INTRODUCTION:

Number of organo sulfur and nitrogen containing compounds are present in living and non-living objects they belong to open chain, alicyclic, aromatic and heterocyclic compounds containing sulphur and nitrogen atoms as a part of chain/ring or both in structure .Among the hetero cyclic compounds containing sulphur, the six and five numbered hetero cyclic compounds containing sulphur and nitrogen has attracted maximum attention as they are full of many ramification especially in the biological and industrial application. Thiazole nucleus particularly is the center of attraction in developing various essential substances in technology and in industries^.The thiazole ring is present along with the quinazoline ring in various marine or terrestrial natural compounds. The main aim is synthesis of combined phenothiazole and quinazoline derivatives in particular as an anti-microbial agent has attracted a special interest^9-10.The structure of the synthesized compounds were established on the basis of IR, H NMR of respective compounds.

ANTIMICROBIAL SCREENING:

The compounds D1 to D4 were screened for their antimicrobial activity against Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) by Filter paper disc method at100 μg per ml Concentration in Dimethyl sulfoxide using amikacin disc (30 μg per disc) as a standard for compression. Thus their average percentage of inhibitions were (76-88) against E.coli and (67-80) against S.aureus.

EXPERIMENTAL:

The melting points of the synthesized compound were found out by open capillary tube method and result was uncorrected. The purity of compound were checked by TLC using silica gel G as an adsorbent. The structure of the synthesized compound was characterized by FT-IR (SHIMADZU) and proton NMR (BRUKER300AV) spectral analysis in which it complies with the normal values.

Synthesis of 4-phenylthiazol-2-amine (I):

A mixture consisting of 0.03 mole of acetophenone preferably liquid, 0.2 mole of thiourea, in 100 ml of ethanol were added, and bromine 0.01 mole added drop wise very slowly. After the addition of bromine the reaction mixture was heated on water bath for 12 hours, and the water was added to it and again heated until most of the solid has gone into solution. The reaction mixture was filtered when hot the filtrate was cooled. It was made alkaline with concentrated ammonium hydroxide to separate 2-amino-4-phenylthiazole. The product was filtered, washed with alcohol. It was recrystallized from ethanol as colorless needles, m.p. 110-113⁰C. (80%). IR (KBR) CM^-1: 3361.69, 3311.55 (NH₂);

H NMR (CDCl₃) δ: 7.24-7.52 (m,5H ArH),6.8(m,1H thiazole),4.25(s,2H NH₂exchangeble with D₂O).

SCHEME

Antibacterial activity of derivatives

S. No.	Compound	Zone of inhibition (%)
S. No.	Compound	*E. coli*	*S. aureus*
1	D₁	76.47	80.00
2	D₂	88.23	73.33
3	D₃	82.35	66.66
4	D₄	82.35	73.33
Solvent	DMSO	00 .00	00 .00
Standard.	Amikacin	100.00	100.00

N-chloroacetyl anthranillic acid (II):

In a 250 ml round bottled flask 6.5 gm (0.06 mole) of anthranillic acid was dissolved in 100 ml of benzene with two or three drops of pyridine. Add 4 ml (0.06 moles) of chloroacetyl chloride in dry benzene under the cold condition and reflux it for 4-5 hrs. Cool and filter, thus the solid obtained was recrystallized from acetone-ethanol mixture (1:1). Melting range 167-169⁰C and the percentage of yield found to be 72%. IR (KBR) CM^-1: 3225 (NH),1688 (CO); H NMR (CDCl₃) δ:10.62 (m,1H COOH exchangeable),7.18-7.8 (m,4H ArH),8.3 (s,1H CONH),3.8 (s,2H CH₂Cl).

2(chloromethyl)-3-[4-phenylthiazol-2-yl] quinazolin-4(3H)–one (III):

N-chloroacetyl anthranillic acid (II) 2.14 gm. (0.01 moles) was refluxed for 6 hrs. with 1.98 gm (0.01 mole) of 4-phenylthiazol-2-amine (I) in the presence of 10 gms of K₂CO₃in 100 ml of dry ethanol under anhydrous condition. The reaction mixture was filtered, ethanol extract was evaporated. The residue washed thoroughly with boiling water. Recrystallized from acetone-ethanol mixture (1:1) Melting range 195-197⁰C, the percentage of yield was found to be 57.50%. IR (KBR) CM^-1: 1643 (CO); H NMR (CDCl₃) δ: 6.95-7.85 (m, 9H ArH), 6.75 (m 1H thiazole), 3.75 (s, 2H CH₂Cl).

N-3-[ 4-phenylthiazol–2–yl ]-[ 2-( substituted amino) methyl ] quinazoline–4 (3H)-one derivatives (IV):

2(chloromethyl)-3-[4-phenylthiazol-2-yl]quinazolin 4(3H)–one(III) (0.01 mole) and respective amine(toluidine, p-amino benzoic acid, p-amino phenol, p-amino pyridine) (0.01 mol) was refluxed in 4 ml of dry pyridine and 20 ml of acetic anhydride for 4 hrs. The excess solvent was distilled off. The mixture was cooled and poured into crushed ice. The product was filtered and recrystallized from the ethanol.

D1: Melting range 139-141⁰C, the percentage of yield was found to be 52.50%. IR (KBR) CM^-1: 3170.76 (NH), 1642.42 (CO); H NMR (CDCl₃) δ: 6.3-7.9 (m, 13H ArH),6.75 (m, 1H thiazole),4.58 (s,1H NH),2.51 (m, 3H Ar-CH₃),3.32 (s, 2H CH₂).

D2: Melting range 145-147⁰C, the percentage of yield was found to be 47.00%.

IR (KBR) CM^-1: 3170.76 (NH),1642.42 (CO),3368.53 (OH) ; H NMR (CDCl₃) δ: 6.3-7.9 (m, 13H ArH),6.75 (m, 1H thiazole),4.58 (s,1H NH),,3.32 (s, 2H CH₂),10.73 (m,1H COOH).

D3: Melting range 156-158⁰C, the percentage of yield was found to be 53.00%.

IR (KBR) CM^-1: 3410.47 (OH), 1643.2 (CO), 43170.76 (NH); H NMR (CDCl₃) δ: 6.3-7.9 (m, 13H ArH), 6.75 (m, 1H thiazole), 4.58 (s, 1H NH), 3.32 (s, 2H CH₂) 5.78 (m, 1H OH exchangeable).

D4: Melting range 133-135⁰C, the percentage of yield was found to be 48.5%.

IR (KBR) CM^-1: 3170.76 (NH), 1643.24(CO); H NMR (CDCl₃) δ: 6.5-7.9 (m, 13H ArH), 6.75 (m, 1H thiazole), 4.43 (s, 1H NH), 3.32 (s, 2H CH₂).

CONCLUSION:

This work indicates that the combination of phenylthiazole and quinazoline, is an efficient route for synthesizing 2- [(Substituted amino) methyl] 3-[4-phenylthiazole – 2 – yl] quinazolin – 4(3H) – one and its derivatives. The synthesized compounds exhibit good antibacterial activity.

Therefore it was concluded that there is a vast scope for quinazoline and thiazoles combination as effective anti-microbial agents.

REFERENCES:

1. N. Kharasch. ”charge transfer properties of sulfur compounds and heterocylic sulfur compounds” Mechanism of Reaction of sulfur compounds. Intra Science Research foundation Santa Monica, California.1966and1975, Vol 2, P.11-12 and 249-250.

2. H.W. Roesky. “The sulfur-nitrogen bond” Sulfur in Organic and Inorganic chemistry, 1971, Vol. No.1, P. 14-16.

3. G.W.Gribble, “Recent development in troger’s base chemistry”, Programme in heterocyclic chemistry, 2001, vol.11, p.1-10.

4. Michael J. Pucci, Joanne J.Bronson. “Anti-microbial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics”, American chemical Society for Microbiology, 2004, Vol 48 and10, P.3697-3701.

5. Tayare T. “Synthesis and Biological Activities of Substituted Aminothiazole”, Journal of Heterocyclic Chemistry, 1980, Vol.17. P.190-205.

6. Schantten Kirchener, “Synthesis and Biological Activities of N,N Substituted Quinazoline”, Journal of Organic Chemistry, 1978, Vol.28. P.270-277.

7. Komastu A., “Synthesis and Antimicrobial Activity of Benzo-quinazoline and Their Ribosides”, Bioorganic and Medicinal Chemistry, 1972. Vol.5, P.130-134.

8. Thierry Besson, Jerome Guillard and Charles W.Rees., “Multistep synthesis of thiazoloquinazolines under microwave irradiation in solution”, Tetrahedron Letters, 2000, Vol. 41, P.1027–1030.

9. Yadgiri Bathini, Inderjit Sidhu, Rajeshwar Singh, Ronald G. Micetich and Peter L. Toogood, “Synthesis of substituted quinazolines”, Tetrahedron Letters, 2002, Vol.43, P.3295–3296.

10. Stephane Frere, Valerie Thiery, Christian Bailly and Thiery Besson, “Novel 6-substituted benzothiazol-2-yl indolo[1,2-c]quinazolines and benzimidazo[1,2-c]quinazolines”, Tetrahedron, 2003, Vol. 59, P. 773–779.

Received on 27.08.2009 Modified on 29.09.2009

Asian J. Research Chem. 2(4):Oct.-Dec. 2009 page 544-546