Synthesis, Characterization and Antimicrobial Screening of Some Novel Chromonyl Isoxazoles

 

Dr. V. P. Sharma1, Dr. Rakesh Kumar2*

1Department of Chemistry, Meerut College, Meerut (UP) India

2Department of Chemistry, M.M.M. (P.G.) College, Bhatpar Rani, Deoria (UP) India

*Corresponding Author E-mail: drrakesh01071982@gmail.com

 

ABSTRACT:

Isoxazolines and chromones are one of the active class of the compounds possessing a wide range of biological and medicinal activities. In this publication, the synthesized some novel compounds containing chromone as well as Isoxazoline moiety together is being studied systematically. The synthesis of 5-(2’-Aryl/heteroaryl chromon-6’-yl)-3-aryl/heteroaryl isoxazoles [II(a-b)] by the condensation of 1-(2’-aryl/furyl chromon-6’-yl)-3-aryl or heteroarylprop-2-en-1-ones [I(a-f)] with hydroxylamine hydrochloride. The synthesized compounds have been characterized by elemental analysis, FT-IR and PMR spectral data. The synthesized compounds have been evaluated for their antibacterial and antifungal activities. Most of the compounds have been found moderately active when compared with the reference standard drugs.

 

KEYWORDS: Chromone, Chalcone, Hydroxylamine Hydrochloride, Antifungal and Antibacterial Activity.

 

 

INTRODUCTION:

Isoxazoline represents one of the active class of the compounds possessing a wide range of biological activities. They are key intermediates for the preparation of some natural compounds and their synthetic analogues1. Indicator moiety is present in several medicines like, sulfonamide drugs (Sulfisoxazoles) and antibiotics (Oxacillin, Cloxacillin, etc.) as antileprous agent2. Compounds with isoxazole ring have also been reported to possess antimicrobial3, insecticidal4, antiparasitic5, anticonvulsant6, anti-inflammatory7, anticancer8, voltage gated sodium channel blockers9 and analgesic 10 activities.

 

The chemistry of chromones and their derivatives have been studied since a century ago or more, due to their important biological activities11. The chromones and related compounds are well known in the plant kingdom from algae to conifers.

 

They possess a wide range of physiological activities like antibacterial12,14, antifungal13,14, antitumor15, anti-allergique16, anticancer17, anti-HIV18,  anti-inflammatory19, antitubercular20, antioxidant21 and antibiotic22 activities. The chromones are also interesting as structural scaffolds and have been found as privileged structure for drug development. In our work, it was intended to synthesize some novel compounds containing chromone and Isoxazoline moiety together.

 

RESULTS AND DISCUSSION:

5-(2’-Aryl/heteroarylchromon-6’-yl)-3-aryl/heteroaryl isoxazoles [II (a-f)] were obtained when a mixture of 1-(2’-aryl/furyl chromon-6’-yl)-3-aryl or heteroarylprop-2-en-1-ones [I (a-f)] (0.01 mol) and hydroxylamine hydrochloride (0.01 mol) in ethanol and dimethylformamide with a catalytic amount of potassium hydroxide was refluxed. The structure details of [II (a-f)] became apparent on the basis of careful analyses of their spectral characteristics. But in case of [II (a-f)] IR did not offer much help in the elucidation of structure of the compounds. Though two characteristic absorption bands appearing at 1660-1655 cm-1 and 1640-1635  cm-1 were may be attributed to the C=O stretching vibrations of Isoxazoline or isoxazoles and C=O group of chromone respectively. The formation of Isoxazolineor Isoxazoline ring could not be decided with certainty since the C=O group of chalcone side-chain in [I (a-f)] also absorb in this region. Spectral characteristics reveal that isoxazole ring is formed which is probably due to aireal oxidation of Isoxazoline first formed. The presence of isoxazole ring was however ascertained by the appearance of a band of medium intensity at 1590 cm-1. But PMR further support the structure assigned to it. This is confirmed on the basis of disappearance of two proton signals of (chalcone) at d:5.57 andd:6.72 and the appearance of the proton signals at d:6.41 (C4-H, Isoxazole ring).

 

EXPERIMENTAL:

The reagent grade chemicals were purchased from commercial sources and purified by either distillation or recrystallization before use. Homogeneity of the compounds was checked on silica gel TLC plates of 2 mm thickness using n-hexane and ethyl acetate as solvent system. The visualization of spots was carried out in an iodine chamber. The physicochemical and spectroscopical data of synthesized compounds were in full agreement. All the melting points were determined in open glass capillary tubes and are uncorrected. The Infra-Red spectra were recorded in a Perkin-Elmer 1000 FT-IR spectrophotometer, using potassium bromide pellets; the frequencies are expressed in cm-1. The proton magnetic resonance spectra were recorded on a Bruker-Advance II 400 NMR spectrophotometer (at 400 MHz) in CDCl3 or DMSO-d­6 as specified; the chemical shifts (d) are expressed in parts per million (ppm) downfield from Tetramethylsilane (TMS) as internal reference. The coupling constants (J) in PMR are reported in Hz.

 

Preparation of 5-(2-aryl or heteroaryl chromon-6-yl)-3-aryl or heteroaryl isoxazoles [II(a-f)]:

A mixture of chalcone [I (a-f)] (0.01 mol) and hydroxylamine hydrochloride (60 mg, 0.01 mol) in 100 ml of EtOH+DMF (3:1) and a catalytic amount of KOH was refluxed for 3-5 hours. The progress of reaction was monitored on TLC. After completion of the reaction the whole reaction mixture was poured on crushed ice; a yellow solid is separated out. This precipitate was filtered and washed with water followed by ethanol and recrystallized by suitable solvents. A yellowish crystalline powder was obtained.

 

5-(2-phenyl chromon-6-yl)-3-phenyl isoxazole [II(a)]:

A mixture of 1-(2’phenylchromon-6’-yl)-3-phenylprop-2-en-1-one [I (a)] (3.52g, 0.01 mol) and hydroxylamine hydrochloride (0.01 mol) in ethanol and dimethylformamide (75 ml + 25 ml) and a few drops of 10% potassium hydroxide solution was refluxed for 5 hours. The progress of reaction was monitored on TLC. After completion of the reaction, reaction mixture was poured on crushed ice; a yellow solid is separated out. This precipitate was filtered with Buckner funnel, washed with water followed by chilled ethanol and recrystallized with chloroform.

 

Chemical Formula: C24H15O3N;Yield: 78%; State (color): Solid (white);m.p.: 184-186°C; m.w.: 365; Elemental analysis (%) [Calculated / found]: C [78.90 / 78.88], H [4.11 / 4.10],  N [3.84 / 3.82]; IR υmax (KBr) cm-1: 590-680, 950-970 (str. –N-O-), 1400-1460, 1580-1680 [(-C=N- str., isoxazole) and (CO str., chromone)];1H-NMR (CDCl3) d:6.40-6.92 [m, 2H, (C4-H isoxazole) (C3-H chromone)], 7.45-7.70 [m, 8H, Ar-H], 7.86-7.92 [m, 3H, (C8-H chromone) and (2H, Ar-H)], 8.40-8.44 [dd, 1H, C7-H chromone, J7,8=9.08 Hz and J7,5=2.5 Hz],8.85-8.87 [d, 1H, C5-H chromone, J5,7=2.5 Hz],

 

5-(2-phenyl chromon-6-yl)-3-furyl isoxazole [II (b)]:

Chemical Formula: C22H13O4N; Yield: 68%; State (color): Solid (Yellow); m.p.: 178-180°C; m.w.: 355; Elemental analysis (%) [Calculated / found]: C [74.37 / 74.33], H [3.66 / 3.65], N [3.94 / 3.92]; IR υmax (KBr) cm-1: 680, 820, 950-970 (str. –N-O-), 1180, 1260, 1575-1670 [(-C=N- str., isoxazole) and (CO str., chromone)]; 1H-NMR (CDCl3) d:6.42-7.08 [m, 4H, (C4-H isoxazole), (C4-H andC3-H,  furan ring) and (C3-H chromone)], 7.41-7.64 [m, 5H, (4H, Ar-H) and (C5-H, furan ring)], 7.82-7.93 [m, 2H, (C8-H chromone) and (1H, Ar-H)], 8.64-8.68 [dd, 1H, C7-H chromone, J7,8=9.08 Hz and J7,5=2.5 Hz], 8.84-8.86 [d, 1H, C5-H chromone, J5,7=2.5 Hz].

 

5-(2-phenyl chromon-6-yl)-3-(p-chlorophenyl) isoxazole [II(c)]:

Chemical Formula: C24H14O3NCl; Yield: 72%; State (color): Solid (cream); m.p.: 184-188 °C; m.w.: 399.5; Elemental analysis (%) [Calculated / found]: C [72.09 / 72.07], H [3.50 / 3.49],N [3.50 / 3.45]; IR υmax (KBr) cm-1: 890, 960-975 (str. –N-O-), 1200, 1280, 1585-1700 [(-C=N- str., isoxazole) and (CO str., chromone)]; 1H-NMR (CDCl3) d:6.42-6.88 [m, 2H, (C4-H isoxazole) (C3-H chromone)],7.42-7.72 [m, 8H, Ar-H],7.88-7.95 [m, 2H, (C8-H chromone) and (1H, Ar-H)],8.42-8.46 [dd, 1H, C7-H chromone, J7,8=9.08 Hz and J7,5=2.5 Hz],8.87-8.89 [d, 1H, C5-H chromone, J5,7=2.5 Hz]

 

5-(2-furyl chromon-6-yl)-3-phenyl isoxazole [II(d)]:

Chemical Formula: C22H13O4N; Yield: 65%; State (color): Solid (yellow); m.p.: 178-180°C; m.w.: 355; Elemental analysis (%) [Calculated / found]: C [74.37 / 74.35], H [3.66 / 3.63], N [3.94 / 3.93]; IR υmax (KBr) cm-1: 680, 820, 950-970 (str. –N-O-), 1180, 1260, 1575-1670 [(-C=N- str., isoxazole) and (CO str., chromone)].; 1H-NMR (CDCl3) d:6.41-7.10 [m, 4H, (C4-H isoxazole), (C4-H andC3-H,  furan ring) and (C3-H chromone)], 7.44-7.68 [m, 5H, (4H, Ar-H) and (C5-H, furan ring)], 7.80-7.90 [m, 2H, (C8-H chromone) and (1H, Ar-H)], 8.78-8.42 [dd, 1H, C7-H chromone, J7,8=9.08 Hz and J7,5=2.5 Hz], 8.85-8.87 [d, 1H, C5-H chromone, J5,7=2.5 Hz].

 

5-(2-furyl chromon-6’-yl)-3-furyl isoxazole [II(e)]:

Chemical Formula: C20H11O5N;Yield: 75%; State (color): Solid (pale yellow); m.p.: 172-174°C; m.w.: 345; Elemental analysis (%): [Calculated / found]: C [69.57 / 69.53], H [3.19 / 3.18], N [4.06 / 4.05]; IR υmax (KBr) cm-1: 670, 820, 948-975 (str. –N-O-), 1200, 1280, 1550-1690 [(-C=N- str., isoxazole) and (CO str., chromone)];1H-NMR (CDCl3) d:6.46-7.10 [m, 6H, (C4-H isoxazole), (C4-H andC3-H,  furan ring A), (C3-H chromone) and (C4-H andC3-H,  furan ring A)], 6.52-7.78 [m, 3H, (C8-H chromone), (C5-H, furan ring A) and (C5-H, furan ring B)], 8.40-8.43 [dd, 1H, C7-H chromone, J7,8=9.08 Hz and J7,5=2.5 Hz], 8.82-8.84 [d, 1H, C5-H chromone, J5,7=2.5 Hz].

 

5-(2-furyl chromon-6-yl)-3-(p-chlorophenyl) isoxazole [II(f)]:

Chemical Formula: C22H12O4NCl; Yield: 60%; State (color): Solid (cream); m.p.: 176-180 °C; m.w.: 389.5; Elemental analysis (%) [Calculated / found]: C [67.78 / 67.75], H [3.08 / 3.05], N [3.59 / 3.58]; IR υmax (KBr) cm-1: 615, 840, 950-970 (str. –N-O-), 1140, 1260, 1565-1680 [(-C=N- str., isoxazole) and (CO str., chromone)]; 1H-NMR (CDCl3) d:6.48-7.12 [m, 4H, (C4-H isoxazole), (C4-H andC3-H,  furan ring) and (C3-H chromone)], 7.47-7.92 [m, 6H, (4H, Ar-H), (C5-H, furan ring) and (C8-H chromone)], 8.39-8.44 [dd, 1H, C7-H chromone, J7,8=9.08 Hz and J7,5=2.5 Hz], 8.86-8.88 [d, 1H, C5-H chromone, J5,7=2.5 Hz].

 

Antimicrobial Screening:

The synthesized compounds were screened for their in vitro antibacterial activity against Escherichia coli, Pseudomonas aeruginosa and antifungal activity against Aspergillus niger, Aspergillus flavus, by measuring the zone of inhibition in mm. The antimicrobial activity was performed by filter paper disc plate method at concentration 100μg/mL and reported in the graph. Muller Hinton agar and Sabouroud Dextrose agar were employed as culture medium and DMSO was used as solvent control for antimicrobial activity. Streptomycin and Fluconazole were used as standard for antibacterial and antifungal activities respectively.

 

*Zone of inhibition was measured in mm. for Escherichia coli (E.c.), Pseudomonas aeruginosa (P.a.), Aspergillus niger (A.n.) and Aspergillus flavus (A.f.).

 

ACKNOWLEDGEMENTS:

The authors are thankful to CSIR, New Delhi for financial support (JRF) during the research work, Director of SAIF, Chandigarh for providing necessary spectral facilities and Head, Department of Chemistry, J.V. College, Baraut, Baghpat (U.P.) for providing the necessary research facilities.

 

CONCLUSION:

Structures of the synthesized substituted compounds were confirmed from their respective IR, 1H-NMR studies. From the antimicrobial screening it was observed that all the compounds exhibited activity against all the organisms employed. The compounds [II (a)], [II (b)] and [II (d)] shows good antibacterial activity where as other compounds showed moderate to good activity. Fungicidal screening data also revealed that compounds [II (b)], [II (e)] and [II (f)] imparted maximum activity, where as other compounds showed moderate to good activity. As we consider all results obtained from antibacterial and antifungal tests together, it may be include all of the compounds tested are active towards bacteria and fungi tested for.

 

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Received on 27.02.2019                    Modified on 20.03.2019

Accepted on 04.04.2019                   ©AJRC All right reserved

Asian J. Research Chem. 2019; 12(2):116-119.

DOI: 10.5958/0974-4150.2019.00025.7