SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF NEW SULPHONAMIDES OF PYRIMIDINE

Results of previous research on synthesis and biological properties of pyrimidine ring have demonstrated that the system is capable of extremely potent biological activity. The obtained derivatives revealed both cytostatic [1,2], immunomodulating [3,4] and first of all antibacterial [5,6,7] properties. That is why we found usefbl to carry out a number of syntheses aiming at obtaining 5-substituted pyrimidine sulphonamides.


Introduction
Results of previous research on synthesis and biological properties of pyrimidine ring have demonstrated that the system is capable of extremely potent biological activity.The obtained derivatives revealed both cytostatic [1,2], immunomodulating [3,4] and first of all antibacterial [5,6,7] properties.That is why we found usefbl to carry out a number of syntheses aiming at obtaining 5-substituted pyrimidine sulphonamides.

CHEMISTRY
The substrate in our studies was 4-aryl-6-methyl-2-phenyl-5-hydroxymethylpyrimidine (I), which after treatment with SOC12, was transformed into 2-aryl-6-methyl-Zphenyl-5chloromethylpyrimidine (2).Next 5-substituted pyrimidine sulphonamides were obtained by means of two methods.The first one consisted in treatment of 5-chlorderivative of pyrimidine 2 with aqueous solution of ammonia gave 5-aminoderivative 3, which was condensed with p-toluilosulphonic acid chloride giving adequate sulphonamides.The second method consisted in direct action of Nacetylsulfanilamide on 5-chloroderivative of pyrimidine 2. Despite of several trials, we failed to obtain double sulphonamides, compound 5.The arylaminegroup at site 4 of the pyrimidine ring does not react with sulphonic chlorides.
Physical and spectral properties of the compounds are given in Table 1.The obtained chemical compounds were examined from the point of view of their microbiological activity, which was assessed on selected bacterial strains.

Key words
Assessment of the activity of ivestigated substances was carried out according to FP V [8].Absolute activity was determined by defining lowest concentration able to inhibit the growth of bacterial stain (MIC) in fluid medium and wxpressed in micrograms (pg) of investigated substanced per 1 ml.Relative activity was determined MIC value of the investigated substance by MIC value of a pattern (Urenil, Erytromycin).Antibacterial potential was determined by means of cylinder-plate method assuming the average from 9 trials (3 weighed samples by 3 measurements).
The obtained results are presented in Table 2, 3.

RESULTS AND DISCUSSION
Seven newly obtained pyr~midine derivatives were studied microbiologically on 10 bacterial s t r a l n s Catldida alhicat~s.In comparison with the pattern (sulphonamide used in medicine -IJret~il), the obtained compounds have revealed interesting antibacterial as well as antihngal activity.Compounds 6b, 6d, 6e have revealed satisfactory antibacterial properties, however their activity increased significantly when the amine group in phenyl ring of sulphonamide group was deblocked from acetyl radical (compounds 7b, 7d, 7e).The activity decreased significantly if alkyl radical was used to replace the amino group in phenyl ring of sulphonamide group as in compound 4. Phenylamine substituent at site 4 of the pyrimidine ring also plays an important role.Substitution of p-chloroaniline, p-aminophenol or p-toluidine at carbon 4 of the pyrimidine ring increases significantly the antibacterial activity.The above mentioned derivatives reveal extremely potent properties of inhibiting the growth of Gram (+) Enterobacter faecalis, Gram (-) Pseudomonas aeruginosa, Gram (-) Klebsiella pneumoniae.

Expeimental
Melting points were determined in Kofler apparatus.
'H NMR spectra were recorded on BS-487-C, 80 MHz Tesla spectrometer.Infrared (IR) spectra were recorded in nujol with a Specord spectrophotometer at Analytical Laboratory of Medical Academy in Wroclaw.Elemental analyses indicated by the symbols were within +I-0.4% of the theoretical values.
4 g (1 2.9 mmol) of 6-methyl-2-phenyl-4-phenylamine-5-chloromethyl-pyrimidine (2) were added to 30 ml of 25% aqueous solution of ammonia.The mixture was heated under reflux condenser and stirred intensively throughout the process.After 5 h the postreaction mixture was diluted with 100 ml of water and three times extracted with chloroform.The chloroform extracts were combined, dried over MgS04 and after filtration vacuum condensed.Obtained oily product was crystallised from acetonechloroform 1: 1 mixture, giving 3.46 g (92.3%) of cream-white crystals with m.p. 1 17-1 19' C.