Synthesis and Antimicrobial Evaluation of New (4-Oxo-thiazolidinyl)quinazolin-4(3H)ones of 2-[(2,6-Dichlorophenyl)amino]phenylacetic acid

Authors

Abstract

Synthesis of 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substitutedphenyl-4-oxo-thiazolidinyl)aryl]-6-bromo quinazolin-4(3H)ones VIa-j have been achieved from the starting material 2-[(2,6-dichlorophenyl)amino] phenylacetic acid I to benzoxazine III, Further reaction with p-phenylindiamine and substituted aromatic aldehyde gave 2-[2-(2,6-dichlorophenyl)amino]phenyl methyl-3-(4-aminoaryl)-6-bromo quinazolin-4(3H)-ones IV and 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substituted arylidene)aryl]-6-bromo quinazolin-4(3H)ones Va-j respectively. Va-j on cyclization with thioglycolic acid gave VIa-j. All the synthesized compounds have been characterized on the basis of elemental analysis, IR and 1H-NMR spectral data. They were screened for antibacterial and antifungal activity at two concentrations and compared with the standard drugs penicillin-G, ampicillin, and amoxicillin. The compounds containing 4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity, compared with the standard drugs.

Keywords


Acute and Subchronic Toxicity?of Teucrium polium Total Extract in Rats
Iranian Journal of Pharmaceutical Research (2007), 6 (4): 251-258
Received: August 2006
Accepted: May 2007

Copyright ? 2007 by School of Pharmacy
Shaheed Beheshti University of Medical Sciences and Health Services

Original Article

Synthesis and Antimicrobial Evaluation of

New (4-Oxo-thiazolidinyl)quinazolin-4(3H)ones of

2-[(2,6-Dichlorophenyl)amino]phenylacetic acid

 

Navin B.Patel* and Virendra N.Patel

Department of Chemistry, Veer Narmad South Gujarat University, SURAT-395007, India.

 

Abstract

Synthesis of 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substitutedphenyl-4-oxo-thiazolidinyl)aryl]-6-bromo quinazolin-4(3H)ones VIa-j have been achieved from the starting material 2-[(2,6-dichlorophenyl)amino] phenylacetic acid I to benzoxazine III, Further reaction with p-phenylindiamine and substituted aromatic aldehyde gave 2-[2-(2,6-dichlorophenyl)amino]phenyl methyl-3-(4-aminoaryl)-6-bromo quinazolin-4(3H)-ones IV and 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substituted arylidene)aryl]-6-bromo quinazolin-4(3H)ones Va-j respectively. Va-j on cyclization with thioglycolic acid gave VIa-j. All the synthesized compounds have been characterized on the basis of elemental analysis, IR and 1H-NMR spectral data. They were screened for antibacterial and antifungal activity at two concentrations and compared with the standard drugs penicillin-G, ampicillin, and amoxicillin. The compounds containing 4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity, compared with the standard drugs.

 

Keywords: Quinazolinone; Thiazolidinone; P-Phenylenediamine; Antibacterial; Antifungal.

Introduction

Quinazolinones are an important class of fused heterocycles, enjoying considerable interest on account of their diverse range of biological activity, such as antimicrobial, antihypertensive, CNS depressants, anti-inflammatory,and potent hypotensive activity in anesthetized rabbits and in conscious spontaneously hypertensive rats. They have also been screened for their analgesic,and acrogenic activities and those compounds, which showed a promising anti-inflammatory activity, were also screened for their cyclo-oxygenase assay (1-3).

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain, fever and inflammation, particularly arthritis. Among the most popular NSAIDs, 2-[(2,6-dichlorophenyl) amino]phenyl acetic acid has been approved in 120 countries since its introduction 25 years ago and is ranked 30thamong the top 200 drug with respect to new prescriptions and in the United States alone (4). Schiff base (arylidene) possesses a variety of activities viz. anticancer, antifungal and hypotensive (5-6). Thiazolidine is an importance class of drugs with several types of biological activity such as anti-HIV, anthelmintic, anti-inflammatory and anti-convulsant properties (7-10).A combination of two or more biologically active moiety could increase or decrease the activity. Keeping this aspects, we thought to extend our previous work on quinazolinone frame work with various substituted aryl acetamides and substituted aryl amines (11, 12).We prepared 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substitutedphenyl-4-oxo-thiazolidinyl)aryl]-6-bromo quinazolin-4(3H)ones VIa-j via 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substitutedarylidene)aryl]-6-bromo quinazolin-4(3H)ones Va-j and studied their antimicrobial activities.

Experimental

Melting points were determined in open capillaries and were left uncorrected. The IR spectra were recorded on Perkin-Elmer-843 spectrometer, using KBr pallets. 1H-NMR spectra were scanned on Bruker DPX-200 FT-NMR spectrometer at 300 MHz, using TMS as the internal standard and CDCl3 as solvent (chemical shift in δ ppm). The compounds gave satisfactory C and N analysis. Samples were routinely purified by crystallization from ethanol: benzene (1:3) and checked by TLC.

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-3-[4-(2-ubstitutedphenyl-4-oxo-thiazolidinyl)aryl]-6-bromo quinazolin-4(3H)ones VIa-j were synthesized by the following synthetic route. Acid I on reaction with thionyl chloride gave the corresponding acid chloride II, that on cyclization with 5-bromo anthranilic acid gave III, which on treatment with p-phenylindiamine gave IV in good yield. Then, IV on reaction with substituted aromatic aldehydes converted to 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substitutedarylidene)aryl]-6-bromo quinazolin-4(3H)ones Va-j, which on cyclization with thioglycolic acid gave 2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(2-substitutedphenyl-4-oxo-thiazolidinyl)aryl]-6-bromo quinazolin-4(3H)ones VIa-j. Structure of compounds Va-j and VIa-j was established on the basis of elemental and spectral data. The bands of methyl and methylene stretching vibrations were observed near 2926 & 2853 cm-1, broad band of N-H stretching at 3450-3350 cm-1, bands of C=O stretching vibrations at 1700-1660 cm-1 and 1725-1738 cm-1 (quinazolinone), A strong absorption band near 1640-1580 cm-1 indicated the presence of ?N=CH- (Schiff base).The C=O stretching of thiazolidin ring was observed at 1760-1755 cm-1. 1H NMR spectra of all synthesized compounds showed a singlet of ?N=CH- at 6.00, a singlet of ?CH2-S- at 3.65. The multiplets of aromatic rings were observed in the range of 6.60-7.85 δ ppm.

 

2-[(2,6-Dichlorophenyl)amino]phenylacetyl chloride II

2-[(2,6-Dichlorophenyl)amino]phenylacetic acid I (0.01 mol) was dissolved in dry benzene (50 ml). To this solution thionyl chloride (0.01 mol) was added dropwise in 1 h, with occasional stirring. The reaction mixture was refluxed on water bath for 2 h and protected from humidity with calcium chloride guard tube. When evolution of HCl and SO2 ceased, the excess of thionyl chloride was removed by distillation with benzene.

 

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-6-bromo-3,1-benzoxazin-4(H)one III

2-[(2,6-Dichlorophenyl)amino]phenylacetyl chloride II (0.01mol) dissolved in pyridine (60 ml). To this solution 5-bromo anthranilic acid (0.01 mol) in pyridine was added dropwise at 0-5 ?C in 1h, stirred for 2h and further refluxed for 1h on an oil bath. The reaction mixture was poured into ice-cold water containing concentrated. HCl.The separated solid was filtered, washed and recrystalized from ethanol. M.P.- 200 ?C, Yield-60%, IR (KBr):νmax (cm-1) 3445 (NH Secondary), 2925, 2842 (C-H), 1672 (C=O), 1615 (C=N); 1310 (C-N), 1140 (C-O-C), 785 (C-Cl), 615 (C-Br); 1H-NMR (chemical shift in δ ppm) -NH- (1H, s, 9.45), Ar-H (10H, m, 6.25-7.63), -CH2- (2H, s, 3.70).

 

2-[2-(2,6-Dichlorophenyl)amino)]phenylmethyl-3-(4-aminoaryl)-6-bromo quinazolin-4(3H)ones IV

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-6-bromo-3,1-benzoxazin-4-(H)one III (0.476 g, 0.001 mol) and p-phenylindiamine (0.108 g, 0.001 mol) were dissolved in pyridine (40 ml), heated on an oil bath at 180-200?C for 5-6h and poured into ice-cold water containing concentrated. HCl. The separated solid was filtered, washed and recrystalized from ethanol. Yield-55%, M.P.- 210 ?C; IR (KBr):νmax (cm-1) 3505 (NH2 Primary), 3440 (NH Secondary), 2920, 2845 (C-H), 1665 (C=O), 1610 (C=N); 1324 (C-N), 1140 (C-O-C), 620 (C-Br); 1H-NMR (chemical shift in δ ppm) -NH- (1H, s, 9.55), Ar-H (14H, m, 6.30-7.60), -NH2 (2H, s, 5.75), -CH2- (2H, s, 3.65).

 

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-3-[4-(4-hydroxyarylidene) aryl]-6-bromo quinazolin-4(3H)ones Vd

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-3-(4-aminoaryl)-6-bromo quinazolin-4(3H)ones IV (0.001 mol) and 4-hydroxy benzaldehyde (0.001 mol) were dissolved in absolute ethanol (40 ml),by the addition of a few drops of glacial acetic acid . The reaction mixture was refluxed for 6h on a water bath and poured into ice cold water. The separated solid was filtered, washed and recrystalized from ethanol.

Similarly, other derivatives were prepared by the same method.

 

 

 

 

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-3-[4-(4-hydroxyphenyl-4-oxo-thiazolidinyl)aryl]-6-bromo quinazolin-4(3H)ones VId

2-[2-(2,6-dichlorophenyl)amino]phenylmethyl-3-[4-(4-hydroxyarylidene) aryl]-6-bromo quinazolin-4(3H)ones Vd (0.001 mol) were dissolved in dry DMF (50 ml), containing a pinch of anhydrous ZnCl2 and thioglycolic acid (0.002 mol) and refluxed for 8h. Excess of solvent was distilled off and the residual reaction mixture cooled and poured into ice cold water. The separated solid was filtered, washed and recrystalized from ethanol.

Similarly, the other thiazolidinone derivatives were prepared by the same method. The characterization data, IR spectral data, 1H-NMR spectral data and antimicrobial activity of all the synthesized compounds are given in s1-4, respectively.

Results and Discussion

Antibacterial and antifungal activity of all the synthesized compounds were screened against four different strain of two gram-positive bacteria (Pseudomonas Sp. & B.subtilis) and two gram-negative (Ceretium & E.coli) bacteria, for two different concentration of 100 μg/ml and 200 μg/ml, using the disk method (13). The growth of inhibition of bacteria was compared with the standard drug penicillin-G, ampicillin, and amoxicillin. These compounds were also tested for their antifungal activity against C.albicans, using amphotericin-B as the standarddrug, and the cup-plate method (14) at the same concentration.

 

 

Antibacterial activity

The screening results of antibacterial activities showed that the presence of bromo group at position-6 of the quinazoline ring,of compounds V bearing R= 4-OCH3 and 3,4,5-(OCH3)3, showed good activity against B.subtilis at 100 ?g/ml concentration. At 200 ?g/ml concentration, compound V bearing R= 4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity against Ceretium, compared with the standard drug penicillin-G.

 

 

Compounds VI bearing R=4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity against Pseudomonas Sp. at 100 ?g/ml concentration. At 200 ?g/ml concentration, compound VI bearing R=4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity against B. subtilis, compared with the standard.

Compounds VI bearing R=4-Cl, 4-OCH3, 3, 4, 5-(OCH3)3 showed good activity against E.Coli at 100 ?g/ml concentration. At 200 ?g/ml concentration, compound VI bearing R= 4-Cl, 4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity against E.Coli, compared with ampicillin.

 

Antifungal activity

In case of bromo group at position-6 of the main moiety, compound VI bearing R=4-OCH3 and 3, 4, 5-(OCH3)3 showed good activity at 100 ?g/ml concentration and at higher concentrations, compound VI bearing R=4-OCH3 and 3, 4, 5-(OCH3)3 displayed moderate activity against C.albicans , compared with Amphotericin-B.

Acknowledgement

The authors are thankful to Professor and Head,of the Department of Chemistry and Librarian of Veer Narmad South Gujarat Univesity, Surat for providing laboratory and library facilities. Also,we wish to thank S.A.I.F, Chandigarh for performing elemental and 1H-NMR spectral analysis.

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