INTRODUCTION:

Quinazoline is a compound made up of two fused six-membered aromatic rings a benzene ring and pyrimidine ring. Its chemical formula is C₈H₆N₂. Quinazoline is yellow colour and found in the crystalline form. Quinazoline is a fused bicyclic compound earlier known as benzo-1,3diazine was first prepared in the laboratory by Gabriell in 1903, although one of its derivatives was earlier known much earlier.

The name quinazoline was proposed for this compound by Weddige, on observing that this was isomeric with the compounds cinnoline and quinoxaline. Paal and Bush suggested the numbering of quinazoline system, which is currently used. The other less commonly used names for this ring system are ‘phenmiazine' and 5,6-benzopyrimidine.

Depending upon the position of keto or oxo group, this compound may be classified into two types: 1,2-(1H) quinazolinone (or) 1,2- dihydro-2-oxo quinazolines,2,4(3H)-quinazoline or 3,4 dihydro-oxo quinazolines. These two system exhibits lactam-lactam tautomerism and undergo hydroxy group replacement reactions.

CHEMISTRY OF QUINAZOLINONE:

Common name: Quinazolinone and Quinazolindion. Chemical name is found to be Quinazolin-4(3H)-one (Chen et al., 2006), 4(3H)- Quinazolinone, 3,4-Dihydroquinazolin-4-one, (3H)-Quinazolone, 4-Oxo-3,4-dihydroquinazoline, 4-oxoquinazolinol, 4-Quinazolinone.Chemicals with two conjoined aromatic rings incorporating two nitrogen atoms and one of the carbons oxidized with keto oxygen. Quinazolinone is a heterocyclic chemical compound.There are two structural isomers, 2-quinazolinone and 4-quinazolinone, with the 4-isomer being the more common. Quinazolinones are also a class of drugs which function as hypnotic/sedatives that contain a 4-quinazolinone core. Their use has also been proposed in the treatment of cancer. Examples include

Aflaqualone, (B) Chloroqualone, and (C) Diproqualone. Alkaloids containing the qyuinazolinone core include Febrifugine and Halofuginone.

Quinazoline nucleus possessed the potent pharmacodynamics nucleus. In addition, several quinazoline derivatives possess diverse biological activities, anticonvulsants anti-inflammatory, hypnotics, diuretics, anti-hypertensive and antitubercular etc. Quinazoline system possess variable sites at 2 and 3 substituted by various heterocyclic moieties afford the potent anticonvulsant agent.

Furthermore, SAR study of different Quinazoline derivatives has revealed that the substitution at 2,3-position has a significant role on hypotensive, quinazoline and condensed quinazoline exhibit potent central nervous system (CNS)activities like anti-anxiety, analgesic, anti-inflammatory andconvulsant.Quinazoline-4-ones with 2,3-di substitution is reported to possess significant analgesic, anti-inflammatory, and anticonvulsant activities.

SYNTHESIS:

1. Quinoxaline is derived from naphthalene by replacement of one of its a –CH group by nitrogen. Second and third methylquinoline (quinaldine and lipidind), 2-quinolone (carbostril), 4-quinolone and the quinolium ion are important derivatives of quinoline.

2. Benzoxazines react with primary amines by exchanging the ring oxygen for nitrogen forming Quinazolinones.3,1-benzoxacin-2-4-diones isotonic anhydrides are prepared by cyclocondensation of anthranilic acid with phosgene or by a oxidation of indole -2-3-dipones with (peroxy acetic acid)

3. The chemical reaction of an anthranilic acid with amides to form 4-oxo-3,4-dihydroquinazoline.

EXPERIMENTAL⁶:

The melting points were taken in open capillary tubes in concentrated in melting point apparatus and therefore the values reported are uncorrected. UV spectra were recorded on Shimadzu 1700, UV-Vis spectrophotometer and spectral grade, ethanol was used as the solvent. The IR spectra of the compounds were recorded in the region, 4000-400 cm-1 using KBr discs on JASCO 4100 FTIR and the NMR spectral study was done using DMSO as the solvent on JOEL FX90Q, FOURIER transformNMR spectrometer. The purity of the compounds was checked by TLC, using plates coated with silica gel G, benzene: chloroform as mobile phase and iodine vapour as the detection method.

1. Synthesis of 3-(4-chloro phenyl) quinazolin-4(3H)-one:

An equimolar amount of 0.01 moles of anthranilic acid, HCHO, chloro aniline were mixed together and dissolved in 25ml of ethanol in RBF. The reflux mixture was stirred for 10 minutes and reflux for 5-7hrs.

The progress of the reaction was monitored by TLC. After the completion of the reaction, the flask content was poured into a 100ml of cold water to get corresponding 3 substituted quinazolones in the solid state. The product was further washed and dried over anhydrous calcium chloride followed by recrystallisation with ethanol.

2. Synthesis of 3-(4-fluro phenyl) quinazolin-4(3H)-one:

An equimolar amount of 0.01 moles of anthranilic acid, HCHO, fluoro aniline were mixed together and dissolved in 25ml of ethanol in RBF. The reflux mixture was stirred for 10 minutes and reflux for 5-7hrs.

3. Synthesis of 3-(4-nitro phenyl) quinazolin-4(3H)-one:

An equimolar amount of 0.01 moles of anthranilic acid, HCHO, nitro aniline was mixed together and dissolved in 25ml of ethanol in RBF. The reflux mixture was stirred for 10 minutes and reflux for 5-7hrs.The progress of the reaction was monitored by TLC. After the completion of the reaction, the flask content was poured into a 100ml of cold water to get corresponding 3 substituted quinazolones in the solid state. The product was further washed and dried over anhydrous calcium chloride followed by recrystallisation with ethanol.

4. Synthesis of 3-(4,4-dimethyl cyclohexa-1,5-dien-1-yl) quinazolin-4(3H)-one:

An equimolar amount of 0.01 moles of anthranilic acid, HCHO, N,N-dimethyl aniline were mixed together and dissolved in 25ml of ethanol in RBF. The reflux mixture was stirred for 10 minutes and reflux for 5-7hrs.

5. Antibacterial Study (Plate Hole Diffusion Method):

The ingredients were dissolved in water, adjust the pH is 7.4±0.2 and autoclave at 120°C for 20 mints.250µg/ml concentration of the test compounds are prepared and Dimethyl Sulphoxide was used as vehicle and gentamycin was used as the standard.

Nutrient agar plates were prepared aseptically to get a thickness of 5-6mm.The plates were allowed to solidify and inverted to prevent condensate falling on the agar surface. The plates were dried at 37°C just before inoculation.

The standard inoculums are inoculated in the plates prepared earlier aseptically by sterile swab in the inoculums, excess of inoculums removed by pressing and rotating the swab in the inoculums. Excess of inoculums removed by the level of the liquid and finally streaking the swab all over the surface of 60 after each application. Finally, press the swab round the edge of the agar surface. The sterilized discs for the test drugs were placed in the petriplates aseptically. Incubate the Petri plate at 37±0.2 for 18-24 hrs, after placing them in the refrigerator for 1 hr to facilitate uniform diffusion. The average zone diameter of the plates was measured and recorded. All compounds synthesized were tested for antibacterial activity against for gram (+ve) and gram(-ve) bacteria.

RESULTS AND DISCUSSION:

Table Showing Zone of Inhibition of Growth in Centimeter

Compound	Bacillus	E.coli
Standard	2.2cm	2cm
Control	1.4cm	1.3cm
Q-C1	1.3cm	1.3cm
Q-C2	1.6cm	1cm
Q-C3	0.9cm	2cm
Q-C4	1cm	2.1cm

Graph Showing the Zone of Inhibition of Microbial Growth Produced By Different Compound with Gentamycin at 250µg/ml

3-(4-chloro phenyl) quinazolin-4(3H)-one:

Q-CI :3056 (Ar-H), 1710 (C=O):1660(C=N):1570(C-N):812(C-Cl),H¹NM,R 7.8(dd,2H,Ar-H) : 7.5(dd,2H, Ar-H): 7.2(m,4H, Ar-H): 8.3(S,1H, Ar-H.)

3-(4-fluro phenyl) quinazolin-4(3H)-one:

Q-C2: 3054(Ar-H),1708 (C=O): 1658 (C=N): 1568(C-N):410(C-Br): H¹NM, R, 7.7(dd,2H, Ar-H),7.4(dd,2H,Ar-H).7.1(m, 4H. Ar-H),8.2 (S, 1H, Ar-H).

3-(4-nitro phenyl) quinazolin-4(3H)-one:

Q-C3: 3060(Ar-H), 1710(C=O):1662(C=N):1567(C-N):1420(N=O), H¹NM, R, 7.9(dd,2H,Ar-H),7.6 (dd,2H,Ar-H).7.2 (m, 4H. Ar-H),8.1 (S, 1H, Ar-H).

3-(4,4-dimethyl cyclohexa-1,5-dien-1-yl) quinazolin-4(3H)-one:

3048 (Ar-H) 1708(C=O):1658(C=N):1568(C-N):2840(R-H)., H¹NM, R , 7.3(m, 8H.Ar-H),8.0 (S, 1H, Ar-H), 2.2(S, 3H,-CH₃)

CONCLUSION:

The synthesis of various 3 substituted -4(2H) quinazolinone was carried out by the reaction of anthranilic acid and various primary aromatic amines with formaldehyde and percentage yield was found to be 70-84%. Antibacterial activity was studied by using plate hole diffusion method and measured inhibition zone in centimeter using bacillus and E.coli and compared with Gentamycin as standard.

The compounds posses good antibacterial activity. The compounds Q-C1, Q-C2, Q-C3 and Q-C4 have ability to inhibit growth of bacteria. The compounds Q-C1 and Q-C2 have good antibacterial activity against bacillus microorganism. The compounds Q-C3 and Q-C4 have good antibacterial activity against E.coli.

The IR absorption of cyclic keto group appears at 1705-1710 cm^-1. The appearance of IR bands at 1655-1662 and at 1565-1570 cm^-1 has confirmed the C=N and C¬N bonds in the products. The aromatic protons have shown the absorption at 3046-3060 cm^-1 with the variation of substitutions. The other substitutions and the functional groupshave shown their characteristic absorptions in IR spectra. All the aromatic protons have shown value at 7.1-7.8 ppm according to the variations of substituents in the aromatic rings. One of the protons in the diazo-ring has shown 1H NMR signal at 7.9-8.3 ppm which is much down field in comparison to other aromatic protons and is justified as the proton is present on the carbon atom in between two nitrogen atoms in the heterocyclicring of the products (Q-C1, Q-C4). The aliphatic protons on substituent groups have shown their characteristic signals in 1H NMR spectra.

A further modification of these molecules can be initiated which would open a new era in developing more therapeutically effective agent against microbial.

ACKNOWLEDGEMENT:

The authors are grateful to the Principal and Management of Grace College of Pharmacy, Palakkad, for Providing support and necessary facilities.

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Received on 22.06.2017 Modified on 10.07.2017

Asian J. Research Chem. 2017; 10(4):577-581.

DOI:10.5958/0974-4150.2017.00096.7