Synthesis and Biological Evaluation of 4-(3-Hydroxy-benzofuran-2-yl)coumarins

Boregowda, Puttaraju; Kalegowda, Shivashankar; Rasal, Vijaykumar Pandurang; Eluru, Jagadeeshreddy; Koyye, Ebenezer

doi:https://doi.org/10.1155/2014/297586

Organic Chemistry International

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Research Article | Open Access

Volume 2014 | Article ID 297586 | https://doi.org/10.1155/2014/297586

Synthesis and Biological Evaluation of 4-(3-Hydroxy-benzofuran-2-yl)coumarins

Puttaraju Boregowda,¹Shivashankar Kalegowda,¹Vijaykumar Pandurang Rasal,²Jagadeeshreddy Eluru,²and Ebenezer Koyye²

Academic Editor: Vito Ferro

Received27 Nov 2013

Accepted27 Jan 2014

Published27 Mar 2014

Abstract

Various 4-bromomethylcoumarins (1a-k) were reacted with methyl salicylate to yield 2-(2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl esters (2a-k). Formations of (3a-k) were achieved by using DBU under microwave irradiation. Structures of all the compounds were established on the basis of their spectral data. All the compounds were tested in vitro for their antimicrobial activity and cell cytotoxicity. All the tested compounds (2b-k) and (3a-k) were shown to be 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.

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 β-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 IC₅₀ value of 0.01 μM [10]. Thiazolyl coumarin derivatives showed significant inhibition against Haemophilus influenzae with a MIC value of 15 μM which is less than that of tetracycline [11]. Benzo[d]thiazolyl coumarins [12] demonstrated anti-HIV activity against HIV-1 cell with EC₅₀ < 7 μg/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-2-yl)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-CH₃) was synthesized by reacting 4-bromomethyl-6-methylcoumarin and methyl salicylate in the presence of anhydrous K₂CO₃. 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 (C₄–CH₂) 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-2-yl)-coumarins were established from IR, ¹H NMR, ¹³C NMR, and LC-MS data as illustrated for a representative example. In the IR spectrum of 2-(7-methyl-2-oxo-2H-chromen-4-ylmethoxy)-benzoic acid methyl ester (2b) (R = 7-CH₃), the lactone carbonyl stretching frequency was appeared at 1720 cm⁻¹, whereas the methyl ester carbonyl stretching frequency was observed at 1742 cm⁻¹. The ¹H NMR spectrum of the compound (2b) displayed a singlet at δ 2.40, 3.85, 5.52, and 6.85 due to CH₃, OCH₃, OCH_2, and C₃–H protons, respectively. The aromatic protons resonated as a multiplet at δ 7.10–7.83.

The IR spectrum of the compound 4-(3-hydroxy-benzofuran-2-yl)-6-methylcoumarin (3a) (R = 6-CH₃) displayed a lactone carbonyl stretching frequency at 1729 cm⁻¹, whereas the –OH stretching frequency appeared at 3450 cm⁻¹. The ¹H NMR spectrum of the compound (3a) showed a singlet at δ 2.42 and 6.93 due to CH₃ and C₃–H protons, respectively. The aromatic protons were resonated as a multiplet at δ 7.23–8.48. The –OH proton observed as a singlet at δ 11.42 that was confirmed by D₂O exchange. The mass spectrum (LC-MS) of the compound (3g) displayed a [M+H] peak at 307. The ¹³C NMR 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 μg/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-CH₃), (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 μg/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 μg/mL. The compound (2i) (R = 6-tert-butyl) displayed high activity against A. fumigatus with MIC of 0.2 μg/mL. The compounds (3a) (R = 6-CH₃) and (3b) (R = 7-CH₃) were found to be highly active against S. aureus, E. faecalis, and S. mutans with MIC of 0.2 μg/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 μg/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 μg/mL. The compound (3k) (R = OMe) showed high activity against S. aureus and C. albicans with MIC of 0.2 μg/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-CH₃), (3c) (R = 6-Cl), (3f) (R = 5,6-benzo), (3g) (R = 6,8-dimethyl), (3h) (R = 6-isopropyl), (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 μg/mL. The compound (2f) (R = 5,6-benzo) was found to be poor active (25%) against DAL cell at the concentration of 100 μg/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).

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. ¹H NMR and ¹³C NMR spectra in DMSO- solution were recorded at 25°C on a Bruker 300 and 400 MHz spectrometer, respectively. The ¹H chemical shifts were reported in δ ppm and referenced to TMS. The mass spectra were 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 K₂CO₃ (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°C; IR (KBr, cm⁻¹): 1720 (lactone C=O), 1742 (methyl ester, C=O); ¹H NMR (300 MHz, DMSO-): δ 2.40 (s, 3H, CH₃), 3.85 (s, 3H, OCH₃), 5.52 (s, 2H, OCH₂), 6.85 (s, 1H, C₃–H), 7.10–7.83 (m, 7H, Ar–H) ppm; Anal. Cald. for C₁₉H₁₆O₅: 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°C; IR (KBr, cm⁻¹): 1730 (lactone C=O), 1750 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 3.81 (s, 3H, OCH₃), 5.46 (s, 2H, OCH₂), 6.90 (s, 1H, C₃–H), 7.07–8.04 (m, 7H, Ar–H) ppm; Anal. Cald. for C₁₈H₁₃ClO₅: 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°C; IR (KBr, cm⁻¹): 1714 (lactone C=O), 1750 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 3.85 (s, 3H, OCH₃), 5.49 (s, 2H, OCH₂), 6.79 (s, 1H, C₃–H), 7.12–7.82 (m, 7H, Ar–H) ppm; Anal. Cald. for C₁₈H₁₃BrO₅: 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°C; IR (KBr, cm⁻¹): 1724 (lactone C=O), 1739 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 3.86 (s, 3H, OCH₃), 5.50 (s, 2H, OCH₂), 6.92 (s, 1H, C₃–H), 7.10–8.12 (m, 7H, Ar–H) ppm; Anal. Cald. for C₁₉H₁₅FO₄: 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°C; IR (KBr, cm⁻¹): 1728 (lactone C=O), 1746 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 3.83 (s, 3H, OCH₃), 5.95 (s, 2H, OCH₂), 7.12–8.42 (m, 11H, Ar–H) ppm; Anal. Cald. for C₂₂H₁₆O₅: 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°C; IR (KBr, cm⁻¹): 1727 (lactone C=O), 1739 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 2.36 (d, 6H, 6,8-dimethyl), 3.85 (s, 3H, OCH₃), 5.47 (s, 2H, OCH₂), 6.84 (s, 1H, C₃–H), 7.08–7.82 (m, 6H, Ar–H) ppm; Anal. Cald. for C₂₂H₂₂O₅: 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°C; IR (KBr, cm⁻¹): 1718 (lactone C=O), 1746 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 1.27 (d, 6H, 2-CH₃ of isopropyl), 3.02 (m, 1H, CH of isopropyl), 3.88 (s, 3H, OCH₃), 5.55 (s, 2H, OCH₂), 6.88 (s, 1H, C₃–H), 7.10–7.87 (m, 7H, Ar–H) ppm; Anal. Cald. for C₂₁H₂₀O₅: 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°C; IR (KBr, cm⁻¹): 1716 (lactone C=O), 1728 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 1.37 (s, 9H, 6-tert-butyl), 3.81 (s, 3H, OCH₃), 5.53 (s, 2H, OCH₂), 6.93 (s, 1H, C₃–H) 7.23–7.91 (m, 7H, Ar–H) ppm; Anal. Cald. for C₂₁H₂₀O₅: 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°C; IR (KBr, cm⁻¹): 1712 (lactone C=O), 1738 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 3.84 (s, 3H, OCH₃), 4.03 (s, 2H, C₆–CH₂), 5.51 (s, 2H, OCH₂), 6.86 (s, 1H, C₃–H), 7.10–7.89 (m, 12H, Ar–H) ppm; Anal. Cald. for C₂₅H₂₀O₅: 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°C; IR (KBr, cm⁻¹): 1720 (lactone C=O), 1739 (methyl ester C=O); ¹H NMR (300 MHz, DMSO-): δ 3.85 (d, 6H, 6-OCH₃, OCH₃), 5.52 (s, 2H, OCH₂), 6.84 (s, 1H, C₃–H), 7.13–7.82 (m, 7H, Ar–H) ppm; Anal. Cald. for C₁₉H₁₆O₆: C, 67.05; 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°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°C; IR (KBr, cm⁻¹): 1729 (lactone C=O), 3450 (OH); ¹H NMR (300 MHz, DMSO-): δ 2.42 (s, 3H, 6-CH₃), 6.93 (s, 1H, C₃–H), 7.23–8.48 (m, 7H, Ar–H), 11.42 (s, 1H, OH, D₂O exchangeable) ppm; Anal. Cald. for C₁₈H₁₂O₄: 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°C; IR (KBr, cm⁻¹): 1730 (lactone C=O), 3440 (OH); ¹H NMR (300 MHz, DMSO-): δ 2.43 (s, 3H, 7-CH₃), 6.91 (s, 1H, C₃–H), 7.21–8.42 (m, 7H, Ar–H), 11.22 (s, 1H, OH) ppm; Anal. Cald. for C₁₈H₁₂O₄: 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°C; IR (KBr, cm⁻¹): 1743 (lactone C=O), 3460 (OH); ¹H NMR (300 MHz, DMSO-): δ 7.04 (s, 1H, C₃–H), 7.34–8.61 (m, 7H, Ar–H), 11.66 (s, 1H, OH) ppm; Anal. Cald. for C₁₇H₉ClO₄: 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°C; IR (KBr, cm⁻¹): 1736 (lactone C=O), 3435 (OH); ¹H NMR (300 MHz, DMSO-): δ 7.00 (s, 1H, C₃–H), 7.35–8.70 (m, 7H, Ar–H), 11.65 (s, 1H, OH) ppm; Anal. Cald. for C₁₇H₉BrO₄: 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°C; IR (KBr, cm⁻¹): 1723 (lactone C=O), 3456 (OH); ¹H NMR (300 MHz, DMSO-): δ 7.06 (s, 1H, C₃–H), 7.35–8.63 (m, 7H, Ar–H), 11.70 (s, 1H, OH) ppm; Anal. Cald. for C₁₇H₉FO₄: 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%; yellow solid; mp. 222–225°C; IR (KBr, cm⁻¹): 1725 (lactone C=O), 3409 (OH); ¹H NMR (300 MHz, DMSO-): δ 6.99 (s, 1H, C₃–H), 7.25–9.30 (m, 10H, Ar–H); 11.5 (s, 1H, OH) ppm; Anal. Cald. for C₂₁H₁₂O₄: 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°C; IR (KBr, cm⁻¹): 1719 (lactone C=O), 3416 (OH); ¹H NMR (300 MHz, DMSO-): δ 2.35 (d, 6H, 6,8-dimethyl), 6.92 (s, 1H, C₃–H), 7.30–8.15 (m, 6H, Ar–H), 10.45 (s, 1H, OH) ppm; LC-MS: 307 [M + H]; Anal. Cald. for C₂₀H₁₈O₅: 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°C; IR (KBr, cm⁻¹): 1714 (lactone C=O), 3428 (OH); ¹H NMR (300 MHz, DMSO-): δ 1.26 (d, 6H, 2-CH₃ of isopropyl), 3.00 (m, 1H, CH of isopropyl), 6.93 (s, 1H, C₃–H), 7.33–8.42 (m, 7H, Ar–H), 11.41 (s, 1H, OH) ppm; ¹³C NMR (400 MHz, DMSO-): δ 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 C₂₀H₁₆O₄: 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°C; IR (KBr, cm⁻¹): 1710 (lactone C=O), 3432 (OH); ¹H NMR (300 MHz, DMSO-): δ 1.37 (s, 9H, tert-butyl), 6.86 (s, 1H, C₃–H), 6.92–8.58 (m, 7H, Ar–H), 11.42 (s, 1H, OH) ppm; Anal. Cald. for C₂₁H₁₈O₄: 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°C; IR (KBr, cm⁻¹): 1717 (lactone C=O), 3422 (OH); ¹H NMR (300 MHz, DMSO-): δ 4.07 (s, 2H, C₆–CH₂), 6.96 (s, 1H, C₃–H), 7.07–8.39 (m, 12H, Ar–H), 11.49 (s, 1H, OH) ppm; Anal. Cald. for C₂₄H₁₆O₄: 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°C; IR (KBr, cm⁻¹): 1718 (lactone C=O), 3424 (OH); ¹H NMR (300 MHz, DMSO-): δ 3.81 (s, 3H, 6-OCH₃), 6.99 (s, 1H, C₃–H), 7.28–8.10 (m, 7H, Ar–H), 11.49 (s, 1H, OH) ppm; Anal. Cald. for C₁₈H₁₂O₅: 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.

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.

Supplementary Materials

S1-S25: 1H NMR spectrum of 1g-j, 2b-k, 3a-k.

S26: LC-MS spectra of 3g.

S27-S28: 13C NMR and HSQC spectrum of 3h

Supplementary Materials

References

J.-Y. Yeh, M. S. Coumar, J.-T. Horng et al., “Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives,” Journal of Medicinal Chemistry, vol. 53, no. 4, pp. 1519–1533, 2010.
View at: Publisher Site | Google Scholar
K. Manna and Y. K. Agrawal, “Design, synthesis, and antitubercular evaluation of novel series of 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin analogs,” European Journal of Medicinal Chemistry, vol. 45, no. 9, pp. 3831–3839, 2010.
View at: Publisher Site | Google Scholar
X. Jiang, W. Liu, W. Zhang et al., “Synthesis and antimicrobial evaluation of new benzofuran derivatives,” European Journal of Medicinal Chemistry, vol. 46, no. 8, pp. 3526–3530, 2011.
View at: Publisher Site | Google Scholar
S. A. Bakunov, S. M. Bakunova, T. Wenzler et al., “Synthesis and antiprotozoal activity of cationic 2-phenylbenzofurans,” Journal of Medicinal Chemistry, vol. 51, no. 21, pp. 6927–6944, 2008.
View at: Publisher Site | Google Scholar
S. Li, W. Li, Y. Wang, Y. Asada, and K. Koike, “Prenylflavonoids from Glycyrrhiza uralensis and their protein tyrosine phosphatase-1B inhibitory activities,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 18, pp. 5398–5401, 2010.
View at: Publisher Site | Google Scholar
Y. Cheng, M. Ono, H. Kimura, M. Ueda, and H. Saji, “Technetium-99m labeled pyridyl benzofuran derivatives as single photon emission computed tomography imaging probes for β-amyloid plaques in Alzheimer's brains,” Journal of Medicinal Chemistry, vol. 55, no. 5, pp. 2279–2286, 2012.
View at: Publisher Site | Google Scholar
H. A. Stefani, K. Gueogjan, F. Manarin et al., “Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)-coumarin derivatives: effect on inducible nitric oxide synthase,” European Journal of Medicinal Chemistry, vol. 58, pp. 117–127, 2012.
View at: Google Scholar
M. Basanagouda, M. V. Kulkarni, D. Sharma et al., “Synthesis of some new 4-aryloxmethylcoumarins and examination of their antibacterial and antifungal activities,” Journal of Chemical Sciences, vol. 121, no. 4, pp. 485–495, 2009.
View at: Google Scholar
J. N. Modranka, E. Nawrot, and J. Graczyk, “In vitro antitumor, in vitro antibacterial activity and alkylating properties of phosphorohydrazine derivatives of coumarin,” European Journal of Medicinal Chemistry, vol. 41, pp. 1301–1309, 2006.
View at: Google Scholar
K. M. Amin, A. A. M. Eissa, S. M. A. Seri, F. M. Awadallah, and G. S. Hassan, “Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor,” European Journal of Medicinal Chemistry, vol. 60, pp. 187–198, 2013.
View at: Google Scholar
A. Arshad, H. Osman, M. C. Bagley, C. K. Lam, S. Mohamad, and A. S. M. Zahariluddin, “Synthesis and antimicrobial properties of some new thiazolyl coumarin derivatives,” European Journal of Medicinal Chemistry, vol. 46, no. 9, pp. 3788–3794, 2011.
View at: Publisher Site | Google Scholar
D. Bhavsar, J. Trivedi, S. Parekh et al., “Synthesis and in vitro anti-HIV activity of N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives using MTT method,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 11, pp. 3443–3446, 2011.
View at: Publisher Site | Google Scholar
K. Shivashankar, M. V. Kulkarni, L. A. Shastri, V. P. Rasal, and S. V. Rajendra, “The synthesis and biological evaluation of regioisomeric benzothiazolyl coumarins,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 181, no. 9, pp. 2187–2200, 2006.
View at: Publisher Site | Google Scholar
K. Shivashankar, L. A. Shastri, M. V. Kulkarni, V. P. Rasal, and S. V. Rajendra, “Synthetic and biological studies on 4-aryloxymethyl coumarinyl thiazolidinones,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 183, no. 1, pp. 56–68, 2008.
View at: Publisher Site | Google Scholar
K. Shivashankar, L. A. Shastri, M. V. Kulkarni, V. P. Rasal, and D. M. Saindane, “Multi-component reactions of formyl-4-aryloxymethylcoumarins under microwave irradiation,” Journal of the Indian Chemical Society, vol. 86, no. 3, pp. 265–271, 2009.
View at: Google Scholar
K. Shivashankar, L. A. Shastri, M. V. Kulkarni, V. P. Rasal, and D. M. Saindane, “Halogenated 4-aryloxymethylcoumarins as potent antimicrobial agents,” Journal of the Indian Chemical Society, vol. 85, no. 11, pp. 1163–1168, 2008.
View at: Google Scholar
D. Shamala, K. Shivashankara, V. P. Rasal, and V. Pandi, “Synthesis of new series of quinolinoxymethylcoumarins as potent anticancer agents,” Mapana Journal of Sciences, vol. 12, pp. 49–56, 2013.
View at: Google Scholar
K. B. Puttaraju, K. Shivashankar, V. P. Rasal, P. N. V. Vivek, R. R. Korivi, and B. S. G. Chand, “InCl₃-assisted, synthesis and cytotoxic studies of some novel heteroaryl thiazoles,” International Journal of Chemical and Pharmaceutical Sciences, vol. 4, pp. 44–47, 2013.
View at: Google Scholar
A. Burger and G. E. Ullyot, “Analgesic studies. β-Ethyl and β-isopropylamine derivatives of pyridine and thiazole,” Journal of Organic Chemistry, vol. 12, no. 2, pp. 342–355, 1947.
View at: Google Scholar
K. B. Puttaraju, K. Shivashankar, Chandra et al., “Microwave assisted synthesis of dihydrobenzo[4, 5]imidazo[1, 2-a]pyrimidin-4-ones, synthesis, in vitro antimicrobial and anticancer activities of novel coumarin substituted dihydrobenzo[4, 5]imidazo[1, 2-a]pyrimidin-4-ones,” European Journal of Medicinal Chemistry, vol. 69, pp. 316–322, 2013.
View at: Publisher Site | Google Scholar
L. A. Shastri, K. Shivashankar, and M. V. Kulkarni, “Facile synthesis of some novel 4-{3-aryl-3, 4-dihydro-2H-benzo[b][1,4] thiazin-2-yl}-2H-chromen-2-one derivatives,” Journal of Sulfur Chemistry, vol. 28, no. 6, pp. 625–630, 2007.
View at: Publisher Site | Google Scholar
H. Nagarajaiah, K. B. Puttaraju, K. Shivashankar, and N. S. Begum, “4-Bromomethyl-6-tert-butyl-2H-chromen-2-one,” Acta Crystallographica E, vol. 69, part 7, article o1056, 2013.
View at: Google Scholar
S. S. Hanamanthgad, M. V. Kulkarni, and V. D. Patil, “Synthesis of some biomimetic 4-substituted coumarins,” Revue Roumaine de Chimie, vol. 30, pp. 735–741, 1985.
View at: Google Scholar
L. A. Shastri, M. V. Kulkarni, V. Gupta, and N. Sharma, “First thermal chemoselective synthesis of novel 2′,3′-dihydro-3′-hydroxy-benzofuranylcoumarins,” Synthetic Communications, vol. 38, no. 9, pp. 1407–1415, 2008.
View at: Publisher Site | Google Scholar
M. Basanagouda, K. Shivashankar, M. V. Kulkarni et al., “Synthesis and antimicrobial studies on novel sulfonamides containing 4-azidomethyl coumarin,” European Journal of Medicinal Chemistry, vol. 45, no. 3, pp. 1151–1157, 2010.
View at: Publisher Site | Google Scholar
N. Jagadish Babu, K. Shivashankar, V. P. Rasal, J. R. Eluru, and E. Koyye, “Synthesis and cytotoxic studies of a new series of pyridinoxymethylcoumarins,” International Journal of Chemical and Pharmaceutical Sciences, vol. 4, pp. 74–77, 2013.
View at: Google Scholar
D. Shamala, K. Shivashankar, V. P. Rasal, P. N. V. Vivek, and V. Pandi, “Synthesis and cytotoxic studies of a new series of quinolinoxymethylcoumarins,” International Journal of Pharmaceutical Sciences Review and Research, vol. 21, pp. 109–114, 2013.
View at: Google Scholar

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Copyright © 2014 Puttaraju Boregowda et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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