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Synthesis and biological evaluation of 4-(3-hydroxy-benzofuran-2-yl)coumarins.

1. Introduction

Benzofuran and its derivatives [1] have attracted considerable interest in recent years for their versatile properties in chemistry and pharmacology. 3-Benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin [2] was found to be the most potent antitubercular agent against Mycobacterium tuberculosis, even better than standard drug isoniazid. Benzofuran derivatives [3] were found to exhibit favorable antibacterial activity against Staphylococcus aureus and Bacillus subtilis which were better than the control drugs Cefotaxime and Ketoconazole. 2-Phenylbenzofurans [4] exhibited enhanced antiprotozoal activity against Trypanosoma brucei rhodesiense and Plasmodium falciparum. 2-Arylbenzofurans [5] were isolated from the roots of Glycyrrhiza uralensis. They showed significant in vitro protein tyrosine phosphate-1B inhibitory activity. Technetium-99m labeled pyridyl benzofuran derivatives [6] was tested as potential probes for imaging [beta]-amyloid plaques in Alzheimer's brains using single photon emission computed tomography.

Coumarin moieties are widely featured in a broad range of pharmacological and biologically active compounds [7, 8]. Phosphorohydrazine derivatives of coumarin displayed high in vivo antitumour activity against P388 leukemia [9]. Coumarin pyrazoline hybrids were found to possess the highest cytotoxicity against colorectal cell line HCT-116 with [IC.sub.50] value of 0.01 10]. Thiazolyl coumarin derivatives showed significant inhibition against Haemophilus influenzae with a MIC value of 15 [micro]M which is less than that of tetracycline [11]. Benzo[d]thiazolyl coumarins [12] demonstrated antiHIV activity against HIV-1 cell with [EC.sub.50] < 7 [micro]g/mL.

Based on the survey of recent literature studies on coumarins and benzofurans and in our effort to discover novel antimicrobial [13-16] and anticancer agents [17,18], the aim of our work is synthesis of 4-(3-hydroxy-benzofuran-2yl)coumarins and the evaluation of them for their therapeutic importance.

2. Chemistry

The synthetic scheme for the target molecules was initiated by the Pechmann cyclisation of phenols with 4-bromoethylacetoacetate [19] leading to the required 4-bromomethylcoumarins [20-22] (1a-k). The compound 4 (6-methyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester [23] (2a) (R = 6-C[H.sub.3]) was synthesized by reacting 4-bromomethyl-6-methylcoumarin and methyl salicylate in the presence of anhydrous [K.sub.2]C[O.sub.3]. Using this method, the compounds (2b-k) were synthesized. These intermediates (2a-k) did not yield the products (3a-k) in the presence of DBU in DMF under thermal conditions. However, when subjected to microwave irradiation afforded the compounds (3a-k) (Scheme 1). The completion of the reaction is monitored by TLC. A plausible mechanistic pathway proposed for the title compounds involves the generation of a carbanion at the active methylene group ([C.sub.4]-C[H.sub.2]) which is stabilized by coumarin ring [24]. The intramolecular ring closure occurred when carbanion attacked the carbonyl carbon of methyl ester and eliminated methanol to form 4-(3-oxo-2,3-dihydro-benzofuran-2-yl)coumarins that underwent in situ aromatization under the reaction conditions to yield 4-(3-hydroxy-benzofuran-2-yl)coumarins (Figure 1). The high melting solids separated in the reaction mixture were filtered off to obtain compounds (3a-k) as crystalline solids.

3. Results and Discussion

The structures of novel (2-oxo-2H-chromen-4-ylmethoxy)benzoic acid methyl esters and 4-(3-hydroxy-benzofuran-2yl)-coumarins were established from IR, 'HNMR, [sup.13]C NMR, and LC-MS data as illustrated for a representative example. In the IR spectrum of 2-(7-methyl-2-oxo-2H-chromen-4ylmethoxy)-benzoic acid methyl ester (2b) (R = 7-C[H.sub.3]), the lactone carbonyl stretching frequency was appeared at 1720 [cm.sup.-1], whereas the methyl ester carbonyl stretching frequency was observed at 1742 cm-. The [sup.1]H NMR spectrum of the compound (2b) displayed a singlet at [delta] 2.40, 3.85, 5.52, and 6.85 due to C[H.sub.3], OC[H.sub.3], OC[H.sub.2], and [C.sub.3]-H protons, respectively. The aromatic protons resonated as a multiplet at [delta] 7.10-7.83.

The IR spectrum of the compound 4-(3-hydroxybenzofuran-2-yl)-6-methylcoumarin (3a) (R = 6-C[H.sub.3]) displayed a lactone carbonyl stretching frequency at 1729 cm-, whereas the-OH stretching frequency appeared at 3450 [cm.sup.-1]. The [sup.1]H NMR spectrum of the compound (3a) showed a singlet at [delta] 2.42 and 6.93 due to C[H.sub.3] and [C.sub.3]-H protons, respectively. The aromatic protons were resonated as a multiplet at [delta] 7.23-8.48. The-OH proton observed as a singlet at [delta] 11.42 that was confirmed by [D.sub.2]O exchange. The mass spectrum (LC-MS) of the compound (3g) displayed a [M+H] peak at 307. The [sup.13]CNMR spectral data of compound (3h) are given in the experimental section.

4. Antimicrobial Activity

All the newly synthesized compounds (2b-k) and (3a-k) were screened for their antibacterial and antifungal activity at different concentrations of 100, 50, 25, 12.5, 6.25, 3.125, 1.6, 0.8, and 0.2 [micro]g/mL via broth microdilution method. The minimum inhibitory concentrations (MIC) were determined by serial dilution method [25].

Antibacterial activity was carried out against three Gram-positive bacteria, namely, Staphylococcus aureus, Enterococcus faecalis, and Streptococcus mutans, and three Gram-negative bacteria, namely, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. Ciprofloxacin was used as a standard. Antifungal activity was carried out against two fungi, namely, Candida albicans and Aspergillus fumigatus. Fluconazole was used as a standard.

The investigation of antimicrobial screening data (Table 1) showed that most of the tested compounds exhibited good bacterial and fungal inhibition. The compounds (2b) (R = 7-C[H.sub.3]), (2c) (R = 6-Cl), (2e) (R = 6-F), and (2f) (R = 5,6-benzo) were found to be very active against S. mutans with MIC of 0.2 [micro]g/mL. The compounds (2c) (R = 6-Cl) and (2i) (R = 6-tert-butyl) were found to be highly active against E. coli with MIC of 0.2 [micro]g/mL. The compound (2i) (R = 6-tert-butyl) displayed high activity against A. fumigatus with MIC of 0.2 [micro]g/mL. The compounds (3a) (R = 6-C[H.sub.3]) and (3b) (R = 7-C[H.sub.3]) were found to be highly active against S. aureus, E. faecalis, and S. mutans with MIC of 0.2 [micro]g/mL. The compounds (3e) (R = 6-F) and (3f) (R = 5,6-benzo) were found to be highly active against S. aureus and C. albicans with MIC of 0.2 [micro]g/mL. The compounds (3g) (R = 6,8-dimethyl), (3h) (R = 6-isopropyl), (3i) (R = 6-tert-butyl), and (3j) (R = 6-benzyl) exhibited high activity against S. aureus, S. mutans, and C. albicans with MIC of 0.2 [micro]g/mL. The compound (3k) (R = OMe) showed high activity against S. aureus and C. albicans with MIC of 0.2 [micro]g/mL. It is to be noted that most of these compounds exhibited moderate activity against P. aeruginosa and inactive against K. pneumonia.

In general, uncyclized compounds (2b-k) are more potent than the cyclized compounds (3a-k) against S. mutans and E. coli. The cyclized compounds (3a-k) are more potent than the uncyclized compounds (2b-k) against E. faecalis and C. albicans. It is interesting to found that both cyclized and uncyclized compounds showed better activity against S. aureus than the standard Ciprofloxacin.

5. In Vitro Cell Cytotoxicity

All the newly synthesized compounds (2b-k) and (3a-k) were evaluated for their cytotoxicity against DAL cell using trypan blue dye exclusion assay. The detail procedure has been described in our earlier publications [26, 27].

The investigation of in vitro cell cytotoxicity (Table 2) revealed that most of the tested compounds exhibited good activity. The compounds (2d) (R = 6-Br), (2h) (R = 6-isopropyl), (2i) (R = 6-tert-butyl), (2j) (R = 6-benzyl), (2k) (R = 6-OMe), (3a) (R = 6-C[H.sub.3]), (3c) (R = 6-Cl), (3f) (R = 5,6-benzo), (3g) (R = 6,8-dimethyl), (3h) (R = 6isopropyl), (3i) (R = 6-tert-butyl), and (3k) (R = 6-OMe) were found to be highly active (>70%) against DAL cell at the concentration of 100 [micro]g/mL. The compound (2f) (R = 5,6-benzo) was found to be poor active (25%) against DAL cell at the concentration of 100 [micro]g/mL. The rest of the compounds were found to be moderately active (>40%). In general, the cyclized compounds (3a-k) were found to be more potent than the uncyclized compounds (2b-k).

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6. Experimental Section

The melting points were measured with an electric melting point apparatus and are uncorrected. The IR spectra were obtained using a Shimadzu-8400S FT-IR spectrophotometer. [sup.1]H NMR and [sup.13]C NMR spectra in DMSO-[d.sub.6] solution were recorded at 25[degrees]C on a Bruker 300 and 400 MHz spectrometer, respectively. The [sup.1]H chemical shifts were reported in [delta] ppm and referenced to TMS. The mass spectrawere recorded on an Agilent-Single Quartz LC-MS. The purity of the compounds was checked by TLC. Microwave reactions were carried out on Milestone Laboratory's microwave reactor. The elemental analyses were carried out using Elemental Vario Micro Cube CHNS Rapid Analyzer. All the compounds gave satisfactory elemental analysis.

General Procedure for the Synthesis of Compounds (2a-k). Methyl salicylate (0.304 g, 2.0 mmol) and anhydrous [K.sub.2]C[O.sub.3] (1.38 g, 10 mmol) were stirred in 25 mL of dry acetone for 30 min. 4-Bromomethylcoumarin (1a-k) (2.0 mmol) was added and stirring was continued for 24 h. The reaction mixture was concentrated to one-fourth volume and poured onto crushed ice. The solid separated was filtered and washed with 10 mL of 5% HCl. Then, it was washed with 50 mL of cold water. The crude product was dried and recrystallised from ethanol.

2-(7-Methyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2b). Yield 90%; colorless solid; mp. 168-170[degrees]C; IR (KBr, [cm.sup.-1]): 1720 (lactone C=O), 1742 (methyl ester, C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 2.40 (s, 3H, C[H.sub.3]), 3.85 (s, 3H, OC[H.sub.3]), 5.52 (s, 2H, OC[H.sub.2]), 6.85 (s, 1H, [C.sub.3]-H), 7.10-7.83 (m, 7H, Ar-H) ppm; Anal. Cald. for [C.sub.19][H.sub.16][O.sub.5]: C, 70.36; H, 4.97. Found: C, 70.27; H, 4.89.

2-(6-Chloro-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2c). Yield 92%; colorless solid; mp. 188-191[degrees]C; IR (KBr, [cm.sup.-1]): 1730 (lactone C=O), 1750 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.81 (s, 3H, OC[H.sub.3]), 5.46 (s, 2H, OC[H.sub.2]), 6.90 (s, 1H, [C.sub.3]-H), 7.07-8.04 (m, 7H, Ar-H) ppm; Anal. Cald. for [C.sub.18]H[sup.13]Cl[O.sub.5]: C, 62.71; H, 3.80. Found: C, 62.65; H, 3.73.

2-(6-Bromo-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2d). Yield 89%; yellow solid; mp. 147-149[degrees]C; IR (KBr, [cm.sup.-1]): 1714 (lactone C=O), 1750 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.85 (s, 3H, OC[H.sub.3]), 5.49 (s, 2H, OC[H.sub.2]), 6.79 (s, 1H, [C.sub.3]-H), 7.12-7.82 (m, 7H, Ar-H) ppm; Anal. Cald. for [C.sub.18][H.sub.13]Br[O.sub.5]: C, 55.55; H, 3.37. Found: C, 55.48; H, 3.32.

2-(6-Fluoro-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2e). Yield 90%; colorless solid; mp. 186-149[degrees]C; IR (KBr, [cm.sup.-1]): 1724 (lactone C=O), 1739 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.86 (s, 3H, OC[H.sub.3]), 5.50 (s, 2H, OC[H.sub.2]), 6.92 (s, 1H, [C.sub.3]-H), 7.10-8.12 (m, 7H, Ar-H) ppm; Anal. Cald. for [C.sub.19][H.sub.15]F[O.sub.4]: C, 69.93; H, 4.63. Found: C, 69.86; H, 4.58.

2-(5,6-Benzo-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2f). Yield 90%; light yellow solid; mp. 183-186[degrees]C; IR (KBr, [cm.sup.-1]): 1728 (lactone C=O), 1746 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.83 (s, 3H, OC[H.sub.3]), 5.95 (s, 2H, OC[H.sub.2]), 7.12-8.42 (m, 11H, Ar-H) ppm; Anal. Cald. for [C.sub.22][H.sub.16][O.sub.5]: C, 73.33; H, 4.48. Found: C, 73.26; H, 4.40.

2-(6,8-Dimethyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2g). Yield 91%; colorless solid; mp. 193-195[degrees]C; IR (KBr, [cm.sup.-1]): 1727 (lactone C=O), 1739 (methylester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 2.36 (d, 6H, 6,8-dimethyl), 3.85 (s, 3H, OC[H.sub.3]), 5.47 (s, 2H, OC[H.sub.2]), 6.84 (s, 1H, [C.sub.3]-H), 7.08-7.82 (m, 6H, Ar-H) ppm; Anal. Cald. for [C.sub.22][H.sub.2]2[O.sub.5]: C, 71.10; H, 5.36. Found: C, 71.03; H, 5.29.

2-(6-Isopropyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2h). Yield 97%; colorless solid; mp. 179-182[degrees]C; IR (KBr, [cm.sup.-1]): 1718 (lactone C=O), 1746 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 1.27 (d, 6H, 2-C[H.sub.3] of isopropyl), 3.02 (m, 1H, CH of isopropyl), 3.88 (s, 3H, OC[H.sub.3]), 5.55 (s, 2H, OC[H.sub.2]), 6.88 (s, 1H, [C.sub.3]-H), 7.10-7.87 (m, 7H, ArH) ppm; Anal. Cald. for [C.sub.21][H.sub.2]0[O.sub.5]: C, 71.58; H, 5.72. Found: C, 71.50; H, 5.66.

2-(6-Tert-butyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2i). Yield 89%; colorless solid; mp. 172-173[degrees]C; IR (KBr, [cm.sup.-1]): 1716 (lactone C=O), 1728 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 1.37 (s, 9H, 6-tert-butyl), 3.81 (s, 3H, OC[H.sub.3]), 5.53 (s, 2H, OC[H.sub.2]), 6.93 (s, 1H, [C.sub.3]-H) 7.23-7.91 (m, 7H, Ar-H) ppm; Anal. Cald. for [C.sub.21][H.sub.2]0[O.sub.5]: C, 72.00; H, 6.05. Found: C, 71.83; H, 5.97.

2-(6-Benzyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2j). Yield 89%; colorless solid; mp. 172-175[degrees]C; IR (KBr, [cm.sup.-1]): 1712 (lactone C=O), 1738 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.84 (s, 3H, OC[H.sub.3]), 4.03 (s, 2H, [C.sub.6]-C[H.sub.2]), 5.51 (s, 2H, OC[H.sub.2]), 6.86 (s, 1H, [C.sub.3]-H), 7.10-7.89 (m, 12H, Ar-H) ppm; Anal. Cald. for [C.sub.25][H.sub.2]0[O.sub.5]: C, 74.99; H, 5.03. Found: C, 74.91; H, 4.95.

2-(6-Methoxy-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2k). Yield 95%; colorless solid; mp. 174-176[degrees]C; IR (KBr, [cm.sup.-1]): 1720 (lactone C=O), 1739 (methyl ester C=O); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.85 (d, 6H, 6-OC[H.sub.3], OC[H.sub.3]), 5.52 (s, 2H, OC[H.sub.2]), 6.84 (s, 1H, [C.sub.3]-H), 7.13-7.82 (m, 7H, Ar-H) ppm; Anal. Cald. for [C.sub.19][H.sub.16][O.sub.6]: C, 6705; H, 4.74. Found: C, 66.97; H, 4.67.

General Procedure for the Synthesis of Compounds (3a-k). A mixture of 2-(2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2a-k) (2.0 mmol), DBU (0.3 g, 2.0 mmol) and DMF (25 mL) were added to a microwave tube equipped with a magnetic stir bar. The microwave tube was fitted with a reflux condenser and irradiated in a microwave reactor at a temperature of 140[degrees]C for 4 min at a maximum power of 370 W. Then, completion of the reaction mixture was poured onto ice cold water and neutralized with dil HCl solution. The solid separated was filtered and washed with 100 mL of cold water. The crude product was dried and recrystallised from ethanol.

4-(3-Hydroxy-benzofuran-2-yl)-6-methyl-chromen-2-one (3a). Yield 90%; yellow solid; mp. 221-224[degrees]C; IR (KBr, [cm.sup.-1]): 1729 (lactone C=O), 3450 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 2.42 (s, 3H, 6-C[H.sub.3]), 6.93 (s, 1H, [C.sub.3]-H), 7.23-8.48 (m, 7H, Ar-H), 11.42 (s, 1H, OH, [D.sub.2]O exchangeable) ppm; Anal. Cald. for [C.sub.18][H.sub.12][O.sub.4]: C, 73.97; H, 4.14. Found: C, 73.89; H, 4.07.

4-(3-Hydroxy-benzofuran-2-yl)-7-methyl-chromen-2-one (3b). Yield 93%; yellow solid; mp. 229-232[degrees]C; IR (KBr, [cm.sup.-1]): 1730 (lactone C=O), 3440 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 2.43 (s, 3H, 7-C[H.sub.3]), 6.91 (s, 1H, [C.sub.3]-H), 7.21-8.42 (m, 7H, Ar-H), 11.22 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.18][H.sub.12][O.sub.4]: C, 73.97; H, 4.14. Found: C, 73.89; H, 4.08.

4-(3-Hydroxy-benzofuran-2-yl)-6-chloro-chromen-2-one (3c). Yield 86%; yellow solid; mp. 260-263[degrees]C; IR (KBr, [cm.sup.-1]): 1743 (lactone C=O), 3460 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 7.04 (s, 1H, [C.sub.3]-H), 7.34-8.61 (m, 7H, Ar-H), 11.66 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.17][H.sub.9]Cl[O.sub.4]: C, 65.30; H, 2.90. Found: C, 65.19; H, 2.81.

4-(3-Hydroxy-benzofuran-2-yl)-6-bromo-chromen-2-one (3d). Yield 90%; yellow solid; mp. 247-250[degrees]C; IR (KBr, [cm.sup.-1]): 1736 (lactone C=O), 3435 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 7.00 (s, 1H, [C.sub.3]-H), 7.35-8.70 (m, 7H, Ar-H), 11.65 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.17][H.sub.9]Br[O.sub.4]: C, 57.14; H, 2.54. Found: C, 57.02; H, 2.41.

4-(3-Hydroxy-benzofuran-2-yl)-6-flouro-chromen-2-one (3e). Yield 84%; yellow solid; mp. 242-244[degrees]C; IR (KBr, [cm.sup.-1]): 1723 (lactone C=O), 3456 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 7.06 (s, 1H, [C.sub.3]-H), 7.35-8.63 (m, 7H, Ar-H), 11.70 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.17][H.sub.9]F[O.sub.4]: C, 68.92; H, 3.06. Found: C, 68.80; H, 2.93.

4-(3-Hydroxy-benzofuran-2-yl)-5,6-benzo-chromen-2-one (3f). Yield 89%; yellowsolid; mp. 222-225[degrees]C; IR (KBr, [cm.sup.-1]): 1725 (lactone C=O), 3409 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): 5 6.99 (s, 1H, [C.sub.3]-H), 7.25-9.30 (m, 10H, Ar-H); 11.5 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.21][H.sub.12][O.sub.4]:C, 76.82; H, 3.68. Found: C, 76.70; H, 3.54.

4-(3-Hydroxy-benzofuran-2-yl)-6,8-dimethyl-chromen-2-one (3g). Yield 91%; colorless solid; mp. 228-231[degrees]C; IR (KBr, [cm.sup.-1]): 1719 (lactone C=O), 3416 (oH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 2.35 (d, 6H, 6,8-dimethyl), 6.92 (s, 1H, [C.sub.3]-H), 7.30-8.15 (m, 6H, Ar-H), 10.45 (s, 1H, OH) ppm; LC-MS: 307 [M + H]; Anal. Cald. for [C.sub.20][H.sub.18][O.sub.5]: C, 71.41; H, 5.36. Found: C, 71.28; H, 5.24.

4-(3-Hydroxy-benzofuran-2-yl)-6-isopropyl-chromen-2-one (3h). Yield 93%; yellow solid; mp. 209-211[degrees]C; IR (KBr, [cm.sup.-1]): 1714 (lactone C=O), 3428 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): 8 1.26 (d, 6H, 2-C[H.sub.3] of isopropyl), 3.00 (m, 1H, CH of isopropyl), 6.93 (s, 1H, [C.sub.3]-H), 7.33-8.42 (m, 7H, Ar-H), 11.41 (s, 1H, OH) ppm; [sup.13]C NMR (400 MHz, DMSO-[d.sub.6]): [delta] 24.5, 32.3, 110.2, 111.9, 112.8, 117.5, 121.8, 125.6, 126.1, 127.4, 128.1, 129.3, 131.7, 145.2, 148.3, 157.6, 158.8, 158.6, 160.1 ppm; Anal. Cald. for [C.sub.20][H.sub.16][O.sub.4]: C, 74.99; H, 5.03. Found: C, 74.88; H, 4.92.

4-(3-Hydroxy-benzofuran-2-yl)-6-tert-butyl-chromen-2-one (3i). Yield 93%; yellow solid; mp. 214-216[degrees]C; IR (KBr, [cm.sup.-1]): 1710 (lactone C=O), 3432 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 1.37 (s, 9H, tert-butyl), 6.86 (s, 1H, [C.sub.3]-H), 6.92-8.58 (m, 7H, Ar-H), 11.42 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.21][H.sub.18][O.sub.4]: C, 75.43; H, 5.03. Found: C, 75.32; H, 4.90.

4-(3-Hydroxy-benzofuran-2-yl)-6-benzyl-chromen-2-one (3j). Yield 96%; yellow solid; mp. 224-227[degrees]C; IR (KBr, [cm.sup.-1]): 1717 (lactone C=O), 3422 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 4.07 (s, 2H, [C.sub.6] - C[H.sub.2]), 6.96 (s, 1H, [C.sub.3]-H), 7.07-8.39 (m, 12H, Ar-H), 11.49 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.24][H.sub.16][O.sub.4]: C, 78.25; H, 4.38. Found: C, 78.12; H, 4.26.

4-(3-Hydroxy-benzofuran-2-yl)-6-methoxy-chromen-2-one (3k). Yield 95%; yellow solid; mp. 220-222[degrees]C; IR (KBr, [cm.sup.-1]): 1718 (lactone C=O), 3424 (OH); [sup.1]H NMR (300 MHz, DMSO-[d.sub.6]): [delta] 3.81 (s, 3H, 6-OC[H.sub.3]), 6.99 (s, 1H, [C.sub.3]-H), 7.28-8.10 (m, 7H, Ar-H), 11.49 (s, 1H, OH) ppm; Anal. Cald. for [C.sub.18][H.sub.12][O.sub.5]: C, 70.13; H, 3.92. Found: C, 70.01; H, 3.81.

7. Conclusion

All the tested compounds (2b-k) and (3a-k) were shown to exhibit better activity against Staphylococcus aureus than the standard Ciprofloxacin. The compound (3k) (R = 6-OMe) was found to be more potent cytotoxic than the standard 5-fluorouracil.

http://dx.doi.org/10.1155/2014/297586

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The authors are thankful to the Council of Scientific and Industrial Research, New Delhi, India, for financial assistance [no. 02(0172)/13/EMR-II]. They are also thankful to Professor Y. S. Bhat, Bangalore Institute of Technology, Bangalore, for providing Microwave Reactor facility and for his encouragement. They are also thankful to Indian Institute of Science, Bangalore, for the spectral analysis.

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Puttaraju Boregowda, (1) Shivashankar Kalegowda, (1) Vijaykumar Pandurang Rasa (1,2) Jagadeeshreddy Eluru, (2) and Ebenezer Koyye (2)

(1) P.G. Department of Chemistry, Central College Campus, Bangalore University, Bangalore, Karnataka 560 001, India

(2) Department of Pharmacology, K.L.E. University's College of Pharmacy, Belgaum, Karnataka 590 010, India

Correspondence should be addressed to Shivashankar Kalegowda; shivashankark@gmail.com

Received 27 November 2013; Accepted 27 January 2014; Published 27 March 2014

Academic Editor: Vito Ferro

TABLE 1: Results of antimicrobial activities of the synthesized
compounds (2b-k) and (3a-k) MICs ([micro]g/mL).

Compounds                                 Gram-positive

Number        R         S. aureus   E. faecalis   S. mutans   E. coli

2b       7-C[H.sub.3]      0.4          50           0.2       6.25
2c           6-Cl          0.4          1.6          0.2        0.2
2d           6-Br          0.8          25           0.4        1.6
2e           6-F           0.4         3.12          0.2        1.6
2f        5,6-benzo        0.4          50           0.2       6.25
2g       6,8-dimethyl      1.6          0.8          0.8       3.12
2h       6-isopropyl       0.8         6.25          0.4        0.4
2i       6-tert-butyl      0.8         6.25          0.8        0.2
2j         6-benzyl        0.8         12.5          0.4        1.6
2k          6-OMe          0.8         3.12          0.8       3.12
3a       6-C[H.sub.3]      0.2          0.2          0.2        50
3b       7-C[H.sub.3]      0.2          0.2          0.2        100
3c           6-Cl          0.2          0.4          0.2        100
3d           6-Br          --           --           --         --
3e           6-F           0.2          0.4          0.4        100
3f        5,6-benzo        0.2          0.4         3.12        50
3g       6,8-dimethyl      0.2          0.4          0.2        100
3h       6-isopropyl       0.2          0.4          0.2        50
3i       6-tert-butyl      0.2          0.8          0.2        50
3j         6-benzyl        0.2          0.8          0.2        100
3k          6-OMe          0.2          0.4         3.12        50
Ciprofloxacin               2            2            2          1
Fluconazole                --           --           --         --

Compounds                       Gram-negative

Number        R         K. pneumonia   P aeruginosa

2b       7-C[H.sub.3]       100            6.25
2c           6-Cl            50            3.12
2d           6-Br           100            3.12
2e           6-F            100            6.25
2f        5,6-benzo         100            6.25
2g       6,8-dimethyl       100             50
2h       6-isopropyl        100             25
2i       6-tert-butyl       100             25
2j         6-benzyl         100            6.25
2k          6-OMe           100            100
3a       6-C[H.sub.3]       100             50
3b       7-C[H.sub.3]        50           > 100
3c           6-Cl           100             25
3d           6-Br            --             --
3e           6-F            100           > 100
3f        5,6-benzo         100            0.2
3g       6,8-dimethyl       100             50
3h       6-isopropyl        100            3.12
3i       6-tert-butyl      > 100           6.25
3j         6-benzyl         100             50
3k          6-OMe           100            6.25
Ciprofloxacin                1              4
Fluconazole                  --             --

Compounds                          Fungi

Number        R         C. albicans   A. fumigatus

2b       7-C[H.sub.3]      12.5           0.4
2c           6-Cl          12.5           0.4
2d           6-Br          12.5           0.4
2e           6-F           > 100          0.8
2f        5,6-benzo        12.5           0.4
2g       6,8-dimethyl       100           1.6
2h       6-isopropyl       12.5           0.4
2i       6-tert-butyl      12.5           0.2
2j         6-benzyl         100           0.8
2k          6-OMe           100           0.8
3a       6-C[H.sub.3]      12.5            --
3b       7-C[H.sub.3]       0.2            --
3c           6-Cl          3.12            --
3d           6-Br           --             --
3e           6-F            0.2            --
3f        5,6-benzo         0.2            --
3g       6,8-dimethyl       0.2            --
3h       6-isopropyl        0.2            --
3i       6-tert-butyl       0.2            --
3j         6-benzyl         0.2            --
3k          6-OMe           0.2            --
Ciprofloxacin               --             --
Fluconazole                 16             8

TABLE 2: Results of in vitro cytotoxicity of the synthesized
compounds (2b/k) and (3a/k) against Dalton's Ascitic Lymphoma
cell (1 x [10.sup.5]) at the concentration of 100 [micro]g/mL.

Number of              R         Live   Number of    % of dead
compounds                               cells Dead     cells

2b                7-C[H.sub.3]   49         51           51
2c                    6-Cl       41         59           59
2d                    6-Br       19         81           81
2e                    6-F        42         58           58
2f                 5,6-benzo     75         25           25
2g                6,8-dimethyl   55         45           45
2h                6-isopropyl    12         88           88
2i                6-tert-butyl   16         84           84
2j                  6-benzyl     13         87           87
2k                   6-OMe       18         82           82
3a                6-C[H.sub.3]   21         79           79
3b                7-C[H.sub.3]   56         44           44
3c                    6-Cl       15         85           85
3d                    6-Br       --         --           --
3e                    6-F        34         66           66
3f                 5,6-benzo     13         87           87
3g                6,8-dimethyl   21         79           79
3h                6-isopropyl    26         74           74
3i                6-tert-butyl   15         85           85
3j                  6-benzyl     53         47           47
3k                   6-OMe       11         89           89
5-Fluorouracil         --        12         88           8
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Title Annotation:Research Article
Author:Boregowda, Puttaraju; Kalegowda, Shivashankar; Rasal, Vijaykumar Pandurang; Eluru, Jagadeeshreddy; K
Publication:Organic Chemistry International
Article Type:Report
Date:Jan 1, 2014
Words:5475
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