Australian Journal of Basic and Applied Sciences, 4(1): 27-36, 2010 ISSN 1991-8178 © 2009, INSInet Publication
Synthesis and Evaluation of Some Tetrahydropyrimidine Derivatives as Antimicrobial 1
Omar Abd El-Fattah, 2 Eman Mostafa Hassan Abbas., 1Neama Ahmed Mohamed and 3Sherien. I. Abd-Elmoez
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Medicinal Chemistry Department, National Research Centre, Dokki, Cairo- Egypt 2 Department of Natural Product, National Research Centre, Dokki, Cairo- Egypt 3 Department of Microbiology and immunology, National Research Centre, Dokki, Cairo, Egypt Abstract: In the present investigation, it was of interest to synthesize some new derivatives containing 5-acetyl-4-(3,4-dimethoxyphenyl)-6-methyl 2-oxo- 1,2,3,4-tetrahydropyrimidine moiety incorporated with different biologicaly active heterocycles such as pyridon,iminopyridines,thiazolidinones,chalcones and 2-alkoxypyridines derivati ves. the antimicrobial activity of some compounds were studied.results revealed that chemical compound no.6a (100µg/ml) gives the highest antimicrobial activity against all tested strain with a mean zone of inhibition equal 8.5mm followed by 3a,5a and 6b(100µg/ml);7.0mm then 9b (100µg/ml);6.63mm then7b (100µg/ml);6.38mm and 7a,9a and 8a (100µg/ml);4.25,4.24 and 4.1mm respectively.compounds no.6a,6b and 5a were highly effective against ps.orginosus then B.Cereus followed by L.mono cytogene and A.flavus. Key words: Tetrahydropyrimidine, Pyridine and Thiazolidinone derivatives, Antimicrobial activity. INTRODUCTION Pyrimidine derivatives play a vital role in many biological processes. (Sadanandam et al,1992) The ring system being present in nucleic acids, several vitamins, coenzymes, uric acid, purines and some marine microorganisms (e.g. Sponge). (Kashman et al,1989) M any synthetic members of pyrimidine are also important as synthetic drugs (e.g. Barbituric acid derivatives) and chemotherapeutic agents (e.g. Sulfadiazine). The 4-aryl1,2,3,4-tetrahydropyrimidines has been given the name Biginelli compounds. The main interest in Biginelli compounds, however, is due to the strong antihypertensive activity exhibited by certain derivatives. Also, a large number of substituted pyrimidines has been maintained to have several biological activities. (Attia et al 1983) Guided by the above observations and in continuation of our previous work in the direction of the synthesis of bioactive compounds. (Fakhr et al, 2008) We report here a convenient synthesis of functionalized chalcones, pyridine and thiazolidinone derivatives incorporating pyrimidine moiety as a common structural subunit. M ATERIAL AND M ETHODS All melting points are uncorrected and measured using Electro-thermal IA 9100 apparatus, (Shimadzu, Tokyo, Japan). IR spectra were recorded as potassium bromide pellets on a Perkin-Elmer 1650 spectrophotometer (Perkin-Elmer, Norwalk, CT, USA). 1H NM R was determined on a Jeol-Ex-300 NMR spectrometer (JEOL, Tokyo, Japan) and chemical shifts were expressed as part per million; ppm ( values) against TM S as internal reference. Mass spectra were recorded on VG 2AM-3F mass spectrometer (Thermo electron corporation, USA) M icroanalyses were operated using Mario El Mentar apparatus, Organic Microanalysis Unit, and the results were within the accepted range (± 0.20) of the calculated values. Follow up of the reactions and checking the purity of the compounds was made by TLC on silica gel-precoted aluminum sheets (Type 60 F254, Merck, Darmstadt, Germany). General Method for Preparation of Im inopyridines (2a-c): A mixture of compound 1 (2.90 g, 0.01 mole), malononitrile (0.6 mL, 0.01 mole), anhydrous ammonium acetate (6.10 g, 0.8 mole) and the appropriate aldehydes namely: p-hydroxybenzaldehyde, 4-hydroxy-3methoxybenzaldehyde (vaniline) and o-hydroxybenzaldehyde (salicylaldehyde) (0.01 mole) in butanol (30 mL) Corresponding Author: Eman Mostafa Hassan Abbas., Department of Natural Product, National Research Centre, Dokki, Cairo- Egypt E-mail:
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010 was refluxed for 3-5 h. After cooling, the reaction mixture was filtered off and recrystallized from the proper solvent to give the compounds 2a-c. 1 ,2 -D ih yd ro -6 -(1 ,2 ,3 ,4 -te tra hyd ro -4 -(3 ,4 -d im etho x yp h e nyl)-6 -m e thyl-2 -o x o p y r im id in-5 -yl)-4 -(4 hydroxyphenyl)-2-iminopyridine-3-carbonitrile (2a) Crystallized from ethanol to give pale yellow powder with m.p. 160-163 ºC and yield 65%. IR spectrum (KBr, , cm -1 ): 3480-3240 (OH), 3400 (NH), 2215 (CN), 1710 (CO), 1610 (C=N), 1580 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 2.12 (3H, s, CH3), 3.85 (6H, s, 2OCH3), 5.41 (1H, s, C4-H), 6.70-7.50 (8H, m, Ar-H including 1H of the iminopyridine), 9.25, 9.60, 10.35, 11.80 (4H, 4s, 4NH, D2O exchangeable) and 13.10 (1 H, s, OH, D2O exchangeable); Analysis for C25H23N5O4 (457.48): required C, 65.63; H, 5.07; N, 15.31; found C, 65.59; H, 5.13; N, 15.35. 1,2-Dihydro-6-(1,2,3,4-tetrahydro-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxopyrimidin-5-yl)-4-(4-hydroxy-3methoxyphenyl)-2-iminopyridine-3-carbonitrile (2b) Crystallized from ethanol to give yellowish brown crystals with m.p. 215-217 ºC and yield 65%. IR spectrum (KBr, , cm -1 ): 3460 (OH), 3380 (NH), 2220 (CN), 1705 (CO), 1608 (C=N), 1590 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 2.10 (3H, s, CH3), 3.80 (9H, s, 3OCH3), 5.41 (1H, s, C4-H of pyrimidinone), 6.80-7.10 (7H, m, Ar-H including 1H of the iminopyridine), 9.95, 10.25, 11.15, 11.75 (4H, 4s, 4NH, D2O exchangeable) and 12.10 (1H, s, OH, D2O exchangeable); MS, m/z (%): 487.51 (M + , 21.34). Analysis for C 2 6 H 2 5 N 5 O 5 (487.51): required C, 64.06; H, 5.17; N, 14.37; found C, 64.11; H, 5.20; N, 14.40. 1 ,2 -D ih yd ro -6 -(1 ,2 ,3 ,4 -te tra hyd ro -4 -(3 ,4 -d im etho xyp h e nyl)-6 -m e thyl-2 -o x o p yrim id in-5 -yl)-4 -(2 hydroxyphenyl)- 2-iminopyridine-3-carbonitrile (2c) Crystallized from methanol to give pale brown crystals with m.p. 250-252 ºC and yield 69%. IR spectrum (KBr, , cm -1 ): 34 10-3230 (OH), 3240 (NH), 2207 (CN), 1705 (CO), 1615 (C=N), 1585 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 2.20 (3H, s, CH3), 3.75 (6H, s, 2OCH3), 5.40 (1H, s, C4-H), 6.80-7.45 (8H, m, Ar-H including 1H of the iminopyridine), 9.30, 9.75, 10.50, 11.25 (4H, 4s, 4NH, D2O exchangeable) and 11.55 (1H, s, OH, D2O exchangeable); MS, m/z (%): 457.48 (M + , 18.43). Analysis for C 2 5 H 2 3 N 5 O 4 (457.48): required C, 65.63; H , 5.07; N, 15.31; found C, 65.60; H, 5.01; N, 15.25. General Method for Preparation of Pyridones (3a,b): A mixture of compound 1 (0.58 g, 0.002 mole), ethyl cyanoacetate (0.23 mL, 0.002 mole), anhydrous ammonium acetate (1.24 g, 0.016 mole) and the aromatic aldehydes namely: o-hydroxybenzaldehyde and 4hydroxy-3-methoxybenzaldehyde (vaniline) (0.002 mole) in n-butanol (10 mL) was refluxed for 5-7 h. The reaction mixture was concentrated to half of its volume under reduced pressure. After cooling the formed precipitate was filtered off, air dried and recrystallized from the proper solvent to give the compounds 3a,b. 1,2-Dihydro-6-(1,2,3,4-tetrahydro-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxopyrimidin-5-yl)-4-(2-hydroxyphenyl)-2oxopyridine-3-carbonitrile (3a) Crystallized from methanol to give yellow crystals with m.p. 25 8-287 ºC and yield 72%. IR spectrum (KBr, , cm -1 ): 3420 (OH), 3360 (NH), 2220 (CN), 1710, 1680 (2CO), 1600 (C=N), 1590 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 2.22 (3H, s, CH3), 3.70 (6H, s, 2OCH3), 5.45 (1H, s, C4H), 6.90-7.50 (8H, m, Ar-H including 1H of the pyridinone), 9.45, 9.75, 10.35 (3H, 3s, 3NH, D2O exchangeable) and 11.25 (1H, s, OH, D2O exchangeable); Analysis for C25H22N4O5 (458.47): required C, 65.49; H, 4.84; N, 12.22; found C, 65.40; H, 4.92; N, 12.32. 1,2-Dihydro-6-(1,2,3,4-tetrahydro-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxopyrimidin-5-yl)-4-(4-hydroxy-3methoxyphenyl)-2-oxopyridine-3-carbonitrile (3b) Crystallized from chloroform to give red crystals with m.p. 227-230 ºC and yield 63% . IR spectrum (KBr, , cm -1 ): 3445 (OH), 3340 (NH), 2217 (CN), 1709, 1695 (2CO), 1605 (C=N), 1585 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 2.15 (3H, s, CH3), 3.75 (9H, s, 3OCH3), 5.42 (1H, s, C4-H), 6.85-7.15 (7H, m, Ar-H including 1H of the pyridone), 9.50, 9.85, 10.50 (3H, 3s, 3NH, D2O exchangeable) and 11.95 (1H, s, OH, D2O exchangeable); MS, m/z (%): 488.49 (M + , 15.95). Analysis for C 2 6 H 2 4 N 4 O 6 (488.49): required C, 63.93; H, 4.95; N, 11.47; found C, 63.85; H, 4.88; N, 11.40. General Method for Preparation of Arylsulfonylhydrazid Derivatives (4a,b): A mixture of compound 1 (2.90 g, 0.01 mole) and the appropriate arylsulfonylhydrazid namely: benzenesulfonylhydrazid and/or toluenesulfonylhydrazide (0.01 mole) in ethanol (30 mL) was refluxed for 6-8 h. The reaction mixture was cooled. The formed precipitate was filtered off, air dried and recrystallized from the proper solvent to give 4a,b. Benzenesulfonyl{1-[4-(3,4-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidin5-yl]-ethylidene}-hydrazide (4a) Crystallized from methanol to give reddish yellow crystals with m.p. 123-125 ºC and yield 71%. IR spectrum (KBr, , cm -1 ): 3400 (NH), 1700 (CO), 1615 (C=N), 1585 (C=C); 1H N M R spectrum (DMSO-d6,
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010 ppm): 1.10 (3H, s, CH3-C=N), 1.95 (3H, s, CH3), 3.75 (6H, s, 2OCH3), 5.40 (1H, s, C4-H), 6.80-7.85 (8H, m, Ar-H), 8.50, 9.35, 9.80 (3H, 3s, 3NH, D2O exchangeable); Analysis for C21H24N4O5S (444.50): required C, 56.74; H, 5.44; N, 12.60; found C, 56.61; H, 5.35; N, 12.52. Toluenesulfonyl{1 -[4-(3,4-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl]-ethylidene}-hydrazide (4b) Crystallized from ethanol to give dark orange crystals with m.p. 167-169 ºC and yield 69%. 1H NMR spectrum (DMSO-d6, ppm): 0.90 (3H, s, CH3-C=N), 1.98 (3H, s, CH3), 2.50 (3H, s, CH3-ph), 3.85 (6H, s, 2OCH3), 5.45 (1H, s, C4-H), 6.95-7.85 (7H, m, Ar-H), 8.25, 8.90, 10.25 (3H, 3s, 3NH, D2O exchangeable); MS, m/z (%): 410.47 (M + , 20.23). Analysis for C 22H 26N 4O 5S (410.47): required C, 64.37; H, 6.38; N, 13.65; found C, 64.21; H, 6.42; N, 13.70. General Method for Preparation of Thiazolidinone Derivatives (5a,b): To a well stirred solution of compound 4a or 4b (0.01 mole) in dry benzene (50 mL), thioglycolic acid (0.01 mole) were added and the reaction mixture was refluxed for 5-8 h. For each on a water bath the reaction mixture was concentrated to 1/3 of its volume under vacuum. And the precipitate formed after cooling was filtered off, dried and recrystallized from dilute ethanol to give the compounds 5a,b, respectively. N -{2-[4-(3,4-D ime tho xy-p henyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-4-oxo-thiazolidin-3-yl}benzenesulfonamide (5a) Crystallized from methanol to give reddish yellow crystals with m.p. 169-172 ºC and yield 73%. 1H NMR spectrum (DMSO-d6, ppm): 1.90 (3H, s, CH3), 1.95 (3H, s, CH3), 2.55 (2H, s, CH2 of thiazolidinone ), 3.65 (1H, s, CH of thiazolidinone ring), 3.85 (6H, s, 2OCH3), 5.45 (1H, s, C4-H), 6.75-7.90 (8H, m, Ar-H), 9.50, 9.90, 10.45 (3H, 3s, 3NH, D2O exchangeable); MS, m/z (%): 518.61 (M + , 25.13). Analysis for C 23H 26N 4O 6S2 (518.61): required C, 53.27; H, 5.05; N, 10.80; found 53.19; H, 4.98; N, 10.75. N -{2-[4-(3,4-D im etho xy-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-4-oxo-thiazolidin-3-yl}toluenesulfonamide (5b) Crystallized from methanol to give greenish yellow crystals with m.p. 249-25 2 ºC and yield 71% . IR spectrum (KBr, , cm -1 ): 3380 (NH), 2220 (CN), 1710, 1695 (2CO), 1610 (C=N), 1590 (C=C); 1H NM R spectrum (DM SO-d6, ppm): 1.80 (3H, s, CH3), 1.98 (3H, s, CH3), 2.20 (3H, s, CH3-ph), 2.60 (2H, s, CH2 of thiazolidinone ), 3.65 (1H, s, CH of thiazolidinone), 3.80 (6H, s, 2OCH3), 5.42 (1H, s, C4-H), 6.80-7.95 (7H, m, Ar-H), 8.55, 8.95, 10.45 (3H, 3s, 3NH, D2O exchangeable); MS, m/z (%): 532.63 (M + , 35.43). Analysis for C24H28N4O6S2 (532.63): required C, 54.12; H, 5.30; N, 10.52; found 54.15; H, 5.41; N, 10.65. General Method for Preparation of Chalcones (6a,b): A mixture of compound 1 (2.90 g, 0.01 mole) and the appropriate aldehydes namely: 5-methyl-furan-2carboxyaldehyde and/or p-florobenzeldehyde (0.01 mole) in ethanol (30 mL) in the presences of few drops of piperidine was heated for 2-5 h. The reaction mixture was cooled and titrated with ethanol then filtered off, air dried and recrystallized from the proper solvent to give 6a,b. 3,4-Dihydro-4-(3,4-dimethoxyphenyl)-5-((E)-3-(5-methylfuran-2-yl)acryloyl)pyrimidin-2(1H)-one (6a) Crystallized from ethanol to give yellow powder with m.p. 100-103 ºC and yield 55%. IR spectrum (KBr, , cm -1 ): 3360 (NH), 1720, 1670 (2CO), 1615 (C=N), 1545 (C=C), 1160,1230 (cyclic ether); 1H NMR spectrum (DMSO-d6, ppm): 1.92 (3H, s, CH3), 2.10 (3H, s, CH3-furan ring), 3.80 (6H, s, 2OCH3), 5.40 (1H, s, C4-H), 6.50-6.80 (2H, dd, CH=CH), 7.15-7.80 (5H, m, Ar-H including 2 protons of furan ring), 8.70, 9.15 (2H, 2s, 2NH, D2O exchangeable); Analysis for C20H20N2O5 (368.38): required C, 65.21; H, 5.47; N, 7.60; found C, 65.28; H, 5.52; N, 7.65. 5-((E)-3-(4-flurophenyl)acryloyl)-3,4-dihydro-4-(3,4-dimethoxyphenyl)pyrimidin-2(1H)-one (6b) Crystallized from chloroform-pet. ether to give yellow crystals with m.p. 8 8-90 ºC and yield 59%. IR spectrum (KBr, , cm -1 ): 3380 (NH), 1710, 1680 (2CO), 1615 (C=N), 1545 (C=C), 1160,1230 (cyclic ether); 1H N MR spectrum (DM SO-d6, ppm): 1.90 (3H, s, CH3), 3.85 (6H, s, 2OCH3), 5.42 (1H, s, C4-H), 6.50-6.75 (2H, dd, CH=CH), 7.10-7.85 (7H, m, Ar-H), 8.25, 8.95 (2H, 2s, 2NH, D2O exchangeable); Analysis for C 2 1 H 1 9 FN 2 O 4 (382.38): required C, 65.96; H, 5.01; N, 7.33; found C, 65.85; H, 4.99; N, 7.30. General Method for Cyclization of Chalcones with Urea (7a,b): A mixture of compound 6a or 6b (0.00 1 mole) and urea (0.1g, 0.001 mole) in ethanol (20 mL) and concentrated hydrochloric acid (5mL) was refluxed for 7h. The reaction mixture was concentrated to half of its volume. Cooled and neutralized with ammonium hydroxide. The precipitated solid was filtered off, washed with water, air dried and recrystallized from the ethanol to give 7a,b.
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010 4 -(1 ,2 ,3 ,4 -T etrahyd ro -4 -(3 ,4 -d imethoxyphe nyl)-6-me thyl-2-oxopyrimidin-5-yl)-6-(5-me thylfura n-2yl)pyrimidin-2(1H)-one (7a) Brown crystals with m.p. 201-203 ºC and yield 65%. IR spectrum (KBr, , cm -1 ): 3420 (NH), 1725, 1700 (2CO), 1610 (C=N), 1580 (C=C), 1160,1230 (cyclic ether); 1H NMR spectrum (DMSO-d6, ppm): 1.97 (3H, s, CH3), 2.17 (3H, s, CH3-furan ring), 3.80 (6H, s, 2OCH3), 5.45 (1H, s, C4-H), 6.82-7.28 (5H, m, Ar-H including 2 protons of furan ring), 9.35, 9.80, 10.75 (3H, 3s, 3NH, D2O exchangeable); Analysis for C 2 2 H 2 2 N 4 O 5 (422.43): required C, 62.55; H, 5.25; N, 13.26; found C, 62.43; H, 5.19; N, 13.18. 6-(4-flurophenyl)-4-(1,2,3,4-Tetrahydro-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxopyrimidin-5-yl)pyrimidin2(1H)-one (7b) Yellow crystals with m.p. 245-248 ºC and yield 62%. IR spectrum (KBr, cm -1 ): 3425(NH), 1725, 1705(2CO), 1615(C=N), 1580(C=C), HNMR spectrum (DMSO-d6, ppm): 1.95 (3H, s, CH3), 3.85 (6H, s, 2OCH3), 5.50 (1H, s, C4-H), 6.80-7.35 (5H, m, Ar-H), 9.55, 10.50, 11.90 (3H, 3s, 3NH, D2O exchangeable); Analysis for C 2 3 H 2 1 FN 4 O 4 (436.44): required C, 63.30; H, 4.85; N, 12.48; found C, 63.45; H, 4.92; N, 12.53. General Method for Cyclization of Chalcones with Thiourea (8a,b): A mixture of compound 6a or 6b (0.001 mole), thiourea (0.11g, 0.001 mole) and sodium hydroxide (0.1g) in ethanol (25 mL) was refluxed for 6-8h. The reaction mixture was concentrated under vacuum, cooled and neutralized with ammonium hydroxide solution. The formed solid was filtered off, washed with water, air dried and recrystallized from the ethanol to give 8a,b. 3,4-Dihydro-5-(1,2-dihydro-6-(5-methylfuran-2yl)-2-thioxo pyrimidin-4-yl)-4-(3,4-dimethoxyphenyl)-6methylpyrimidin-2(1H)-one (8a) Dark brown crystals with m.p. 133-135 ºC and yield 61%. IR spectrum (KBr, cm -1 ): 3440 (NH), 1720 (CO), 1605 (C=N), 1575 (C=C), 1273 (C=S); MS, m/z (%): 438.50 (M + , 25.12). Analysis for C 22 H 2 2 N 4 O 4 S (438.50): required C, 60.26; H, 5.06; N, 12.78; found C, 60.30; H, 5.15; N, 12.81. 5 -(6 -(4 -fluro p henyl)-1 ,2 -d ihyd ro -2 -thioxopyrimidin-4 -yl)-3 ,4 -d ihyd ro-4 -(3,4-d im e tho xyp he nyl)-6methylpyrimidin-2(1H)-one (8b) Dark red powder with m.p. 110-113 ºC and yield 65%. IR spectrum (KBr, , cm-1): 3420 (NH), 1715 (CO), 1610 (C=N), 1550 (C=C); 1H NMR spectrum (DM SO-d6, ppm): 1.95 (3H, s, CH3), 3.75 (6H, s, 2OCH3), 5.42 (1H, s, C4-H), 6.85-7.70 (8H, m, Ar-H including 1H of pyrimidinthione), 8.30, 8.55, 9.25 (3H, 3s, 3NH, D2O exchangeable); Analysis for C 2 3 H 21FN 4O 3S (452.50): required C, 61.05; H, 4.68; N, 12.38; found C, 61.15; H, 4.85; N, 12.42. General Method for Preparation of 2-alkoxy-3-cyano-4-arylpyridine Derivatives (9a,b): Compound 6a or 6b (0.00 1 mole) were added during stirring to a freshly prepared sodium alkoxide solution (0.001 mole of sodium in 20 mL of each absolute methanol or ethanol). Malononitrile (0.002 mole) was then added with continuous stirring at room temperature until the precipitate was separated out. The solid separated was collected by filtration and recrystallized from the suitable solvent. 4 -(4 -fluo ro p henyl)-6-(1,2,3,4-tetrahydro-4-(3,4-dime thoxyphe nyl)-6-me thyl-2-oxopyrimidin-5-yl)-2methoxypyridine-3-carbonitrile (9a) Crystallized from methanol to give pale yellow crystals with m.p. 175-178 ºC and yield 69%. IR spectrum (KBr, , cm -1 ): 3424 (NH), 2216 (CN), 1710 (CO), 1608 (C=N), 1567 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 1.98 (3H, s, CH3), 3.75 (9H, s, 3OCH3), 5.45 (1H, s, C4-H), 7.00-7.85 (8H, m, Ar-H including 1H of the pyridine), 9.95, 10.55 (2H, 2s, 2NH, D2O exchangeable); Analysis for C26H23FN4O4 (474.48): required C, 65.81; H, 4.89; N, 11.81; found C, 65.89; H, 5.11; N, 11.90. 2-Ethoxy-4-(4-fluorophenyl)-6-(1,2,3,4-tetrahydro-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxopyrimidin-5yl)pyridine-3-carbonitrile (9b) Crystallized from methanol to give orange crystals with m.p. 130-13 3 ºC and yield 55%. IR spectrum (KBr, , cm -1 ): 3389 (NH), 2249 (CN), 1670 (CO), 1611 (C=N), 1560 (C=C); 1H NMR spectrum (DMSO-d6, ppm): 1.35 (3H, t, CH3), 1.98 (3H, s, CH3), 3.75 (6H, s, 2O CH3), 3.95 (2H, q, CH2), 5.40 (1H, s, C4-H), 7.10-8.15 (8H, m, Ar-H including 1H of the pyridine), 9.35, 9.80 (2H, 2s, 2NH, D2O exchangeable); Analysis for C 2 7 H 2 5 FN 4 O 4 (488.51): required C, 66.38; H, 5.16; N, 11.47; found C, 66.41; H, 5.22; N, 11.51.
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010 RESULTS AND DISCUSSION The starting material namely: 5-acetyl-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine (1) (El hamouly et al, 2006) allowed to react with appropriate aromatic aldehydes namely: phyd ro xyb e nz ald ehyd e, 4 -hyd ro xy-3 -m ethoxybe nz alde hyde (vaniline) and o-hydroxybe nz alde hyde (salicylaldehyde) in presence of ammonium acetate and ethyl cyanoacetate in butanol to afford compounds 2a-c (Scheme 1). By the same method (Ibeid et al,1991) compounds 3a,b were achieved by heating of compound 1 and appropriate aromatic aldehydes namely: o-hydroxybenzaldehyde and 4-hydroxy-3-methoxybenzaldehyde in presence of excess of ammonium acetate and malononitrile in butanol. Furthermore compound 1 reacted with arylsulfonylhydrazides namely: benzenesulfonylhydrazid and toluenesulfonyl- hydrazide to give 4a,b (Scheme 1). Cyclocondensation (Fathalla et al,2005) of 4a,b with thioglycolic acid in dry benzene gave the corresponding thiazolidinone derivatives 5a,b (Scheme 1).
Chalcone, á,â (-unsaturated ketones) are interesting precursors and display interesting biological activities, including Cytotoxic and anticancer properties.(Edwards et al, 1990) Condensation of compound 1 with different aldehydes namely: 5-methyl-furan-2-carboxyaldehyde and p-florobenzeldehyde in the presences of 20% NaOH solution at 60 ºC afforded the corresponding 6a,b (Scheme 2). Moreover, condensation of compounds 6a,b with urea in boiling ethanolic hydrochloric acid gave 7a,b (Scheme 2). Similarly compounds 6a,b reacted with thiourea in boiling ethanolic potassium hydroxide solution to give compounds 8a,b (Scheme 2). In the present work, new compounds containing 2-alkoxypyridine moieties have been designed for their biological activity, particularly for antitumor properties. The preparation of 2-alkoxycyanopyridines in good yields was reported via Micheal addition of malononitrile to, á,â unsaturated carbonyl system. (Al-Arab et al, 1988) Herein, 5-chalconyl pyrimidine derivative 6b was condensed with malononitrile in either sodium ethoxide/ethanol or sodium methoxide/ethanol(Radwan et al. ,2009) to yield the corresponding 2alkoxypyridines 9a,b (Scheme 2).
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010
Pharmacology: Antibacterial as well as antifungal activity of seven tested compounds were in vitro evaluated using agar well diffusion test (Sgouras et al., 2004) using two different concentration of the compounds (100 µg/ml) dissolved in 1ml DMSO as a qualitative method for studying the antimicrobial activity of the tested compounds against the following tested stains; bacterial strains: E.coli O157, S. typhimurium, Ps. areginosus, S. aureus, L. monocytogenes, B. cereus. Fungal strains are Candida albicans and Aspergillus flavus. As control positive tobramycin (10µg/ml) was used as standard antibacterial while flucanazole (25µg/ml) was used as standard antifungal while dimethyl sulphoxide (DMSO) was used as control negative. Conclusion: Antimicrobial activity of the 13 compounds was evaluated against the following tested stains; bacterial strains: E. coliO157, S. typhimurium, Ps. areginosus, S. aureus, L. monocyto genes, B. cereus. Fungal strains are Candida albicans and Aspergillus flavus. As control positive tobramycin (10µg/ml) was used as standard antibacterial while flucanazole (25µg/ml) was used as standard antifungal while dimethyl sulphoxide (DMSO) was used as control negative. Results revealed that chemical compound no 6a (100µg/ml) gives the highest
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010 antibacterial activity against all tested strains with a mean zone of inhibition equal 8.5 mm followed by 3a, 5a and 6b (100µg/ml); 7.0 mm then 9b (100µg/ml); 6.63 mm then 7b (100µg/ml); 6.38 mm and 7a , 9a and 8a (100µg/ml); 4.25, 4.24 and 4.1 mm respectively . On the contrary compound no gives no inhibitory effect against all tested strains as shown in table (1) and figures (1-10). Compounds no 6a, 6b and 5a were highly effective against Ps. arginosus then B.cereus followed by L.monocytogenes and A.flavus as showen in table (1) The Antim icrobial activity od the tested com pounds against bacterial and fungal strains isolated from food and m ilk of anim al origin Com pounds E.coli S.typhim urium L.m onocytogenes S.aureus Ps.arginosus B.cereus C.albicans A.flavus M ean no. O 157 zone of inhibition 2a 9 10 2.38 2b 0.00 3a 7 7 7 7 7 7 7 7 7.00 3b 7 7 7 2.63 4b 8 7 1.88 5a 9 9 10 10 14 12 9 10 7.00 6a 7 10 10 9 12 11 8 10 8.5 6b 9 9 8 11 10 9 9 7.00 7a 8 9 8 9 4.25 7b 9 8 9 10 7 8 6.38 8a 9 10 7 7 4.10 9a 10 8 8 8 4.24 9b 7 8 9 12 8 9 6.63 Tobram ycin (10µg/m l) 20 18 20 19 18 19 19 Flucanazole (25µg/m l) 17 16 16.50 D M SO Table 1:
Fig. 1: Zone of inhibition of compounds 2a, 2b, 3a, 3b, 4a and 5a in sequence with the arrow against E.coli O157.
Fig. 2: Zone of inhibition of compounds 6a, 6b, 7a, 7b, 8a, 9a and 9b in sequence with the arrow against E.coli O157.
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010
Fig. 3: Zone of inhibition of compounds 2a, 2b,3a, 3b,4a and 5a in sequence with the arrow against S.typhimurium.
Fig. 4: Zone of inhibition of compounds 6a, 6b, 7a, 7b, 8a, 9a and 9b in sequence with the arrow against S.typhimurium.
Fig. 5:
Zone of inhibition of compounds 2a, 2b, 3a, 3b,4a and 5a in sequence with the arrow against L.monocyto genes
Fig. 6: Zone of inhibition of compounds 6a, 6b, 7a, 7b, 8a, 9a and 9b in sequence with the arrow against L.monocyto genes.
Fig. 7: Zone of inhibition of compounds 2a, 2b, 3a, 3b,4a and 5a in sequence with the arrow against S.aureus
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010
Fig. 8: Zone of inhibition of compounds 6a, 6b, 7a, 7b, 8a, 9a and 9b in sequence with the arrow against S.aureus
Fig. 9: Zone of inhibition of compounds 2a, 2b, 3a, 3b,4a and 5a in sequence with the arrow against Ps. are ginosus,
Fig. 10: Zone of inhibition of compounds 6a, 6b, 7a, 7b, 8a, 9a and 9b in sequence with the arrow against Ps. areginosus,
Fig. 9: Zone of inhibition of compounds 2a, 2b, 3a, 3b,4a and 5a in sequence with the arrow against B.cereus
.
Fig. 10: Zone of inhibition of compounds 6a, 6b, 7a, 7b, 8a, 9a and 9b in sequence with the arrow against B.cereus.
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Aust. J. Basic & Appl. Sci., 4(1): 27-36, 2010 REFERENCES Al-Arab, M.M., H.D. Tabba, L.A. Abu-Yousef and M.O. Marilyn, 1988 .Condensation of cinnamonitriles with arylacetonitriles. Tetrahedron, 44: 729. Attia, M., A.S. Aly. and S. Abdel Meguid, 1983. Synthesis of some 3-cyano-5,6-Dihydropyridin-2-ones and their N-substituted Derivatives.Egypt J.Chem., 26: 447. Edwards, M.L., D.M. Stemerick and P.S. Sunkara, 1990. Chalcones:A New class of antimitotic agents. J.Med.Chem., 33: 1948. El-Hamouly, W .S., A.A. El-Khamry and E.M. Abbas, 2006. Synthesis of new 4-aryl-isoxazolo[5 ,4d]pyrimidin-6-one(thione) and 4-arylpyrazolo[3,4-d]pyrimidin-6-one derivatives of potential antihypertensive activity.Indian J.Chem., 45b: 2091. Fakhr, I.M.I., M .A.A. Radwan, S. El-Batran, O.M. Abd El-Salam and S. El-Shenawy, 2009. Synthesis and pharmacological evaluation of 2-sub stituted benzo[b]thiophenes as anti-inflammatory and analgesic agents.Eur.J.Med.Chem., 44: 17-18. Fathalla, O.A., I.F. Zeid, M.E. Haiba and W .S. Serwy, 2005. Synthesis of Uracil and Thiouracil Derivatives with Expected Biological Activity,Egypt Pharma.J., 4(2): 593. Ibeid, M.Y., M.M. Kamel, N.A. Abdallah, E.M.M. Kassem and N.A.M. Abdou, 1991. New tetrahydronaphthyl pyridines of possible analgesic activity.Bull.Fac.Pharm.(cairo univ.), 29(3): 1-5. Kashman, Y. and H. Shulamit, A.A. Ptitomycalin, 1989. Novel polycyclic guanidine alkaloid of marine origin, J.Amer.Chem.Soc., 11: 8925. Radwan, M.A.A. and E.M .H. Abbas, 2009. Synthesis of some pyridine,thiopyrimidine,and isoxazoline derivatives based on the pyrrole moiety.Monatsh Chem., 140: 229. Sadanandam.Y. S., M.M. Shetty and P.V. Diwan, 1992. Synthesis and biological evaluation of new 3,4-dihydro6-methyl-5-N-methylcarbamoyl-4-(substituted phenyl)-2(1H) pyrimidinones and pyrimidinethiones. Eur. J. Chem., 27: 87. Sgouras, D., P. Maragkoudakis, K. Petraki, B. Martinez-Gonzalez, E. Eriotou, S. Michopoulos, G. Kalantzopoulos, E. Tsakalidou and A. Mentis, 2004. In vitro and vivo inhibition of helicobacter pylori by lactobacillus casei strain Shirota.Appl.Environ.Microbiol., 70: 5-18.
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