chemical modification of these compounds have led to a large number of mono- and di - s and n - substituted analogs showing therapeutic properties , especially antivirial , antithyroid , and antitumor activities [ 17 ] .
the antimetabolites of 5,6-dimethyluracil 5-morpholinomethyl-6-methyl-2-thiouracil   and 5-piperidinomethyl-6-methyl-2-thiouracil   have been synthesized via the mannich reaction . however , to the best of our knowledge no work has been published on the synthesis as well as on physicochemical properties of the monochlorobenzylthio - substituted derivatives of these compounds . this fact has stimulated us to investigate the reaction of chlorobenzylation of 2-thio-5-piperidinomethyl-6-methylthiouracil and 2-thio-5-morpholinomethyl-6-methylthiouracil as well as the mannich reaction of 2-o-(m- and p-)chlorobenzylthio-6-methylthiouracils , formaldehyde , and piperidine ( or morpholine ) .
recently novel pharmacological action of 2,4-di - o-(m- and p-)bromo-(chloro- and nitro-)benzylthio-5-bromouracils ( and 6-methyluracils )   as well as disulfides of n , o-(n , n- or o , o-)-di- and n , n , o - tri-(o- , m- and p-)-bromobenzyl-2-thiouracils   has been found on the basis of the computer - aided drug discovery approach with the compounds program prediction of activity spectra for substances ( pass ) [ 1215 ] . since only the structural formula of the chemical compound is necessary to obtain a pass prediction , this approach was used in the present work . this paper deals with the synthesis and physicochemical properties of 16 .
additionally , the analysis of biological activity spectra prediction for 16 made in this paper is a good example of in silico studies of chemical compounds .
a series of six new 2-o-(m- and p-)chlorobenzylthio-5-piperidinomethyl-6-methyluracils 13 and 2-o-(m- and p-)chlorobenzylthio-5-morpholinomethyl-6-methyluracils 46 were synthesized by the reaction of 2-thio-5-piperidinomethyl-6-methyluracil or 2-thio-5-morpholinomethyl-6-methyluracil in 3  n naoh in methanol with o-(m- and p-)chlorobenzyl chlorides at room temperature for 24  h ( scheme 1 ) .
compounds 1 , 3 , 4 , and 6 were also produced in well - known mannich reaction   from 2-o-(and p-)chlorobenzylthio-6-methyluracils   when refluxed with paraformaldehyde and piperidine ( or morpholine ) in ethanol ( scheme 2 ) .
compounds 2 and 5 were not produced in the mannich reaction of relatively soft 2-m - chlorobenzylthio-6-methyluracils with paraformaldehyde and piperidine ( or morpholine ) when heated in ethanol ( scheme 2 ) .
the 2 o-(m- and p-)chlorobenzylthio - containing compounds 16 were confirmed by examination of their uv / vis , ft - ir , h nmr and c nmr spectra ( tables 1 and 2 ) , and hmbc ( table 3 ) as well as elemental analyses ( table 4 ) .
the h nmr and c nmr data of 16 are given in tables 1 and 2 , respectively .
assignments of the h nmr and c nmr resonances of these compounds were deduced on the basis of the signal multiplicities and by the corrected application of two - dimensional nmr technique h - h cosy and hmbc .
the singlets of c5ch2 of 16 are situated at 3.283.58  ppm , and the singlets of c6ch3 of 16 are situated at 2.222.33  ppm , respectively .
the cnmr spectra of compounds 16 in dmsod6 showed characteristic signals in the range of 31.5532.81  ppm and 53.0453.71  ppm assigned to s  ch2 and n  ch2 , respectively .
the thiouracil ring exhibited signals in the range 110.01114.71  ppm and 158.81162.11  ppm assigned to c5=c6 , respectively .
the c nmr spectra of compounds 16 showed the presence of a methyl group from the 6-methyl-2-thiouracil ring at 20.9021.30  ppm .
the hmbc spectrum clearly shows the connectivities of all hydrogen and carbon atoms involved , including quaternary carbons .
the hmbc results allow an unequivocal assignment of s - substitution of benzyl group at uracil ring of 16 ( table 3 ) .
the hmbc experiment is conducted without c decoupling so that correlations via one or more bond can be discerned and one - bond correlation affords double cross - peaks in the h dimension . for compounds
16 the h nmr spectrum exhibits three singlets at 4.294.46 , 3.283.58 , and 2.222.33  ppm ascribed to protons of s 
the hmbc of 16 shows peaks corresponding to two - bond correlations for c6ch3/c6 ( 158.81162.11  ppm ) and three - bond correlations for s 
the ft - ir spectra of 16 show absorption bands of medium intensities in the region 809820  cm assigned to  c  cl vibration as well as in the region 10351091  cm assigned to  c  cl vibration ( table 1 ) .
the ft - ir spectra of 16 show also absorption bands in the region 28522864  cm assigned to  ch2s as well as in the region 14441447  cm assigned to  ch2s vibration ( table 1 ) .
the uv / vis spectra of 16 show max in the range 245250 nm ( table 1 ) . in the present paper
the biological activity spectra were predicted for all six synthesized compounds ( 16 ) using pass [ 1215 ] .
we have also selected the types of activities that were predicted for a potential compound with the highest probability ( focal activities ) .
the most frequently predicted types of biological activities are antiviral ( influenza ) , antiseborrheic , and prolyl aminopeptidase inhibitor .
it ought to be pointed out that in the series of compounds 1 , 3 and 6 such activity as mucomembranous protector has also been predicted , as well as in the series of compounds 2 , 3 , 5 , and 6 such activity as prolyl aminopeptidase inhibitor .
the reaction of 2-thio-5-piperidinomethyl-6-methyluracil and 2-thio-5-morpholinomethyl-6-methyluracil with o-(m- and p-)chlorobenzyl chlorides in 3  n naoh in methanol at room temperature leads to 2-o-(m- and p-)chlorobenzylthio-5-piperidinomethyl-6-methyluracils 13 and 2-o-(m- and p-)-chlorobenzylthio-5-morpholinomethyl-6-methyluracils 46 .
the mannich reaction of 2-o-(and p-)chlorobenzylthio-6-methyluracils with paraformaldehyde and piperidine ( or morpholine ) refluxed in ethanol leads to 1 , 3 , 4 , and 6 .
the results obtained by pass method of identification of the prospective pharmacological properties of 16 exhibit the possibility of finding new pharmacological agents from this class of compounds .
the purity of all described compounds was checked by melting points , tlc , and elemental analyses .
rf values refer to silica gel f254 tlc plates ( merck ) developed with chcl3  :  ch3oh ( 10  :  1 ) and observed under uv light (  = 254 and 366  nm ) .
uv / vis spectra were recorded with a specord uv / vis spectrophotometer in methanol . ir spectra were recorded with ft - ir bruker ifs-113 spectrophotometer in kbr pellets .
the h nmr ( 300  mhz ) and c nmr ( 75  mhz ) spectra were determined with varian gemini 300 spectrometer in dmsod6 solution at a concentration between 0.25 and 0.40  m in the 5  mm sample tubes at ambient temperature .
2-thio-5-piperidinomethyl-6-methyluracil , 2-thio-5-morpholinomethyl-6-methyl - uracil , and 2-o-(m- and p-)-chlorobenzylthio-6-methyluracils   have been obtained according to the literature .
the synthesis of 2-o-(and p-)chlorobenzylthio-5-piperidinomethyl-6-methyluracils ( 1 and 3 ) and 2-o-(and p-)chlorobenzylthio-5-morpholinomethyl-6-methyluracils ( 4 and 6 ) is as follows .  
general procedure a : 0.2  g ( 0.8  mmole ) of 2-thio-5-piperidino-(morpholino-)-methyl-6-methyluracils [ 8 , 9 ] was dissolved with stirring in room temperature in 2.5  ml of 3  n naoh in methanol .
next , to the solution 0.116  ml ( 0.9  mmole ) of o - chlorobenzyl chloride or 0.146  g ( 0.9  mmole ) of p - chlorobenzyl chloride was added . after stirring at room temperature for 24 hours
the synthesis of 2-m - chlorobenzylthio-5-piperidinomethyl-6-methyluracils ( 2 ) and 2-m - chlorobenzylthio-5-morpholinomethyl-6-methyluracils ( 5 ) is as follows .  
general procedure a : 0.2  g ( 0.8  mmole ) of 2-thio-5-piperidino-(morpholino-)methyl-6-methyluracils [ 8 , 9 ] was dissolved with stirring in room temperature in 2.5  ml of 3  n naoh in methanol .
next , to the solution 0.116  ml ( 0.9  mmole ) of m - chlorobenzyl chloride was added .
the reaction mixture was stirred in room temperature for 24 hours and after that time 5  ml distilled water was added .
the obtained crude product was collected by filtration , washed with distilled water , and dried in the exicator .
the obtained dry solid was dissolved in 10  ml of chcl3 and separated by silica gel column chromatography ( merck 203400 mesh ) using the following solvent mixtures : chcl3  :  ch3oh 50  :  1 ( 40  ml ) , 40  :  1 ( 40  ml ) , 30  :  1 ( 30  ml ) , 20  :  1 ( 30  ml ) , and 10  :  1 ( 20  ml ) . the fractions of 20  ml were collected . on the basis of analytical tlc fractions of product desired were obtained by combining 20 ml fractions .
the synthesis of 2-o-(and p-)chlorobenzylthio-5-piperidinomethyl-6-methyluracils ( 1 and 3 ) and 2-o-(and p-)chlorobenzylthio-5-morpholinomethyl-6-methyluracils ( 4 and 6 ) is as follows .  
general procedure b : a mixture of 0.1  g ( 0.38  mmole ) 2-o-(or p-)chlorobenzylthio-6-methyluracils , 0.024  g ( 0.4  mmole ) paraformaldehyde , and 0.0035  ml ( 0.4  mmole ) morpholine ( or 0.0046  ml , 0.4  mmole piperidine ) was suspended in 6  ml of ethanol ( 99.8% ) and refluxed for 8 hours .
the precipitated solid was isolated by filtration , dried in room temperature , and recrystallized from methanol .
 six new 2-o-(m- and p-)chlorobenzylthio-6-methyl-5-piperidino-(or morpholino- ) methyluracils have been prepared . 
 the structures of these compounds were confirmed by spectroscopic ( ft - ir , uv - vis , 1h nmr , 13c nmr , and hmbc ) and elemental analyses . 
 estimation of pharmacotherapeutic potential has been made for synthesized compounds on the basis of prediction of activity spectra for substances ( pass ) . 
1. Introduction
2. Results and Discussion
3. Conclusions
4. Experiment