INTRODUCTION:

Thiazole and its derivatives have been associated with a wide variety of biological and pharmacological activity^1-2. The 2-aminothiazole-ring system has found application in the drug development for the treatment of HIV infection, allergy, hypertension and inflammation³. Thiazole derivatives are also well known for their bactericidal, fungicidal and anthehelmintic properties⁴. Further many azetidinone and thiazolidinone derivatives were also reported for their antimicrobial agents⁵.

Taking these views in to consideration and in continuation of our research work on the synthesis of biologically active agents^6-8 and it was thought of interest to synthesized several arylthiazole derivatives possessing azetidinone and thiazolidinone moieties with the interest to possess better antimicrobial activity.

In the present course of study, 1-bromoacetyl-4-methoxyphenyl 2 was used as starting material for the synthesis of above titled compounds and it was synthesized by the bromination of 4-methoxy acetophenone 1 with bromine in acetic acid.

The reaction of compound 2 with various substituted arylthiourease in anhydrous ethanol at reflux temperature for 3hrs gave 2-arylamino-4-(4-methoxyphenyl-2-yl)thiazoles 2a-d in good yields.

Similarly the reaction of 2 with substituted arylidine thiosemicarbazides⁸ in anhydrous ethanol at boiling temperature for 3hr furnished 2-arylidinehydrazino-4-(4-methoxyphenyl-2-yl)thiazoles 3a-d.

The interaction of 1-bromoacetyl-4-methoxyphenyl 2 with the thiourea in ethanol to gave 2-amino-4-(4-methoxyphenyl-1-yl)thiazole 4. Compound 4 was treated with various aromatic aldehydes in boiling ethanol to get 2-[(substituted arylidine)amino]-4-(4-methoxyphenyl-1-yl)thiazoles(schiff’s bases) 4a-e. These compounds 4a-e on further reaction with chloroacetylchloride and mercaptoacetic acid produced 3-chloro-4-(substituted phenyl)-1-[4-(4-methoxyphenyl)-1, 3-thiazol-2-yl]azitidin-2-ones 5a-e and 3-[4-(4-methoxyphenyl)-1, 3-thiazol-2-yl]-2-substituted phenyl 1, 3-thiazolidine-4-ones 6a-e (Scheme-1).

The structures of all newly prepared arylthiazole derivatives were established on the basis of spectral and analytical data and these compounds were evaluated for their antibacterial, antifungal activities and some selected compounds were determined for their pharmacological studies.

Antimicrobial activity

The invitro antimicrobial activity of synthesized compounds were determined by using Cup-plate diffusion method⁹. The organisms selected for antibacterial activity are S.epidermiitatis and Escherichia coli and for antifungal activity Aspergillus niger and Candida albicans. These organisms were procured from the Department of Microbiology, Gulbarga University, Gulbarga. The Ciprofloxacin and Fluconazole were used as standard drugs for antibacterial and antifungal activity respectively. The test compounds and standard drugs were used at the concentration of 100μ/0.1ml.

Amongst the tested compounds 2c, 3e, 5b, 4b, 5e and 6e have shown high antibacterial activity against S.epidermitatis and E.coli where as compounds 3a, 3d, 4e, 5c and 6b exhibited moderate activity against both bacteria.

Compounds 2c, 3c, 5b, 5d and 6e were exhibited good antifungal activity against A.niger and Candidica albicans. Compounds 3b, 3d, 4e, 6c and 6d showed moderate activity against Aspergillus niger and Candida albicans and remaining compounds showed moderate to weak activity against both fungi.

MATERIALS AND METHODS:

Melting points of all compounds were determined by open capillaries and are uncorrected and the purity of all synthesized compounds were checked using TLC on silica gel plates. The IR Spectra (KBr) cm-1 were recorded on FTIR-8400S (Shimadzu) Spectrometer. ¹HNMR Spectra (CDCl₃) were recorded on ACF 200Supercone Switzerland NMR Spectrophotometer and mass spectra were recorded on LC-MS 2010A(SHIMADZU)mass spectrophotometer using TMS as internal standards and expressed in d(ppm).

1-Bromoacetyl-4-methoxyphenyl (2)

A solution of 4-methoxyacetophenone 1 (0.02mole) in acetic acid (100ml) was added to bromine(0.18mole) in acetic acid. The reaction mixture kept at room temperature for 5hr . Then it was poured in to ice cold water, the solid separated was collected and crystallized from ethanol.

IR(KBr)cm-1 1439, 1506, 1599(C=C str), 1678(C=O), 2937(C-Hstr OCH₃). ¹HNMR (CDCl₃) d 3.8(s, 3H, OCH₃), 4.4(s, 2H, CH₂), 7.8(m, Ar-H), mass spectra m/z 231(M+, 100%), 151, 127, 71.

2-Arylamino-4-(4-methoxyphenyl-2-yl)thiazoles (2a-d)⁸

General procedure

A mixture of 1-bromoacetyl-4-methoxy phenyl 2 (0.002mole) in anhydrous ethanol (10ml) and substituted thiourea (0.002mole) and the reaction mixture was refluxed for 3hr. After cooling the mixture was poured in to water and neutralized with aqueous sodium acetate solution(5% w/v), the solid separated was collected and purified by recrystallised using suitable solvent system.

2a: IR (KBr) cm^-1 3100 (N-Hstr), 1601 (C=N), 2934(C-Hstr OCH₃). ¹HNMR (CDCl₃) d 3.8 ( s, 3H, OCH₃), 6.6 ( s, 1H, thiazole), 6.4-7.4 ( m, Ar-H ), 7.6 (s, 1H, NH). Mass Spectra m/z 301(M^-1, 289, 771, 209, 166, 120.

2b:, IR (KBr) cm^-1 2922 (CHstr, OCH₃), 1601 (C=N), 3166(N-Hstr). ¹HNMR (CDCl₃) d 1.3( s, 3H, CH₃), 3.8 ( s, 3H, OCH₃), 6.6(s, 1H, thiazole), 6.8-7.3(m, Ar-H) 7.7 (s, 1H, NH). Mass Spectra m/z 297(M⁺¹, 100%).

2c: IR (KBr) cm^-1 1610 (C=N), 2930(C-Hstr,OCH₃), 3170 (N-Hstr).¹HNMR (CDCl₃) d 3.8 ( s, 3H, OCH₃), 6.5 ( s, 1H, thiazole), 6.7-7.4 ( m Ar-H), 7.6 (s, 1H, NH).

2-Arylidene hydrazine-4-(4-methoxy Phenyl-2-yl) thiazoles (3a-e)⁸

General Procedure:

To a solution of 1-bromoacetyl-4-methoxy phenyl (0.002mol) 2 in anhydrous ethanol (10ml) was added arylidenethiosemicarbazide IIa-e (0.002mol) in anhydrous ethanol (15ml) and the reaction mixture was refluxed for 3hr. After cooling the reaction mixture was poured into water and neutralized with aqueous sodium acetate (5% w/v). The solid separated was collected and crystallized from suitable solvent.

3a: IR (KBr) cm^-1 1612 (C=N), 2930(C-Hstr,OCH₃), 3180 (N-Hstr).¹HNMR (CDCl₃) d 3.8 ( s, 3H, OCH₃), 6.5 ( s, 1H, thiazole), 6.7-7.4 (m, Ar-H), 7.6 (s, 1H, NH), 10.8(s, 1H, -N=CH). Mass Spectra m/z 301(M⁺, 289).

3b: IR (KBr) cm^-1 1605 (C=N), 2930 (C-Hstr, OCH₃), 3180(N-Hstr). ¹HNMR (CDCl₃) d 3.8( s, 3H, OCH₃), 10.2 ( s, 1H, OH), 6.7 (s, 1H, thiazole), 7.0-8.1(m, Ar-H) . 8.8 ( s, 1H, NH), 11.0 (s, 1H, -N=CH). Mass Spectra m/z 326(M⁺, 100%), 241(25%), 279(10%), 253 (5%), 207(5%), 193(8%), 122(5%), 77(2%).

3c: IR (KBr) cm^-1 1601 (C=N), 2927(C-Hstr, OCH₃), 3383(N-Hstr). ¹HNMR (CDCl₃) d 3.9( s, 3H, OCH₃), 10.3 ( s, 1H, OH), 6.5 (s, 1H, thiazole), 6.9-7.5( m, Ar-H ), 8.5 ( s, 1H, NH), 11.0 (s, 1H, -N=CH). Mass Spectra m/z 326(M⁺, 100%).

2-Amino-4-(4-methoxy-2-phenyl)Thiazole (4)

General procedure:-

To a solution of 1-bromoacetyl-4-methoxy phenyl (0.002 mole) 2 in anhydrous ethanol (10ml) was added thiourea (0.002mol). the reaction mixture was refluxed for 3hr. after cooling the reaction mixture was decomposed in ice cold water and neutralized with aqueous sodium acetate solution (5% w/v), the solid separated was collected and recrystallised from ethanol. IR(KBr) Yield: 70%, m.p 182⁰C. IR (KBr) cm^-1 1620 (C=N), 2927(C-Hstr, OCH₃), 3100-3383(N-Hstr, NH₂). ¹HNMR (CDCl₃) d 3.9( s, 3H, OCH₃), 6.8 (s, 1H, thiazole), 7.2-7.6( m, Ar-H ). Mass Spectra m/z 326(M⁺, 100%), 189(10%), 140(20%) and 71(5%).

2-[(substituted arylidene)amino]-4-(4-methoxyphenyl-1-yl) thiazoles (Schiff bases) (4a-e).

General procedure:-

A mixture of 4 (0.01mol) and various aromatic aldehydes (0.01mol) in ethanol (40ml) along with glacial acetic acid (2-3drops). The reaction mixture was refluxed for 3hrs, cooled. Thus solid separated was washed with ethanol and purification was carried out using suitable solvent.

4a: IR (KBr) cm^-1 1600 (C=N), 2973(C-Hstr.OCH₃).¹HNMR (CDCl₃) d 3.8( s, 3H, OCH₃), 6.8 (s, 1H, thiazole), 7.2-7.6( m, Ar-H ), 10.9(s, 1H, -N=CH).

3-chloro-4-(substituted phenyl)-1-[4-(4-methoxyphenyl)-1, 3-Thiazol-2-yl]azitidin-2-ones (5a-e).

General procedure:-

A ethanolic solution of compound 4a-e (0.01mol), choroacetylchoride (0.01mol) was added drop wise with constant starring in presence of triethylamine (0.01mol) at 0-5⁰C. The reaction mixture was refluxed for 8hrs. After completion of reaction excess of ethanol distilled off. The resulting residual mass cooled, poured into ice water, filtered, washed with water, dried and recrystallised from suitable solvent ethanol to yield compound 5a-e.

Table-1 Characterization data of synthesized compounds

Compound	R	M.P (⁰C)	Yield (%)	Molecular formula	Solvent for crystallization
2a	C₆H₅	92	61	C₁₆H₁₄N₂OS	Ethanol
2b	C₆H₄CH₃(p)	110	67	C₁₇H₁₆N₂OS	Ethanol
2c	C₆H₄Cl(p)	118	60	C₁₆H₁₃N₂OS	Ethanol
2d	C₆H₄F(p)	100	65	C₁₆H₁₃FN₂OS	Ethanol
3a	C₆H₅	102	62	C₁₇H₁₅N₃OS	Ethanol
3b	C₆H₄OH(o)	128	68	C₁₇H₁₅N₃O₂S	Ethanol
3c	C₆H₄OH(p)	100	68	C₁₇H₁₅N₃O₂S	Ethanol
3d	C₆H₄OCH₃(p)	95	63	C₁₈H₁₇N₃O₂S	Ethanol
3e	C₆H₄Cl(p)	90	65	C₁₇H₁₄ClN₃O₂S	Ethanol
4a	C₆H₅	220	62	C₁₇H₁₄N₂OS	Ethanol
4b	C₆H₄OH(o)	120	68	C₁₇H₁₄N₂O₂S	Ethanol
4c	C₆H₄OH(p)	85	68	C₁₇H₁₄N₂O₂S	Ethanol
4d	C₆H₄OCH₃(p)	82	63	C₁₈H₁₆N₂O₂S	Ethanol
4e	C₆H₄Cl(p)	102	65	C₁₇H₁₃ClN₂OS	Ethanol
5a	C₆H₅	230	52	C₁₉H₁₅ClN₂O₂S	Ethanol
5b	C₆H₄OH(o)	170	58	C₁₉H₁₅ClN₂O₃S	Ethanol
5c	C₆H₄OH(p)	125	60	C₁₉H₁₅ClN₂O₃S	Ethanol
5d	C₆H₄OCH₃(p)	165	63	C₂₀H₁₇ClN₂O₃S	Ethanol
5e	C₆H₄Cl(p)	155	55	C₁₉H₁₄ClN₂O₂S	Ethanol
6a	C₆H₅	115	62	C₁₉H₁₆N₂O₂S	Ethanol
6b	C₆H₄OH(o)	220	57	C₁₉H₁₆N₂O₃S	Ethanol
6c	C₆H₄OH(p)	135	60	C₁₉H₁₆N₂O₃S	Ethanol
6d	C₆H₄OCH₃(p)	110	53	C₂₀H₁₈N₂O₃S₂	Ethanol
6e	C₆H₄Cl(p)	205	59	C₁₉H₁₅N₂O₂S₂	Ethanol

All the compounds were shown C, H and N analysis satisfactory

Table-2 Antimicrobial activity of synthesized compounds

Compound	Zone of inhibition in mm Antibacterial Antifungal
Compound	S. epidermatitis E. coli	A.niger C.albicans
Control(DMF)	8 8	8 8
Standard Ciprofloxacin Fluconazole	23 24 - -	- - 25 24
2a	17 13	17 14
2b	15 17	16 13
2c	21 18	23 22
2d	22 20	21 20
3a	16 18	17 13
3b	11 13	16 18
3c	21 17	22 21
3d	16 17	21 17
3e	22 22	17 18
4	11 14	16 14
4a	11 10	16 13
4b	21 19	20 17
4c	20 20	16 17
4d	16 13	20 18
4e	15 17	21 16
5a	12 13	21 17
5b	22 21	20 21
5c	18 17	18 19
5d	22 16	20 22
5e	23 22	22 21
6a	14 15	12 13
6b	15 16	18 19
6c	16 17	17 18
6d	14 15	16 17
6e	20 21	20 23

*Diameter of the well 8mm

6.4-7.3( m, Ar-H ) .Mass Spectra m/z 461(m⁺, 100%), 379, 350, 290, 271, 229, 185, 165, 115.

3-[4-(4-methoxyphenyl)-1, 3-thiazol-2-yl]-2-substituted phenyl 1,3-thiazolidine-4-ones (6a-e)

General procedure:-

To a solution of compound 4a-e (0.01mol) in methanol (50ml), thioglycollic acid (0.02mol) was added dropwise in presence of anhydrous zinc chloride and this reaction.

mixture was refluxed for 8hrs. After completion of reaction excess of ethanol distilled off. The resulting residual mass cooled, poured into ice water, filtered, washed with water, dried and recrystallised from suitable solvent.

6c: IR (KBr) cm^-1 1178(C-S), 1396(C-N), 1630(C=N), 2923(C-Hstr, OCH₃), 1740(C=O) 3402(OH). ¹HNMR (CDCl₃)d 4.4( s, 2H,-CH₂), 4.8(s, 1H, Ph-thiazolidinone), 3.8( s, 3H, OCH₃), 6.6 (s, 1H, thiazole), d6.4-6.8( m, Ar-H), 10.2(s, 1H, OH). Mass Spectra m/z 463(M⁺, 100%)

6d: IR (KBr) cm^-1 1390(C-N), 1627(C=N), 2923(C-Hstr, OCH₃), 1396 (C-N), 1741(C=O) 3400(O-H). ¹HNMR d 4.4( s, 2H, -CH₂), 4.9(s,1H, Ph-thiazolidinone), 6.6 (s, 1H, thiazole), 6.4-6.8 ( m, Ar-H) .Mass Spectra m/z 399(M⁺100), 379(60%), 320(38%), 290(46%), 251(28%), 229(15%), 195(80%), 169(25%), 119(10%).

RESULTS AND DISCUSSION

Thiazole and its derivatives have been associated with its wide range of its biological and pharmacological properties. The arylthiazole derivatives (2a-d) and (3a-e) were synthesized by the reaction of 1-bromoacetyl-4-methoxyphenyl 2 with substituted thiourea and arylidinethiosemicarbazide in ethanol at refluxed temperature. The reaction of 2-amino-4-(4-methoxy-2-phenyl)thiazole (4) with various substituted aromatic aldehydes in ethanol in presence of catalytic quantity of glacial acetic acid to obtained corresponding schiff’s bases (4a-e) which further underwent cyclisation upon treatment with chloroacetylchloride in presence of triethylamine and thioglycollic acid in presence of anhydrous zinc chloride to afforded 3-chloro-4-(substituted phenyl)-1-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl)azitidin-2-ones (5a-e) and 3-[4-(4-methoxyphenyl)-1,3-thizol-2-yl]-2-substituted phenyl-1,3-thiazolidine-4-ones respectively (6a-e).

All synthesized compounds were purified by crystallization method and its purity was checked by TLC with suitable solvent system. The structures of all prepared compounds were established by using IR, ¹HNMR, mass spectra and analytical data. These compounds were screened for their antibacterial and antifungal activities and some of the compounds were exhibited good antibacterial and antifungal activity.

ACKNOWLEDGEMENT

The authors wish to express their sincere thanks to Sirse Krantikumar, Principal, Karnataka college of pharmacy Bidar and Channabasappa hallahali, president, management members of K.R.E. society’s Bidar for help during our research work. Thanks to Central University, Hyderabad for providing ¹HNMR and mass spectral data.

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Received on 04.06.2009 Modified on 08.08.2009

Asian J. Research Chem. 2(4):Oct.-Dec. 2009 page 440-444