SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-HYDROXY-2-PHENYL-4H-CHROMEN-4 ONES

MANGESH GHARPURE¹*, VISWAS INGLE², HARJEET JUNEJA³, RATIRAM CHOUDHARI^4
1Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, MS, India
²Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, MS, India
³Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, MS, India
⁴Department of Chemistry, Seth Kesarimal Porwal College Kamptee, Nagpur, MS, India
* Corresponding Author : mangesh.gharpure@gmail.com

Received : 28-02-2012     Accepted : 06-03-2012     Published : 15-03-2012
Volume : 3     Issue : 1       Pages : 148 - 150
Int J Knowl Eng 3.1 (2012):148-150

Conflict of Interest : None declared
Acknowledgements/Funding : The authors are thankful to the Head, Department of Chemistry and Head, Department of Pharmacy, R.T.M. Nagpur University, India for providing necessary facilities. Thanks are due to SAIF Chandigarh, India for providing spectral analysis.

33-Hydroxy-2-phenyl-4H-chromen-4-ones (4a-n) have been synthesised from appropriate 1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (3a-n). All compounds were evaluated for antimicrobial activity against S. Aureus, B. Subtilis, E. Coli and P. Aerugenosa as well as fungi e.g. C. Albicans and A. Niger and good results were obtained as in comparison with the standards. These compounds have been characterized on the basis of IR, 1H NMR, Mass spectrometry and elemental analysis.

Chalcones, flavones, antimicrobial activity.

Chromones constitute one of the major class of naturally occurring compounds, and interest in their chemistry continues unabated because of their usefulness as biologically active agents. Some of the biological activities attributed to chromone derivatives include cytotoxic (anticancer), neuroprotective, HIV-inhibitory, antimicrobial, antifungal and antioxidant activity, due to their abundance in plants and their low mammalian toxicity, chromone derivatives are present in large amounts in the human diet. The synthesis of chromone derivatives is a research field of great interest and has long history. Flavonoids (2-phenyl chromone derivatives) are phenolic compounds widely distributed in the plant kingdom. They are known to exhibit antioxidant, anti-inflammatory, antimicrobial, antihypertensive, antiplatelet, gastroprotective, antitumor, antiallergic, etc activies. Flavonoids and iso-flavonoids, which are natural components of plants with antifungal properties, have been investigated. Consideration has been given to increase the understanding of the mode of action of these natural fungicides and of improving their effectiveness through substitutions. These vast literatures prompted us to modify the benzopyrone ring to explore the biological activities associated with this nucleus. ^[1-8]
In the present work, 3-Hydroxy-2-phenyl-4H-chromen-4-ones (2-Aryl/heteryl-3-hydroxy chromones) have been synthesized and explored for antimicrobial activities.

Acetylation (esterification) of phenols followed by Fries migration gave 2-hydroxy acetophenones, reaction of 2-hydroxy acetophenones with different aromatic aldehydes produced 1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (chalcones) (3a-n), which on cyclization in alkaline H₂O₂ yielded 2-aryl/heteryl-3-hydroxychromones (flavones) (4a-n) in excellent yield (Scheme (1)).
The IR spectrum of 4a shows a broad peak at 3222 (Ar-OH), due to presence of phenolic –OH group, 3033, 3075 (aromatic str.), 1611 (C=O pyrone ring). 1H NMR δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 9H, Ar-H). All the compounds (4a-n) gave satisfactory IR, NMR, Mass spectra and Elemental analysis data correlation with the assigned structure.

The synthesized compounds were screened for their antibacterial activities against pathogenic bacteria such as E. Coli, S. Aureus, B. Subtilis and P. Aeruginosa using the cup plate diffusion method. The test compounds were dissolved in dimethyl sulphoxide at a concentration of 100 µg/mL using Ciprofloxacin and Sulphacetamide as a standard drug. All the inoculated plates were incubated at 35 ◦C and the results were evaluated after 24 h of incubation.

The synthesized compounds were also screened for their antifungal activity against A. Niger and C. Albicans using the cup plate diffusion method. The test compounds were dissolved in dimethyl sulphoxide at a concentration of 100µg/mL. The zone of inhibition was observed after 7 days at 25 ⁰C and it was compared with Gentamycin and Clotrimazole as standard drugs as shown in [Table-1] .

All the chemicals and solvents were obtained from Merck (LR grade) and were used without further purification. Melting points were taken in an open capillary tube and are uncorrected. FT-IR spectra were recorded (KBr disk) on a Shimadzu 8101A FT-IR spectrophotometer. ¹H-NMR were obtained from Bruker Avance II 400MHz spectrophotometer using tetramethylsilane as an internal standard in CDCl3. Mass spectra were recorded on water Micromass Q-T of Micro spectrometer equipped with an ESI source. All the elemental analyses were done using Perkin Elmer 2400 CHN analyzer. The reactions were monitored on pre-coated TLC plates (Silica gel 60 F254, Merck), using iodine vapor as visualizing agent.

The mixture of 1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one 3 (2.24 gm, 0.01 mol), ethanol (50 mL), NaOH (10%, 56 mL) and H₂O₂ (30%, 13 mL) was stirred vigorously for 30 minutes and kept for 4 hrs at ice cold condition. It was poured on to cold 5N, 80 mL HCl. The solid was filtered, washed with water, dried and crystallised from alcohol (yield 66%); mp 170 °C; FT-IR (KBr): 3222 (Ar-OH), due to presence of phenolic –OH group, 3033, 3075 (aromatic str.), 1611 (C=O pyrone ring) cm–1; ¹H NMR (400 MHz, CDCl₃): δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 9H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 238. Anal. Calcd for C₁₅H₁₀O₃: C, 75.62; H, 4.23%. Found: C, 75.71; H, 4.13%. Similarly, other flavones (4b-n) were synthesized using this method and spectral data of these compounds are given as follows.

Yield 69%; mp 206 °C; FT-IR (KBr): 3218 (Ar-OH), 1615 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 2.35 (s, 3H, CH₃), 7.02 (s, 1H, OH), 7.26-8.27 (m, 8H, Ar-H) ppm; MS-EI, m/z = 252 (M)⁺. Anal. Calcd for C₁₆H₁₂O₃: C, 76.18; H, 4.79%. Found: C, 76.11; H, 4.85%.

Yield 68%; mp 210 °C; FT-IR (KBr): 3212 (Ar-OH), 1622 (C=O pyrone ring) cm^–1; 1H NMR (400 MHz, CDCl₃): δ 3.95 (s, 3H, OCH₃), 3.97 (s, 3H, OCH₃), 7.02 (s, 1H, OH), 7.00-8.25 (m, 7H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 298. Anal. Calcd for C₁₇H₁₄O₅: C, 68.45; H, 4.73%. Found: C, 68.53; H, 4.67%.

Yield 67%; mp 262 °C; FT-IR (KBr): 3226 (Ar-OH), 1618 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 3.95 (s, 3H, OCH³), 3.97 (s, 3H, OCH3), 7.02 (s, 1H, OH), 7.00-8.25 (m, 6H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 332. Anal. Calcd for C₁₇H₁₃ClO₅: C, 61.36; H, 3.94%. Found: C, 61.42; H, 3.99%.

Yield 65%; mp 192 °C; FT-IR (KBr): 3202 (Ar-OH), 1619 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 8H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 272. Anal. Calcd for C15H9ClO3: C, 66.07; H, 3.33%. Found: C, 66.14; H, 3.29%.

Yield 66%; mp 232 °C; FT-IR (KBr): 3212 (Ar-OH), 1608 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 7H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 306. Anal. Calcd for C₁₅H₈Cl₂O₃: C, 58.66; H, 2.63%. Found: C, 58.72; H, 2.69%.

Yield 68%; mp 169 °C; FT-IR (KBr) : 3227 (Ar-OH), 1616 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 8H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 272. Anal. Calcd for C₁₅H₉ClO₃: C, 66.07; H, 3.33%. Found: C, 66.19; H, 3.45%.

Yield 66%; mp 242 °C; FT-IR (KBr): 3215 (Ar-OH), 1632 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 3.06 (s, 6H, N(CH₃)₂), 6.89 (s, 1H, OH), 6.87-8.24 (m, 7H, Ar-H) ppm; MS-EI , m/z = (M)⁺ = 315. Anal. Calcd for C₁₇H₁₄ClNO₃: C, 64.67; H, 4.47; N, 4.44%. Found: C, 64.71; H, 4.39; N, 4.48%.

Yield 64%; mp 151 °C; FT-IR (KBr): 3218 (Ar-OH), 1617 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 11.22 (s, 1H, OH), 5.11-8.16 (m, 7H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 228. Anal. Calcd for C₁₃H₈O₄: C, 68.42; H, 3.53%. Found: C, 68.47; H, 3.59%.

Yield 64%; mp 212 °C; FT-IR (KBr): 3229 (Ar-OH), 1615 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 11.22 (s, 1H, OH), 5.11-8.16 (m, 6H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 262. Anal. Calcd for C₁₃H₇ClO₄: C, 59.45; H, 2.69%. Found: C, 59.55; H, 2.63%.

Yield 63%; mp 162 °C; FT-IR (KBr): 3220 (Ar-OH), 1614 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 8H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 256. Anal. Calcd for C₁₅H₉FO₃: C, 70.31; H, 3.54%. Found: C, 70.44; H, 3.51%.

Yield 65%; mp 215 °C; FT-IR (KBr): 3221 (Ar-OH), 1613 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 7.02 (s, 1H, OH), 7.26-8.27 (m, 7H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 290. Anal. Calcd for C₁₅H₈ClFO₃: C, 61.98; H, 2.77%. Found: C, 61.92; H, 2.83%.

Yield 68%; mp 219 °C; FT-IR (KBr): 3225 (Ar-OH), 1617 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl3): δ 3.95 (s, 3H, (OCH₃), 7.02 (s, 1H, OH), 7.00-8.25 (m, 7H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 302. Anal. Calcd for C₁₆H₁₁ClO₄: C, 63.48; H, 3.66%. Found: C, 63.40; H, 3.74%.

Yield 62%; mp 196 °C; FT-IR (KBr): 3227 (Ar-OH), 1621 (C=O pyrone ring) cm^–1; ¹H NMR (400 MHz, CDCl₃): δ 3.06 (s, 6H, N(CH₃)₂), 6.89 (s, 1H, OH), 6.87-8.24 (m, 8H, Ar-H) ppm; MS-EI, m/z = (M)⁺ = 281. Anal. Calcd for C₁₇H₁₅NO₃: C, 72.58; H, 5.37; N, 4.98%. Found: C, 72.70; H, 5.25; N, 5.03%.

3-Hydroxy-2-phenyl-4H-chromen-4-ones were synthesized with good yield as well as purity. The compounds 4i and 4j were more active in reducing microbial growth than the other corresponding compounds. The present study demonstrates that the antimicrobial potential of certain flavonoids increases significantly by a simple chemical modification.

The authors are thankful to the Head, Department of Chemistry and Head, Department of Pharmacy, R.T.M. Nagpur University, India for providing necessary facilities. Thanks are due to SAIF Chandigarh, India for providing spectral analysis.

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	Scheme 1. Synthesis of 3-Hydroxy-2-phenyl-4H-chromen-4-ones (4a-n)
	Table 1- Biological activity of 3-Hydroxy-2-phenyl-4H-chromen-4-ones (4a-n). Key to symbols; SA= S. Aureus, BS= B. Subtilis, EC=E. Coli, PA= P. Aeruginosa, CA=C. Albicans and AN=A. Niger b = average zone of inhibition in mm, for antibacterial activity: Std. 1 = Ciprofloxacin and Std. 2= Sulphacetamide, for antifungal activity: Std. 1 = Gentamycin and Std. 2 = Clotrimazole