Studies on Synthesis of Some Novel Heterocyclic Azlactone Derivatives and Imidazolinone Derivatives and their Antimicrobial Activity

p Methyl benzoic acid on reaction with phosphorus pentachloride gives p methyl benzoyl chloride derivative which on condensation with glycine gives p methyl benzoyl glycine derivative. Now, this p methyl benzoyl glycine derivative on condensation with various substituted aldehydes gives corresponding substituted 4 [aryl methylidine] 2 [p methyl phenyl] oxazole 5 one derivatives [1(a-j)]. Further, these derivatives [1(a-j)] on condensation with 4 , 4’ diamino diphenyl sulphone gives corresponding substituted imidazolinone dibenzsulphone derivatives [2(a-j)], on condensation with 4 , 4’ diamino diphenyl methane gives corresponding substituted imidazolinone dibenzmethane derivatives [3(a-j)], on condensation with 4,4’diamino benzanilide gives corresponding substituted imidazolinone benzanilide derivatives [4(a-j)] and on condensation with 2 amino pyridine gives corresponding substituted imidazolinone pyridine derivatives [5(a-j)] respectively. Structure elucidation of synthesised compounds has been made on the basis of elemental analysis, I.R. spectral studies and H N.M.R. spectral studies. The antimicrobial activity of the synthesised compounds has been studied against the cultures “Staphylococcus aureus”, “Escherichia coli” and “Candela albicans”.


Introduction
The study incorporates the topic "AZLACTONE" because it provides a basic skeleton structure and which is also a part of a great importance for its drug Characteristics.The basic nucleus imidazole emerges from the drug intermediate azlactone.The azlactones possess oxazolone moiety.The azlactones are known to exhibit antifungal 1 , antibacterial 2 and anti-inflammatory activities.They are also of great importance to produce penicillin type of drug intermediates 3 and they are also useful to produce synthetic hormonal compounds 4 - 5 .
Imidazole is a planer five-membered heterocyclic ring system with three carbon and two nitrogen atoms in 1 and 3 positions.Imidazolones are keto dihydro imidazoles.Imidazolone that is known as oxoimidazoline is a five-membered heterocyclic ring system having nitrogen atoms in 1 and 3 positions and carbonyl group in 5 position.Oxoimidazoline, which is also known as imidazolinone is reported to exhibit a wide variety of therapeutic activities such as sedative, hypnotic, CNS depressant 6 etc. Imidazolinone derivatives have also been reported to possess antihistaminic 7 , antihypertensive 8 and antiparkinsonian 9 activities.
All these observations and the essential role of heterocyclic azlactone derivatives and imidazolinone derivatives, in certain biological reactions prompted us to synthesise all these heterocyclic derivatives [1(a-j) to 5(a-j)].

Experimental Preparation of p -Methyl Benzoyl Chloride Derivative
A mixture of p -methyl benzoic acid (0.10 mol) and phosphorus pentachloride (0.12 mol) was placed in a round -bottomed flask and the reaction mixture was refluxed in an oil bath at 120-130 o c gently for about 2-3 hours.The reaction mixture was then allowed to cool and the phosphorus oxychloride was removed by distillation.The temperature of an oil bath was raised again up to 110 o c and the residual p -methyl benzoyl chloride was solidified on cooling, which was recrystallised from carbon tetrachloride.M. P. 108 o C., Yield 85%.

Preparation of p -Methyl Benzoyl Glycine Derivative-
A glycine (0.10 mol) was dissolved in a 100 ml of 10% sodium hydroxide solution and to it, p -methyl benzoyl chloride (0.12 mol) was added portion-wise and the reaction mixture was shaked vigorously after each addition until all the chloride has been reacted.The reaction mixture was then poured over crushed ice and acidified with concentrated HCl with constant stirring until the reaction mixture was acidic to Congo red paper.The resulting precipitate of p -methyl benzoyl glycine so obtained was filtered, washed several times with cold distilled water, dried and crystallised from carbon tetrachloride.M. P. 184 o C., Yield 76%.

Preparation of 4 -[Phenyl Methylidine] -2 -[p -Methyl Phenyl] -Oxazole -5 -One Derivative [1(a)]
A mixture of benzaldehyde (0.01 mol), p -methyl benzoyl glycine (0.01 mol), acetic anhydride (0.03 mol) and anhydrous sodium acetate (0.01 mol) was taken in a 500 ml.conical flask and the reaction mixture was heated on an electric hotplate with constant shaking.As soon as the reaction mixture has been liquefied completely, the conical flask was transfered to a water bath and heated for about 2-3 hours.Then ethanol (50 ml) was added slowly to the contents of the conical flask and the reaction mixture was allowed to stand overnight.The resulting precipitate so obtained was filtered, washed with ice-cold ethanol (25 ml) and then with boiling water, dried and crystallised from benzene.M. P. 166 o C., Yield 65%.
Similarly, the remaining substituted oxazolone derivatives [1(b-j)] were prepared by the same procedure as discussed above.
Physical and Analytical data of compounds [1(a-j)] are presented in Table-1 and Antimicrobial data of compounds [1(a-j)] are presented in Table-6.
Similarly, the remaining substituted imidazolinone -dibenzsulphone derivatives [2(b-j)] were prepared by the same procedure as discussed above.
Physical and Analytical data of compounds [2(a-j)] are presented in Table-2 and Antimicrobial data of compounds [2(a-j)] are presented in Table -7.
Similarly, the remaining substituted imidazolinone -dibenzmethane derivatives [3(b-j)] were prepared by the same procedure as discussed above.
Physical and Analytical data of compounds [3(a-j)] are presented in Table -3 and Antimicrobial data of compounds [3(a-j)] are presented in Table -8.
Similarly, the remaining substituted imidazolinone -benzanilide derivatives [4(b-j)] were prepared by the same procedure as discussed above.
Physical and Analytical data of compounds [4(a-j)] are presented in Table -4 and Antimicrobial data of compounds [4(a-j)] are presented in Table -9.
Similarly, the remaining substituted imidazolinone -pyridine derivatives [5(b-j)] were prepared by the same procedure as discussed above.
Physical and Analytical data of compounds [5(a-j)] are presented in

Antimicrobial Activity
Antimicrobial activity of newly synthesised compounds was studied against gram-positive bacteria "Staphylococcus aureus" and gram-negative bacteria "Escherichia coli" (for antibacterial activity) and against the culture "Candela albicans" (for antifungal activity).The antimicrobial screening was carried out by cup -plate method 10 at a concentration of 50 µg/mL in solvent D.M.F.The zone of inhibition was measured in mm.The antimicrobial activity of the synthesised compounds was compared with standard drugs Ampicillin, Penicillin and Tetracycline at the same concentration.

Results and Discussion
The antimicrobial activities of newly synthesised compounds were compared with known antibiotics like Ampicillin, Penicillin and Tetracycline and all the compounds show moderate to good activity.Structure elucidation of synthesised compounds has been made on the basis of elemental analysis, I.R. spectral studies and 1 H N.M.R. spectral studies and all the compounds gave satisfactory elemental analysis, I.R. and 1 H N.M.R. spectral measurements.

Table - 5
PHYSICAL AND ANALYTICAL DATA OF COMPOUNDS [5(a-j)] Table -5 and Antimicrobial data of compounds [5(a-j)] are presented in Table -10.

Table - 6
ANTIMICROBIAL DATA OF COMPOUNDS [1(a-j)]All melting points were determined in open capillaries in a liquid paraffin bath and are uncorrected.The I.R. spectra were recorded with KBr pellets on Shimadzu FT-IR 8300 spectrophotometer and 1 H N.M.R. spectra were recorded on a Varian Geminy 200 MHz spectrophotometer with CDCl 3 / DMSOd 6 as a solvent using tetramethylsilane (T.M.S.) as an internal standard; the chemical shift values are in δ ppm.The purity of the compounds was checked by thin layer chromatography (T.L.C.) on silica gel coated glass plates.The elemental analysis (i.e.C, H and N analysis) has been done on Perkin -Elmer model 240 B CHN analyzer and the values are within the permissible limits (i.e.+ 0.5) of their calculated values.