and m, multiplet. 2.2. Chemistry 2.2.1. General procedure for 1-aryl-5-chloro-3-methyl-1Hpyrazole-4-carbaldehyde (1a–c) 1-Aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1a–c) were prepared, according to literature procedure (Xiao et al., 2005), by Vilsmeier–Haack reaction of 1-aryl-3-methyl-1Hpyrazol-5(4H)-one (Scheme 1). To ice cold dimethylformamide (0.4 mol) was added dropwise with stirring phosphorus oxychloride (0.4 mol) over a period of 30 min, stirring was continued for further 45 min keeping the reaction mixture at 0 C. Appropriate 1-aryl-3methyl-1H-pyrazol-5(4H)-one (0.08 mol) was then added and the reaction mixture was allowed to attain room temperature. The mixture was then heated at 90 C for 4 h, allowed to cool and poured onto mixture of crushed ice and water. The precipitates obtained were filtered, dried and crystallized from ethanol to obtain the required 1-aryl-5-chloro-3-methyl-1Hpyrazole-4-carbaldehyde (1a–c). 2.2.2. General procedure for Meldrum’s acid (2,2-dimethyl-1,3dioxane-4,6-dione) (2) Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (2) was synthesized, according to literature method (Davidson and Bernhard, 1948), by a condensation reaction of malonic acid

Scheme 1 Synthetic pathway for the intermediate 1-aryl-5chloro-3-methyl-pyrazole-4-carbaldehydes (1a–c).

Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole

77

Physical and analytical data of the compounds 4a–l are given in Table 1 and spectroscopic characterization data of the compounds 4a–l are given hereafter:

Scheme 2

Synthetic pathway for Meldrum’s acid (2).

with acetone in acetic anhydride with sulfuric acid at 0 C (Scheme 2). A suspension of powdered malonic acid (0.5 mol) in acetic anhydride (0.64 mol) was added, while stirring, 1.5 mL of conc. sulfuric acid. Most of the malonic acid dissolved with spontaneous cooling. To the resulting solution, acetone (0.55 mol) was added while cooling to maintain the temperature at 20–25 C. The reaction mixture was allowed to stand overnight in the refrigerator and the resulting crystals filtered by suction and washed three times with sufficient ice water. Recrystallization was effected without heating by dissolving 10 g of the product in 20 mL of acetone, filtering and adding 40 mL of water to get crystals of Meldrum’s acid (2). 2.2.3. General procedure for 3-arylamino-5,5-(un) substitutedcyclohex-2-enones (3a–d) 3-Arylamino-5,5-(un)substitutedcyclohex-2-enones (3a–d) were synthesized, according to literature procedure (Chanda et al., 2004), by the solid phase reaction of 1,3-dicarbonyl compound and 4-fluoroaniline under microwave irradiation (Scheme 3). A reaction mixture of equimolar amount of appropriate 5,5disubstitutedcyclohexane-1,3-dione (0.05 mol) and 4-substitutedaniline (0.05 mol) was irradiated in the microwave oven at 350 W level (50% of the total power) for 9 min (three pulses each of 3 min). After the completion of the reaction (which was monitored by TLC), crude product was cooled to room temperature, dissolved in diethyl ether and the mixture was stirred for 15–20 min and filtered. The product was repeatedly washed with ether and dried, to give 3-(4-arylamino)-5,5-disubstitutedcyclohex-2-enone, which were used without further purification. 2.2.4. General procedure for 4-(1-aryl-5-chloro-3-methyl-1Hpyrazol-4-yl)-1-aryl-7,7-(un)substituted-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4a–l) A mixture of 1-aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1a–c) (30 mmol), Meldrum’s acid (2) (30 mmol), and appropriate b-enaminone (3a–d) (30 mmol) in ethanol (20 mL) containing 3 drops of piperidine was slowly heated and refluxed with stirring for 6 h. The completion of reaction was monitored by TLC (ethyl acetate:toluene 3:7). The reaction mixture was cooled to room temperature and the solid separated was filtered and washed with a mixture of chloroform and methanol (1:1) to obtain the pure compounds 4a–l.

Scheme 3

2.2.4.1. 4-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-(4fluorophenyl)-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4a). IR (KBr, m, cm1): 3005 (ArC–H str.), 1705 (C‚O str.), 1650 (cyclic N–C‚O str.), 1185 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 1.80–2.33 (m, 6H, 3·CH2), 2.36 (s, 3H, CH3), 2.64 (d, J = 16.8 Hz, 1H, H3), 3.04 (dd, J = 16.4 Hz, J0 = 8.0 Hz, 1H, H3), 4.36 (d, J = 8.8 Hz, 1H, H4), 6.94–7.98 (m, 9H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.86 (CH3), 21.38 (C8), 26.88 (C4), 28.58 (C7), 36.66 (C3), 38.61 (C6), 111.93, 114.99, 117.70, 122.09, 123.73, 127.25, 130.90, 133.92, 136.19, 142.83, 145.35, 153.55, 155.04 (Ar–C), 169.53 (C2), 196.14 (C5). 2.2.4.2. 4-(5-Chloro-1-(3-chlorophenyl)-3-methyl-1H-pyrazol4-yl)-1-(4-fluorophenyl)-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)dione (4b). IR (KBr, m, cm1): 3010 (ArC–H str.), 1695 (C‚O str.), 1640 (cyclic N–C‚O str.), 1170 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 1.85–2.24 (m, 6H, 3 · CH2), 2.32 (s, 3H, CH3), 2.65 (d, J = 16.0 Hz, 1H, H3), 3.13 (dd, J = 15.6 Hz, J0 = 7.2 Hz, 1H, H3), 4.53 (d, J = 7.6 Hz, 1H, H4), 6.99–7.85 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.77 (CH3), 22.49 (C8), 27.38 (C4), 28.45 (C7), 37.36 (C3), 38.82 (C6), 111.80, 113.17, 115.69, 116.34, 121.52, 124.50, 128.12, 131.42, 134.72, 144.03, 146.60, 149.61, 154.84, 155.81, 157.20 (Ar–C), 168.24 (C2), 195.56 (C5). 2.2.4.3. 4-(5-Chloro-3-methyl-1-p-tolyl-1H-pyrazol-4-yl)-1-(4fluorophenyl)-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4c). IR (KBr, m, cm1): 3000 (ArC–H str.), 1715 (C‚O str.), 1650 (cyclic N–C‚O str.), 1200 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 1.75–2.19 (m, 6H, 3·CH2), 2.25 (s, 3H, pyz-CH3), 2.35 (s, 3H, tolyl–CH3), 2.71 (d, J = 15.2 Hz, 1H, H3), 3.12 (dd, J = 16.8 Hz, J0 = 7.2 Hz, 1H, H3), 4.45 (d, J = 8.0 Hz, 1H, H4), 7.04–8.17 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.85 (pyz–CH3), 21.03 (tolyl–CH3), 22.80 (C8), 27.22 (C4), 28.37 (C7), 36.38 (C3), 37.90 (C6), 112.23, 113.86, 118.46, 124.53, 127.01, 128.68, 129.36, 132.26, 133.71, 136.63, 145.14, 152.59, 155.08 (Ar–C), 168.44 (C2), 197.05 (C5). 2.2.4.4. 4-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1(4-fluorophenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinoline-2, 5(1H,6H)-dione (4d). IR (KBr, m, cm1): 3005 (ArC–H str.), 1690 (C‚O str.), 1660 (cyclic N–C‚O str.), 1210 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 0.80 (s, 3H, CH3), 0.94 (s, 3H, CH3), 1.86–2.25 (m, 4H, 2·CH2), 2.31 (s, 3H, CH3), 2.78 (d, J = 16.0 Hz, 1H, H3), 3.26 (dd,

Synthetic pathway for the intermediate enaminones (3a–d).

78 Table 1

N.J. Thumar, M.P. Patel Physical and analytical characterization data of compounds 4a–l.

Compound

Yield (%)

m.p. (C.)

Mol. formula (Mol. Wt.)

Elemental analysis (%), Found (Calcd.) C

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l

68 72 66 70 65 60 65 55 65 58 70 72

234–235 202–204 221–223 243–245 177–180 218–221 250–253 186–188 222–224 239–241 191–192 215–216

C25H21ClFN3O2 (449.90) C25H20Cl2FN3O2 (484.35) C26H23ClFN3O2 (463.93) C27H25ClFN3O2 (477.96) C27H24Cl2FN3O2 (512.40) C28H27ClFN3O2 (491.98) C26H24ClN3O3 (461.94) C26H23Cl2N3O3 (496.39) C27H26ClN3O3 (475.97) C28H28ClN3O3 (489.99) C28H27Cl2N3O3 (524.44) C29H30ClN3O3 (504.02)

J = 15.2 Hz, J0 = 7.6 Hz, 1H, H3), 4.54 (d, J = 8.8 Hz, 1H, H4), 7.02–7.86 (m, 9H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.61 (pyz–CH3), 26.53, 26.86 (CH3), 27.93 (C4), 32.36 (C7), 38.43 (C6), 42.08 (C8), 51.97 (C3), 112.16, 115.74, 117.37, 124.54, 125.11, 129.43, 132.21, 134.27, 135.06, 138.49, 144.31, 153.58, 156.47 (Ar–C), 169.62 (C2), 195.14 (C5). 2.2.4.5. 4-(5-Chloro-1-(3-chlorophenyl)-3-methyl-1H-pyrazol4-yl)-1-(4-fluorophenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4e). IR (KBr, m, cm1): 3010 (ArC–H str.), 1700 (C‚O str.), 1645 (cyclic N–C‚O str.), 1200 (ArC– F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 0.88 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.94–2.32 (m, 4H, 2·CH2), 2.35 (s, 3H, CH3), 2.83 (d, J = 16.4 Hz, 1H, H3), 3.10 (dd, J = 16.0 Hz, J0 = 8.4 Hz, 1H, H3), 4.49 (d, J = 7.2 Hz, 1H, H4), 7.05–8.21 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.57 (pyz–CH3), 26.18, 27.12 (CH3), 28.86 (C4), 32.13 (C7), 37.45 (C6), 41.56 (C8), 52.72 (C3), 112.96, 114.97, 119.94, 122.55, 123.23, 128.65, 130.28, 134.79, 136.02, 139.44, 142.87, 143.38, 147.79, 153.85, 156.32 (Ar–C), 169.16 (C2), 195.63 (C5). 2.2.4.6. 4-(5-Chloro-3-methyl-1-p-tolyl-1H-pyrazol-4-yl)-1(4-fluorophenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinoline-2, 5(1H,6H)-dione (4f). IR (KBr, m, cm1): 3015 (ArC–H str.), 1715 (C‚O str.), 1665 (cyclic N–C‚O str.), 1185 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 0.90 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.84–2.21 (m, 4H, 2·CH2), 2.32 (s, 3H, pyz–CH3), 2.37 (s, 3H, tolyl–CH3), 2.67 (d, J = 15.6 Hz, 1H, H3), 3.19 (dd, J = 16.8 Hz, J0 = 8.0 Hz, 1H, H3), 4.53 (d, J = 7.6 Hz, 1H, H4), 6.95–8.03 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.50 (pyz–CH3), 20.98 (tolyl–CH3), 25.62, 26.24 (CH3), 27.99 (C4), 31.21 (C7), 38.64 (C6), 39.75 (C8), 52.16 (C3), 113.45, 116.75, 118.56, 120.15, 125.29, 128.66, 132.22, 137.78, 140.67, 145.07, 148.89, 153.39, 155.40 (Ar–C), 169.13 (C2), 196.37 (C5). 2.2.4.7. 4-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-(4methoxyphenyl)-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4g). IR (KBr, m, cm1): 3025 (ArC–H str.), 1705 (C‚O str.), 1655 (cyclic N–C‚O str.), 1215 and 1065 (asym. and sym. str. of ArC–OMe), 1175 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 1.90–2.22 (m, 6H, 3·CH2), 2.37 (s, 3H,

67.06 62.28 66.96 68.03 62.04 68.00 67.81 63.28 67.89 68.82 63.84 68.82

H (66.74) (61.99) (67.31) (67.85) (63.29) (68.36) (67.60) (62.91) (68.13) (68.63) (64.13) (69.11)

5.02 3.95 5.27 4.92 5.02 5.77 4.95 4.40 5.72 5.59 5.30 5.85

N (4.70) (4.16) (5.00) (5.27) (4.72) (5.53) (5.24) (4.67) (5.51) (5.76) (5.19) (6.00)

9.19 9.04 8.85 9.06 7.91 8.87 8.83 8.61 9.13 8.31 7.88 8.56

(9.34) (8.68) (9.06) (8.79) (8.20) (8.54) (9.10) (8.47) (8.83) (8.58) (8.01) (8.34)

CH3), 2.67 (d, J = 15.2 Hz, 1H, H3), 3.19 (dd, J = 15.6 Hz, J0 = 7.2 Hz, 1H, H3), 3.72 (s, 3H, OCH3), 4.31 (d, J = 8.8 Hz, 1H, H4), 6.81–7.88 (m, 9H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.62 (CH3), 21.78 (C8), 26.96 (C4), 27.58 (C7), 36.57 (C3), 38.85 (C6), 55.80 (OCH3), 113.19, 115.02, 117.65, 124.24, 125.40, 128.57, 129.58, 130.16, 131.00, 138.27, 148.23, 157.10, 159.42 (Ar–C), 168.76 (C2), 196.98 (C5). 2.2.4.8. 4-(5-Chloro-1-(3-chlorophenyl)-3-methyl-1H-pyrazol4-yl)-1-(4-methoxyphenyl)-3,4,7,8-tetrahydroquinoline-2, 5(1H,6H)-dione (4h). IR (KBr, m, cm1): 3015 (ArC–H str.), 1690 (C‚O str.), 1650 (cyclic N–C‚O str.), 1230 and 1075 (asym. and sym. str. of ArC–OMe), 1205 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 1.72–2.20 (m, 6H, 3·CH2), 2.27 (s, 3H, CH3), 2.63 (d, J = 16.0 Hz, 1H, H3), 3.06 (dd, J = 16.4 Hz, J0 = 8.8 Hz, 1H, H3), 3.85 (s, 3H, OCH3), 4.44 (d, J = 8.0 Hz, 1H, H4), 6.93–8.07 (m, 8H, Ar– H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.88 (CH3), 21.67 (C8), 27.37 (C4), 27.12 (C7), 36.41 (C3), 38.56 (C6), 55.78 (OCH3), 114.14, 115.53, 118.59, 120.87, 121.42, 123.58, 126.07, 130.18, 130.62, 136.20, 138.75, 141.21, 149.39, 153.92, 155.43 (Ar–C), 170.27 (C2), 197.23 (C5). 2.2.4.9. 4-(5-Chloro-3-methyl-1-p-tolyl-1H-pyrazol-4-yl)-1-(4methoxyphenyl)-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4i). IR (KBr, m, cm1): 3000 (ArC–H str.), 1710 (C‚O str.), 1645 (cyclic N–C‚O str.), 1245 and 1055 (asym. and sym. str. of ArC–OMe), 1170 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 1.79–2.31 (m, 6H, 3·CH2), 2.37 (s, 3H, pyz–CH3), 2.41 (s, 3H, tolyl–CH3), 2.75 (d, J = 15.6 Hz, 1H, H3), 3.27 (dd, J = 15.2 Hz, J0 = 8.4 Hz, 1H, H3), 3.79 (s, 3H, OCH3), 4.47 (d, J = 8.4 Hz, 1H, H4), 7.08–7.99 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.73 (pyz–CH3), 21.06 (tolyl–CH3), 22.03 (C8), 27.33 (C4), 28.23 (C7), 36.48 (C3), 38.50 (C6), 55.81 (OCH3), 113.68, 117.62, 118.24, 121.46, 122.33, 127.91, 127.36, 132.29, 137.66, 139.62, 146.17, 150.30, 154.45 (Ar–C), 168.85 (C2), 196.79 (C5). 2.2.4.10. 4-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1(4-methoxyphenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinoline2,5(1H,6H)-dione (4j). IR (KBr, m, cm1): 3010 (ArC–H str.), 1695 (C‚O str.), 1655 (cyclic N–C‚O str.), 1210 and 1060 (asym. and sym. str. of ArC–OMe), 1175 (ArC–F str.); 1H

Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole NMR (400 MHz, DMSO-d6) dH (ppm): 0.94 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.88–2.17 (m, 4H, 2·CH2), 2.29 (s, 3H, CH3), 2.67 (d, J = 16.8 Hz, 1H, H3), 3.21 (dd, J = 16.0 Hz, J0 = 7.6 Hz, 1H, H3), 3.75 (s, 3H, OCH3), 4.30 (d, J = 7.2 Hz, 1H, H4), 7.02–7.94 (m, 9H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.69 (pyz–CH3), 25.39, 26.01 (CH3), 28.32 (C4), 31.02 (C7), 38.90 (C6), 41.99 (C8), 51.73 (C3), 55.84 (OCH3), 112.94, 113.72, 114.53, 122.35, 128.37, 129.26, 132.15, 134.27, 135.80, 143.06, 149.54, 151.74, 158.05 (Ar–C), 170.98 (C2), 195.20 (C5). 2.2.4.11. 4-(5-Chloro-1-(3-chlorophenyl)-3-methyl-1H-pyrazol4-yl)-1-(4-methoxyphenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinoline-2,5(1H,6H)-dione (4k). IR (KBr, m, cm1): 3000 (ArC–H str.), 1700 (C‚O str.), 1660 (cyclic N–C‚O str.), 1250 and 1020 (asym. and sym. str. of ArC–OMe), 1180 (ArC–F str.); 1H NMR (400 MHz, DMSO-d6) dH (ppm): 0.88 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.82–2.30 (m, 4H, 2·CH2), 2.38 (s, 3H, CH3), 2.72 (d, J = 16.4 Hz, 1H, H3), 3.08 (dd, J = 15.6 Hz, J0 = 8.0 Hz, 1H, H3), 3.82 (s, 3H, OCH3), 4.35 (d, J = 8.8 Hz, 1H, H4), 6.90–7.91 (m, 8H, Ar– H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.54 (pyz– CH3), 26.05, 27.77 (CH3), 28.14 (C4), 33.24 (C7), 37.55 (C6), 40.24 (C8), 50.83 (C3), 55.71 (OCH3), 113.43, 114.85, 115.64, 120.29, 126.18, 127.76, 133.47, 135.45, 136.25, 139.76, 141.98, 143.81, 146.10, 152.48, 154.31 (Ar–C), 169.39 (C2), 196.41 (C5). 2.2.4.12. 4-(5-Chloro-3-methyl-1-p-tolyl-1H-pyrazol-4-yl)-1(4-methoxyphenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinoline2,5(1H,6H)-dione (4l). IR (KBr, m, cm1): 3005 (ArC–H str.), 1710 (C‚O str.), 1640 (cyclic N–C‚O str.), 1240 and 1040 (asym. and sym. str. of ArC–OMe), 1175 (ArC–F str.); 1H

Table 2

NMR (400 MHz, DMSO-d6) dH (ppm): 1.03 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.89–2.23 (m, 4H, 2·CH2), 2.35 (s, 3H, pyz–CH3), 2.40 (s, 3H, tolyl–CH3), 2.60 (d, J = 16.0 Hz, 1H, H3), 3.19 (dd, J = 16.4 Hz, J0 = 7.6 Hz, 1H, H3), 3.76 (s, 3H, OCH3), 4.41 (d, J = 8.0 Hz, 1H, H4), 6.91–8.03 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 12.65 (pyz–CH3), 20.94 (tolyl–CH3), 25.93, 26.40 (CH3), 27.35 (C4), 32.32 (C7), 38.10 (C6), 40.81 (C8), 49.68 (C3), 55.85 (OCH3), 112.01, 114.87, 115.90, 121.13, 125.57, 126.98, 129.00, 135.12, 138.98, 140.63, 141.90, 152.02, 157.39 (Ar–C), 169.01 (C2), 196.82 (C5). 2.3. Antimicrobial screening The in vitro antimicrobial activity of all the compounds and standard drugs were assessed against three representatives of Gram-positive bacteria viz. S. pneumoniae (MTCC 1936), C. tetani (MTCC 449), B. subtilis (MTCC 441), three Gram-negative bacteria viz. S. typhi (MTCC 98), V. cholerae (MTCC 3906), E. coli (MTCC 443) and two fungi viz. A. fumigatus (MTCC 3008) and C. albicans (MTCC 227) by the Broth Microdilution MIC method according to National Committee for Clinical Laboratory Standards (NCCLS). The strains employed for the activity were procured from (MTCC – MicroType Culture Collection) Institute of Microbial Technology, Chandigarh. Mueller Hinton Broth was used as a nutrient medium to grow and dilute the compound suspension for the test bacteria and Sabouraud Dextrose Broth was used for fungal nutrition. Ampicillin, chloramphenicol, ciprofloxacin, gentamicin and norfloxacin were used as standard antibacterial drugs, whereas griseofulvin and nystatin were used as standard antifungal drugs.

Antimicrobial activity of the compounds 4a–l.

Compounds

Minimum inhibitory concentration (MIC, lg/mL) Gram-positive bacteria

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l Ampi. Chlora. Cipro. Genta. Grise. Nyst.

79

Gram-negative bacteria

Fungi

S. p. MTCC (1936)

C. t. MTCC (449)

B. s. MTCC (441)

S. t. MTCC (98)

V. c. MTCC (3906)

E. c. MTCC (443)

A. f. MTCC (3008)

C. a. MTCC (227)

250 100 250 500 200 200 50 500 500 250 500 500 100 50 50 0.5 – –

200 1000 100 100 200 500 500 100 250 200 200 250 250 50 100 5 – –

500 100 250 200 200 200 250 500 100 500 500 100 250 50 50 1 – –

250 250 150 200 500 500 100 250 100 500 100 1000 100 50 25 5 – –

250 1000 50 500 500 500 1000 150 250 250 250 500 100 50 25 5 – –

100 100 100 100 100 200 50 500 200 100 200 500 100 50 25 0.05 – –

1000 500 500 1000 500 500 1000 1000 500 1000 1000 1000 – – – – 100 100

1000 1000 500 1000 1000 1000 500 1000 500 1000 500 1000 – – – – 500 100

Ampi.: ampicillin; Chlora.: chloramphenicol; Cipro.: ciprofloxacin; Genta.: gentamicin; Grise.: griseofulvin; Nyst.: nystatin. S. p.: Streptococcus pneumoniae; C. t.: Clostridium tetani; B. s.: Bacillus subtilis; S. t.: Salmonella typhi; V. c.: Vibrio cholerae; E. c.: Escherichia coli; A. f.: Aspergillus fumigatus; C. a.: Candida albicans.

80

N.J. Thumar, M.P. Patel

Bacterial strains were primarily inoculated into Mueller– Hinton agar for overnight growth. A number of colonies were directly suspended in saline solution until the turbidity matched the turbidity of the McFarland standard (approximately 108 CFU mL1), i.e., inoculum size for test strain was adjusted to 108 CFU mL1 (Colony Forming Unit per milliliter) per well by comparing the turbidity (turbidimetric method). Similarly, fungi were inoculated on Sabouraud Dextrose Broth and the procedures of inoculum standardization were similar. DMSO was used as diluents/vehicle to get desired concentration of the synthesized compounds and standard drugs to test upon standard microbial strains, i.e., the compounds were dissolved in DMSO and the solutions were diluted with a culture medium. Each compound and standard drugs were diluted obtaining 2000 lg/mL concentration, as a stock solution. By further progressive dilutions with the test medium, the required concentrations were obtained for primary and secondary screening. In primary screening 1000, 500 and 250 lg/ mL concentrations of the synthesized compounds were tested. The active compounds found in this primary screening were further diluted to obtain 200, 100, 62.5, 50, 25, 12.5 and 6.250 lg/mL concentrations for secondary screening to test in a second set of dilution against all microorganisms. Briefly, the control tube containing no antibiotic is immediately sub cultured [before inoculation] by spreading a loopful evenly over a quarter of plate of medium suitable for the growth of the tested organism. The tubes are then put for incubation at 37 C for 24 h for bacteria and 48 h for fungi. Growth or a lack of growth in the tubes containing the antimicrobial agent was determined by comparison with the growth control, indicated by turbidity. The lowest concentration that completely inhibited visible growth of the organism was recorded as the minimal inhibitory concentration (MIC, lg/mL), i.e., the amount of growth from the control tube before incubation (which represents the original inoculum) is compared. A set of tubes containing only seeded broth and the solvent controls were maintained under identical conditions so as to make sure that the solvent had no influence on strain growth. The result of this is much affected by the size of the inoculum. The test mixture should contain 108 CFU mL1 organisms. The interpreta-

Scheme 4

tion of the results was based on griseofulvin and nystatin breakpoints for the fungi and also on ampicillin, chloramphenicol, ciprofloxacin, gentamicin and norfloxacin for bacterial pathogens. The protocols were summarized in Table 2 as the minimal inhibitory concentration (MIC, lg/mL).

3. Results and discussion 3.1. Chemistry Vilsmeier–Haack reaction of 1-aryl-3-methyl-1H-pyrazol5(4H)-one lead to chloroformylation to give required 1-aryl5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1a–c) (Xiao et al., 2005) (Scheme 1). Moreover, Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (2) was synthesized (Davidson and Bernhard, 1948) by a condensation reaction of malonic acid with acetone in acetic anhydride with sulfuric acid at 0 C (Scheme 2). The required b-enaminones (3a–d) were synthesized, according to literature procedure (Chanda et al., 2004), by the solid phase reaction of 1,3-dicarbonyl compound and 4-fluoroaniline under microwave irradiation (Scheme 3). In continuation of our interest on synthesizing biologically active heterocyclic derivatives (Ladani et al., 2009a,b, 2010; Mungra et al., 2009, 2010; Nirmal et al., 2009; Shah et al., 2009; Thumar and Patel, 2009a,b, 2011; Thakor et al., 2008), we report herein a new series of 4-pyrazolyl-N-arylquinoline2,5-dione (4a–l) derivatives which were synthesized by one pot three component cyclocondensation reaction of 1-aryl-5chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1a–c), Meldrum’s acid (2) and 3-arylamino-5,5-disubstitutedcyclohex-2enone (3a–d) (Scheme 4). Trials to obtain the title 4H-quinolone derivatives (4a–l), following the reported procedures, when the reaction was carried out in aqueous media under neutral conditions failed to proceed even on prolong refluxing. The reaction was then tried under microwave irradiation, without any success. When the reaction proceeded under basic conditions such as pyridine, morpholine, K2CO3 and DMAP, under reflux for a long time

Synthetic pathway for the synthesis of carbostyril derivatives of 1H-pyrazole (4a–l).

Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole gave poor yield. Finally, upon refluxing the reaction mixture in ethanol for 6 h in the presence of piperidine as basic catalyst gave moderate to good yield (58–72%) (Scheme 4). Hence, these conditions were considered as the most optimized conditions for the synthesis of title derivatives 4H-quinolone derivatives (4a–l). The structures of all the new compounds were established by 1H NMR, 13C NMR and FT-IR spectrometry. 1H NMR (DMSO-d6) spectrum of compounds 4a–l exhibited doublet around d 4.30–4.54 for methine (H4) and doublet around d 2.60–2.83 and doublet of doublet around d 3.04–3.27 ppm stands for methylene protons (H3) of the quinolone ring, respectively. Aromatic protons resonate as multiplets at around d 6.81–8.21 ppm of quinolone derivatives (4a–l). The 13 C NMR spectrum of compounds 4a–l showed a signal around d 26.88–28.86 and d 36.38–52.72 ppm standing for methine (C4) and methylene carbon (C3) of quinolone ring, respectively. The distinctive peaks at d 168.24–170.98 ppm (C2) and 195.14–197.23 ppm (C5) are assigned to carbonyl carbons of quinolone ring. All the aromatic carbons showed signals around d 111.93–159.42 ppm in the 13C NMR spectra confirming the structure 4a–l. The IR spectrum of compounds 4a–l exhibited characteristic absorption band around 1715– 1690 and 1665–1640 cm1 for both carbonyl (C‚O) functional group of carbostyril skeleton, respectively. The obtained elemental analysis values are in good agreement with theoretical data. Similarly, all the compounds were characterized on the basis of spectral studies. Physical, analytical and spectroscopic characterization data of the synthesized 4a–l derivatives are given in Section 2. All the compounds were screened for their antibacterial and antifungal activity. 3.2. Antimicrobial screening The examination of the data (Table 2) reveals that most of the compounds showed antibacterial and antifungal activity when compared with standard drugs ampicillin and griseofulvin. Compounds 4c (R = 4-Me, R1 = H, R2 = F), 4g (R = H, R1 = H, R2 = OMe) and 4i (R = 4-Me, R1 = H, R2 = OMe) were found to be highly potent against most of the employed strains to inhibit the growth of organism. In particular, compounds 4g (R = H, R1 = H, R2 = OMe) were found to be more efficient (MIC < 100 lg/mL), whereas 4b (R = 3-Cl, R1 = H, R2 = F) exhibited comparable activity to ampicillin against S. pneumoniae (MIC = 100 lg/mL). The compounds 4a (R = H, R1 = H, R2 = F), 4c (R = 4Me, R1 = H, R2 = F), 4d (R = H, R1 = Me, R2 = F), 4e (R = 3-Cl, R1 = Me, R2 = F), 4h (R = 3-Cl, R1 = H, R2 = OMe), 4j (R = H, R1 = Me, R2 = OMe) and 4k (R = 3-Cl, R1 = Me, R2 = OMe) were found to be more efficient (MIC < 250 lg/mL), whereas 4i (R = 4-Me, R1 = H, R2 = OMe) and 4l (R = 4-Me, R1 = Me, R2 = OMe) were found equally potent to ampicillin, towards C. tetani (MIC = 250 lg/mL). The compounds 4b (R = 3-Cl, R1 = H, R2 = F), 4d (R = H, R1 = Me, R2 = F), 4e (R = 3-Cl, R1 = Me, R2 = F), 4f, 4i (R = 4-Me, R1 = H, R2 = OMe) and 4l (R = 4-Me, R1 = Me, R2 = OMe) show better activity (MIC < 250 lg/mL), whereas 4c (R = 4-Me, R1 = H, R2 = F) and 4g (R = H, R1 = H, R2 = OMe) were found equally potent, to ampicillin, against B. subtilis (MIC = 250 lg/mL). Towards Gram-negative strain S. typhi,

81

compounds 4g (R = H, R1 = H, R2 = OMe), 4i (R = 4Me, R1 = H, R2 = OMe) and 4k (R = 3-Cl, R1 = Me, R2 = OMe) were equally active to ampicillin (MIC = 100 lg/mL). The compounds 4c (R = 4-Me, R1 = H, R2 = F) were found to exhibit better activity than ampicillin against V. cholerae. The compound 4g (R = H, R1 = H, R2 = OMe) shows better (MIC < 100 lg/mL) and 4a (R = H, R1 = H, R2 = F), 4b (R = 3-Cl, R1 = H, R2 = F), 4c (R = 4-Me, R1 = H, R2 = F), 4d (R = H, R1 = Me, R2 = F), 4e (R = 3-Cl, R1 = Me, R2 = F) and 4j (R = H, R1 = Me, R2 = OMe) were found to exhibit comparable activity to ampicillin towards E. coli (MIC < 100 lg/mL). Against fungal pathogen C. albicans, compound 4c (R = 4Me, R1 = H, R2 = F), 4g (R = H, R1 = H, R2 = OMe), 4i (R = 4-Me, R1 = H, R2 = OMe) and 4k (R = 4-Me, R1 = Me, R2 = OMe) were found to be equipotent compared to the standard griseofulvin (MIC = 500 lg/mL). None of the tested compounds was found to be potent against fungal strain A. fumigatus. The remaining compounds showed moderate to good activity to inhibit the growth of microbial pathogens and are all less effective than standard drugs. The investigation of the structure–activity relationship of antibacterial screening revealed that the compounds (4c–e) with p-fluorophenyl at the 1-position of the quinoline nucleus gave better results against C. tetani, B. subtilis and E. coli. Similarly, towards C. tetani, compounds (4h–l) with p-methoxyphenyl substituent at the 1-position of the nucleus were found to be highly active. Against C. tetani, B. subtilis and E. coli, compounds (4b, 4e, 4h and 4k) containing chloro substituted phenyl ring in pyrazole were found to be more potent. Compounds (4c, 4f, 4i and 4l) with methyl substituted phenyl ring in pyrazole have exhibited better activity against C. tetani and B. subtilis. Similarly, unsubstituted phenyl ring is found to be active against C. tetani and E. coli. Antifungal evaluation results revealed none of the effect of the presence of particular group. From antimicrobial screening results, it is interesting to note that a minor alteration in the molecular configuration of the investigated compounds may have a pronounced effect on antimicrobial activity. 4. Conclusion A new series of substituted 4-pyrazolyl-N-arylquinoline-2,5dione (4a–l) derivatives has been synthesized via multi component reaction approach and characterized through elemental and spectral analysis. This synthetic strategy allows the construction of relatively complicated nitrogen containing fused heterocyclic system as well as the introduction of various (hetero)aromatic substitutions into 1 and 4-position of quinoline system. It can be concluded from antimicrobial screening (Table 2), against panel of human pathogens that most of the synthesized quinoline derivatives were found to be active, compared to the standard drugs, against bacterial pathogens. Among them, many compounds were found to be the most active against B. subtilis, C. tetani and E. coli compared to the rest of the employed species. Antifungal activity of the compounds shows that most of the compounds were found to be potent against C. albicans compared to A. fumigatus. It is worth mentioning that minor changes in molecular configuration of these compounds profoundly influence the activity.

82 Further synthetic modification is required to enhance the potency of carbostyril derivatives by changing molecular configuration, which is in progress at our laboratory. The present study throws light on the identification of this new structural class as antimicrobials which can be of interest for further detailed preclinical investigations.

Acknowledgments The authors are thankful to the Head, Department of Chemistry, Sardar Patel University for providing 1H NMR, 13C NMR spectroscopy and research facilities. We are also thankful to SICART, Vallabh Vidyanagar, for the FT-IR and elemental analysis and Dhanji P. Rajani, Microcare Laboratory, Surat, for antimicrobial screening of the compounds reported herein. One of the authors is grateful to UGC, New Delhi for Research Fellowship in Sciences for Meritorious Students. References Abadi, A.H., Eissa, A.A.H., Hassan, G.S., 2003. Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents. Chem. Pharm. Bull. 51, 838– 844. Bekhit, A.A., Ashour, H.M.A., Ghany, Y.S.A., Bekhit, A.E.A., Baraka, A.M., 2008. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as antiinflammatory antimicrobial agents. Eur. J. Med. Chem. 43, 456– 463. Biot, C., Francois, N., Maciejewski, L., Brocard, J., Poulin, D., 2000. Synthesis and antifungal activity of a ferrocene–fluconazole analogue. Bioorg. Med. Chem. Lett. 10, 839–841. Buchanan, J.O., Fleming, J.S., Cornish, B.T., Baryla, U.M., Gillespie, E., Stanton, H.C., Seiler, S.M., Keely, S.L., 1989. Pharmacology of a potent, new antithrombotic agent, 1,3-dihydro-7,8-dimethyl-2imidazo[4,5-b]quinolin-2-one (BMY-20844). Thrombosis Res. 56, 333–346. Chanda, K., Dutta, M.C., Vishwakarma, J.N., 2004. An efficient microwave assisted solvent-free general route to cyclic enaminones. Indian J. Chem. 43B, 2475–2477. Chen, I.L., Chang, K.M., Miaw, C.L., Liao, C.H., Chen, J.J., Wang, T.C., 2007. Synthesis, antiproliferative, and antiplatelet activities of oxime- and amide-containing quinolin-2(1H)-one derivatives. Bioorg. Med. Chem. 15, 6527–6534. Cheng, P., Zhang, Q., Ma, Y.B., Jiang, Z.Y., Zhang, X.M., Zhang, F.X., Chen, J.J., 2008. Synthesis and in vitro anti-hepatitis B virus activities of 4-aryl-6-chloroquinolin-2-one and 5-aryl-7-chloro-1,4benzodiazepine derivatives. Bioorg. Med. Chem. Lett. 18, 3787– 3789. Chilin, A., Dodoni, G., Frezza, C., Guiotto, A., Barbieri, V., Lisa, F.D., Canton, M., 2005. 4-Hydroxymethyl-1,6,8-trimethylfuro[2,3h]quinolin-2(1H)-one induces mitochondrial dysfunction and apoptosis upon its intracellular oxidation. J. Med. Chem. 48, 192–199. Chovatia, P.T., Akabari, J.D., Kachhadia, P.K., Zalawadia, P.D., Joshi, H.S., 2007. Synthesis and selective antitubercular and antimicrobial inhibitory activity of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives. J. Serb. Chem. Soc. 71, 713–720. Chung, H.S., Woo, W.S., 2001. A quinolone alkaloid with antioxidant activity from the aleurone layer of anthocyanin-pigmented rice. J. Nat. Prod. 64, 1579–1580. Creaven, B.S., Devereuxm, M., Foltyn, A., McClean, S., Rosair, G., Thangella, V.R., Walsh, M., 2010. Quinolin-2(1H)-one-triazole

N.J. Thumar, M.P. Patel derived Schiff bases and their Cu(II) and Zn(II) complexes: possible new therapeutic agents. Polyhedron 29, 813–822. Damljanovic, I., Vukicevic, M., Radulovic, N., Palic, R., Ellmerer, E., Ratkovic, Z., Joksovic, M.D., Vukicevic, R.D., 2009. Synthesis and antimicrobial activity of some new pyrazole derivatives containing a ferrocene unit. Bioorg. Med. Chem. Lett. 19, 1093–1096. Davidson, D., Bernhard, S.A., 1948. The structure of Meldrum’s supposed b-lactonic acid. J. Am. Chem. Soc. 70, 3426–3428. Hashem, A.I., Youssef, A.S.A., Kandeel, K.A., Abou-Elmagd, W.S.I., 2007. Conversion of some 2(3H)-furanones bearing a pyrazolyl group into other heterocyclic systems with a study of their antiviral activity. Eur. J. Med. Chem. 42, 934–939. He, J., Lion, U., Sattler, I., Gollmick, F.A., Grabley, S., Cai, J., Meiners, M., Schunke, H., Schaumann, K., Dechert, U., Krohn, M., 2005. Diastereomeric quinolinone alkaloids from the marinederived fungus Penicillium janczewskii. J. Nat. Prod. 68, 1397–1399. Ito, C., Itoigawa, M., Furukawa, A., Hirano, T., Murata, T., Kaneda, N., Hisada, Y., Okuda, K., Furukawa, H., 2004. Quinolone alkaloids with nitric oxide production inhibitory activity from Orixa japonica. J. Nat. Prod. 67, 1800–1803. Jayashree, B.S., Thomas, S., Nayak, Y., 2009. Design and synthesis of 2-quinolones as antioxidants and antimicrobials: a rational approach. Med. Chem. Res. doi:10.1007/s00044-009-9184-x. Joseph, B., Darro, F., Behard, A., Lesur, B., Collignon, F., Decaestecker, C., Frydman, A., Guillaumet, G., Kiss, R., 2002. 3-Aryl-2quinolone derivatives: synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration. J. Med. Chem. 45, 2543–2555. Joksovic, M.D., Markovic, V., Juranic, Z.D., Stanojkovic, T., Jovanovic, L.S., Damljanovic, I.S., Szecsenyi, K.M., Todorovic, N., Trifunovic, S., Vukicevic, R.D., 2009. Synthesis and selective antitubercular and antimicrobial inhibitory activity of 1-acetyl-3,5diphenyl-4,5-dihydro-(1H)-pyrazole derivatives. J. Organomet. Chem. 694, 3935–3942. Ladani, N.K., Patel, M.P., Patel, R.G., 2009a. A convenient one-pot synthesis of series of 3-(2,6-diphenyl-4-pyridyl)hydroquinolin-2-one under microwave irradiation and their antimicrobial activities. Indian J. Chem. 48B, 261–266. Ladani, N.K., Patel, M.P., Patel, R.G., 2009b. An efficient three component one-pot synthesis of some new octahydroquinazolinone derivatives and investigation of their antimicrobial activities. Arkivoc X 292, 302. Ladani, N.K., Patel, M.P., Patel, R.G., 2010. A convenient one-pot synthesis of some new 3-(2-phenyl-6-(2-thienyl)-4-pyridyl)hydroquinolin-2-ones under microwave irradiation and their antimicrobial activities. Phosphorus Sulfur Silicon 185, 658–662. Letellier, M.A., Guillard, J., Caignard, D.H., Ferry, G., Boutin, J.A., Massuard, M.C.V., 2008. Synthesis of potential Rho-kinase inhibitors based on the chemistry of an original heterocycle: 4,4dimethyl-3,4-dihydro-1H-quinolin-2-one. Eur. J. Med. Chem. 43, 1730–1736. McCort, G., Hoornaert, C., Aletru, M., Denys, C., Duclos, O., Cadilhac, C., Guilpain, E., Dellac, G., Janiak, P., Galzin, A.M., Delahaye, M., Guilbert, F., Connor, S.O., 2001. Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: discovery of mixed 5-HT1B/ 5-HT2A receptor antagonists. Bioorg. Med. Chem. 9, 2129–2137. Mungra, D.C., Patel, M.P., Patel, R.G., 2009. An efficient one-pot synthesis and in vitro antimicrobial activity of new pyridine derivatives bearing the tetrazoloquinoline nucleus. Arkivoc XIV 64, 74. Mungra, D.C., Patel, M.P., Patel, R.G., 2010. Microwave-assisted synthesis of some new tetrazolo[1,5-a]quinoline-based benzimidazoles catalyzed by p-TsOH and investigation of their antimicrobial activity. Med. Chem. Res. doi:10.1007/s00044-010-9388-0. NCCLS (National Committee for Clinical Laboratory Standards), 2002. Performance standards for antimicrobial susceptibility testing: twelfth informational supplement. ISBN: 1-56238-454-6, M100-S12 (M7).

Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole Nirmal, J.P., Patel, M.P., Patel, R.G., 2009. Microwave-assisted synthesis of some new biquinoline compounds catalyzed by DMAP and their biological activities. Indian J. Chem. 48B, 712–717. Oeveren, A.V., Pio, B.A., Tegley, C.M., Higuchi, R.I., Wu, M., Jones, T.K., Marschke, K.B., Vilar, A.N., Zhi, L., 2007. Discovery of an androgen receptor modulator pharmacophore based on 2-quinolinones. Bioorg. Med. Chem. Lett. 17, 1523–1526. Peara, S., Patterson, T.F., 2002. Antifungal resistance in pathogenic fungi. Clin. Infect. Dis. 35, 1073–1080. Peifer, C., Urich, R., Schattel, V., Abadleh, V., Rottig, M., Kohlbacher, O., Laufer, S., 2008. Implications for selectivity of 3,4diarylquinolinones as p38aMAP kinase inhibitors. Bioorg. Med. Chem. Lett. 18, 1431–1435. Rathelot, P., Azas, N., El-Kashef, H., Delmas, F., Giorgio, C.D., Timon-David, P., Maldonado, J., Vanelle, P., 2002. 1,3-Diphenylpyrazoles: synthesis and antiparasitic activities of azomethine derivatives. Eur. J. Med. Chem. 37, 671–679. Shah, N.K., Patel, M.P., Patel, R.G., 2009. Reaction of 3-aminocyclohex-2-en-1-ones with arylidenemalononitriles: synthesis, characterization and antimicrobial activity of some new quinoline bearing pyrazole nucleus. Indian J. Chem. 48B, 1170–1173. Shetty, S.C., Bhagat, V.C., 2008. Synthesis and pharmacological activities of 3-(4-substituted phenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde and its aldimines derivatives. Asian J. Chem. 20, 5037–5045. Suarez, M., Ochoa, E., Verdecia, Y., Pita, B., Moran, L., Martin, N., Quinteiro, M., Seoane, C., Soto, J.L., Novoa, H., Blaton, N., Peters, O.M., 1999. A joint experimental and theoretical structural study of novel substituted 2,5-dioxo-l,2,3,4,5,6,7,8-octahydroquinolines. Tetrahedron 55, 875–884. Thakor, S.F., Parmar, P.V., Patel, M.P., Patel, R.G., 2008. Synthesis and antimicrobial activity of some new substituted 9-(1H-pyrazolo[3,4-b]quinoline-1-yl)acridines. Saudi Pharm. J. 16, 64–68. Thumar, N.J., Patel, M.P., 2009a. Synthesis and in vitro antimicrobial evaluation of 4H-pyrazolopyran, benzopyran and naphthopyran derivatives of 1H-pyrazole. Arkivoc XIII 363, 380.

83

Thumar, N.J., Patel, M.P., 2009b. Synthesis, characterization, and biological activity of substituted thiazole-5-carboxaldehydes and its ylidenenitriles derivatives. Phosphorus Sulfur Silicon 184, 2720– 2732. Thumar, N.J., Patel, M.P., 2011. Synthesis and antimicrobial activity of some new N -substituted quinoline derivatives of 1 H -pyrazole. Arch. Pharm. Chem. Life Sci. 344, 91–101. Tu, S.J., Wei, Q., Ma, H., Shi, D., Gao, Y., Cui, G., 2001. The synthesis of novel substituted 2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinolines without solvent under microwave irradiation. Synth. Commun. 31, 2657–2661. Tu, S.J., Zhu, X., Zhang, J., Xu, J., Zhang, Y., Wang, Q., Jia, R., Jiang, B., Zhang, J., Yao, C., 2006. New potential biologically active compounds: design and an efficient synthesis of N-substituted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-diones under microwave irradiation. Bioorg. Med. Chem. Lett. 16, 2925–2928. Wang, X.S., Zhang, M.M., Jiang, H., Yao, C.S., Tu, S.J., 2007. Threecomponent green synthesis of N-arylquinoline derivatives in ionic liquid ½Bmimþ ½BF 4 : reactions of arylaldehyde, 3-arylamino-5,5dimethylcyclohex-2-enone, and active methylene compounds. Tetrahedron 63, 4439–4449. Xiao, H.Q., Ouyang, G.P., Sun, X.D., Yao, X.D., Bao, G.Q., Qi, C.Z., 2005. Synthesis of pyrazole oxime esters. Chin. J. Synth. Chem. 13, 600–602. Zanatta, N., Alves, S.H., Coelho, H.S., Borchhardt, D.M., Machado, P., Flores, K.M., Silva, F.M.D., Spader, T.B., Santurio, J.M., Bonacorso, H.G., Martins, M.A.P., 2007. Synthesis, antimicrobial activity, and QSAR studies of furan-3-carboxamides. Bioorg. Med. Chem. 15, 1947–1958. Zhang, Q., Chen, Y., Zheng, Y.Q., Xia, P., Xia, Y., Yang, Z.Y., Bastow, K.F., Morris-Natschke, S.L., Lee, K.H., 2003. Synthesis and bioactivity of 4,10-dimethylpyridino[2,3-h]quinolin-2(1H)-one9-carboxylic acid and its esters. Bioorg. Med. Chem. 11, 1031–1034.