An efficient synthesis, characterization and anti-bacterial activity of pyrimidine bearing 1,3,4-thiadiazole derivatives

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Indian Journal of Chemistry Vol. 54B, March 2015, pp. 406-411 An efficient synthesis, characterization and anti-bacterial activity of pyrimidine bearing 1,3,4-thiadiazole derivatives Andrews B* a,b & Mansur Ahmed a a PG and Research Department of Chemistry, Islamiah College, Vaniyambadi 635 752, India b Department of Chemistry, Priyadarshini Engineering College, Vaniyambadi 635 751, India (Affiliated to Thiruvalluvar University, Vellore, Tamilnadu, India) E-mail: bandrews2006@yahoo.com Received 14 October 2013; accepted (revised) 20 January 2015 A series of pyrimidine bearing 1,3,4-thiadiazole derivatives have been synthesized and evaluated for antibacterial activity. All the structures of the newly synthesized compounds have been supported by IR, 1 H and 13 C NMR, GC-MS and CHN analysis. Most of the compounds have shown promising antibacterial activity when compared with the standard drug Ciprofloxacin. Keywords: Pyrimidine, thiadiazole, hydrazine carbothioamide, antibacterial activity Literature survey has been revealed the importance of pyrimidine derivatives and antimicrobial agent 1, which are found to be associated with variety of biological activities such as insecticidal, antimicrobial, antiviral and so on. Pyrimidine derivatives 2-8 are powerful C-C bond forming agents and have wide applications for the preparation of diverse aminoalkyl derivatives. It involves the condensation of a compound capable of supplying one or more active hydrogen atom with aldehyde and primary or secondary amine. Mannich bases are physiologically reactive because of the basic function rendering the molecule soluble in aqueous solvent whence it is transformed into ammonium salt. Several medicinally useful Mannich bases have been reviewed by Tromontini and Angiolini 9. Besides this, considerable work has been reported on synthesis and pharmacological activities of various Mannich bases for analgesic, antispasmodic, anesthetic and antimalarial as well as intermediates in drug synthesis. Antiviral properties of certain thiourea and urea derivatives have been reported in which the antiviral effect is attributed to the presence of an intact NH-(C=S)-NH and NH-(C=O)-NH grouping 10. In this context the synthesis and pharmacological study of Mannich bases of 3-and 5-mercapto derivatives of 1,2,4-triazole have been reported in literature 11-16. Further, pyrimidine, fused heterocyclic pyrimidine derivatives and dihydropyrimidones are well known for their potential biological activity such as antiviral, antitumor, antimicrobial fungicide, algaecide and as antibiotics 17-22. Moreover, the presences of different interacting functional groups determine their great synthetic potential. In continuation of this work, herein is reported the synthesis and in vitro study of antibacterial activity of heterocyclic N-Mannich bases of 5-(5- amino-1, 3, 4-thiadiazol-2-yl)-3,4-dihydro-6-methyl-4- phenylpyrimidin-2(1h)-one 3 against Pseudomonas aeruginosa (Gram ve), Staphylococcus aureus (Gram +ve) and Escherichia coli (Gram ve). Ciprofloxacin was used as standard drug. For this purpose, heterocyclic precursor DHPMs 1a-j were synthesized by Biginelli reaction of aromatic aldehydes, ethylacetoacetate and thiourea according to the literature procedure. Subsequently, these DHPMs were used to synthesis compounds 2a-j. All the synthesised compounds were characterized by using elemental analysis, mass spectra, 1 Hand 13 C NMR spectral studies. Results and Discussion Compounds 3a-j were synthesized as per the Scheme I, where final compound 3 prepared by reacting hydrazine carbothioamide, compound 2 with conc. H 2 SO 4 and NH 3. Hydrazine carbothioamide, compound 2 were synthesized by reacting pyrimidine ethyl ester 1 with thiosemicarbazide in acetone followed by condensation reaction 23-26. The pyrimidine ethyl ester compound 1 was prepared by reacting benzaldehyde, ethylacetoacetate and urea or thiourea in the presence of mineral acid followed by Biginelli reaction. The structures of the synthesized compounds

ANDREWS et al.: PYRIMIDINE BEARING 1,3,4-THIADIAZOLE DERIVATIVES 407 5-(5-Amino-1,3,4-thiadiazole-2-yl)-3,4-dihydro-6-methyl-4-phenylpyrimidin-2(1H)-one 3a Scheme I Table I Physical and analytical characterization data of compounds 2a-j Compd Mol. formula R R 1 X Mol. Wt. Yield(%) m.p. ( C) 2a C 13 H 15 N 5 O 2 S H H O 305 85 140 2b C 13 H 14 N 5 O 2 SCl Cl H O 339 70 145 2c C 15 H 20 N 6 O 2 S N(CH 3 ) 2 H O 348 78 170 2d C 13 H 14 N 6 O 4 S H NO 2 O 350 81 132 2e C 13 H 15 N 5 O 3 S OH H O 321 83 160 2f C 13 H 15 N 5 OS 2 H H S 321 65 143 2g C 13 H 14 N 5 OS 2 Cl N(CH 3 ) 2 H S 355 72 110 2h C 15 H 20 N 6 OS 2 Cl H S 364 75 148 2i C 13 H 14 N 6 O 3 S 2 H NO 2 S 366 70 125 2j C 13 H 15 N 5 O 2 S 2 OH H S 337 78 118 Calcd (%) Found C N H S 51.17 (51.94 46.05 (46.30 52.35 (52.79 44.60 (44.06 48.62 (48.75 48.63 (48.46 43.90 (43.41 49.47 (49.00 42.65 (42.59 46.32 (46.53 22.50 22.24 20.65 20.94 24.42 24.77 24.00 24.07 21.18 21.19 21.80 21.97 19.72 19.42 23.08 23.26 22.95 23.00 20.77 21.03 4.94 4.85 4.15 4.60 5.84 5.83 4.02 4.43 4.70 4.32 4.70 4.55 3.97 4.09 5.49 5.22 3.85 3.54 4.47 4.70 10.47 10.94) 9.42 9.49) 9.28 9.85) 9.13 9.22) 9.95 9.36) 19.91 20.10) 18.00 18.06) 17.56 17.69) 17.46 17.72) 18.96 19.06) were confirmed by IR, 1 H and 13 C NMR, GC-MS and CHN analysis (Table I). Formation of compound 2 was confirmed by the presence of N-H stretching peaks at 3365, 3241 and 3116 cm -1 and C=O stretching peaks at 1724 cm -1 in IR and singlet at δ 6.50 for NH 2 group in 1 H NMR spectra. Treatment of compound 2 with conc. H 2 SO 4 and NH 3 furnished 5-(5-amino-1,3,4- thiadiazol-2-yl)-3, 4-dihydro-6-methyl-4-phenylpyrimidin-2(1H)-one 3. The structure of 3 was elucidated on the basis of C-S linkage in the thiadiazole ring, which gave a sharp absorption band at 1225 cm -1 in its IR spectrum. 1 H NMR spectrum showed a singlet at δ 4.00 due to NH 2 functionality confirmation of the structure 3. Physical and analytical data are given in Table II. IR and 1 H NMR spectral data revealed carbonyl absorption band at 1689 cm -1 of NH-CO-NH group, N-N stretching band at 1098 cm -1, aliphatic C-H and aromatic C-H stretching at 2976 cm -1 and 3027 cm -1 for pyrimidine moiety 3. Mass spectrum also supported the proposed structure by displaying molecular ion peak at m/z 287 M +. All these compounds were screened for antibacterial activity by Pseudomonas aeruginosa (Gram ve), Staphylococcus aureus (Gram +ve) and Escherichia coli (Gram ve). Ciprofloxacin was used as standard drug. Most of the synthesized compounds showed moderate to good inhibition at 10 µg/ml concentration. However, the activity was less compared to the standard drugs. Experimental Section Melting points were determined using open capillary method and are uncorrected. The compounds were

408 INDIAN J. CHEM., SEC B, MARCH 2015 Table II Physical and analytical characterization data of compounds 3a-j Compd Mol. formula R R 1 X Mol. Wt. Yield (%) m.p.( C) Calcd (%) Found C N H S 3a C 13 H 13 N 5 OS H H O 287 92 175 3b C 13 H 12 N 5 OSCl Cl H O 321 85 170 3c C 15 H 18 N 6 OS N(CH 3 ) 2 H O 330 86 210 3d C 13 H 12 N 6 O 3 S H NO 2 O 332 82 162 3e C 13 H 13 N 5 O 2 S OH H O 303 83 220 3f C 13 H 13 N 5 S 2 H H S 303 75 185 3g C 15 H 18 N 6 S 2 N(CH 3 ) 2 H S 346 85 188 3h C 13 H 12 N 5 S 2 Cl Cl H S 337 70 161 3i C 13 H 12 N 6 O 2 S 2 H NO 2 S 348 72 150 3j C 13 H 13 N 5 OS 2 OH H S 319 82 130 54.38 (54.35 48.63 (48.28 54.57 (54.34 47.02 (47.51 51.51 (51.11 51.52 (51.45 52.05 (52.44 46.32 (46.15 44.86 (44.64 48.93 (48.53 24.39 24.64 21.80 21.79 25.45 25.67 25.30 25.85 23.10 23.02 23.10 23.95 24.28 24.84 20.77 20.44 24.14 24.57 22.06 22.50 4.56 4.56 3.76 3.50 5.49 5.60 3.64 3.88 4.32 4.89 4.32 4.35 5.24 5.39 3.58 3.31 3.47 3.51 4.10 4.01 11.13 11.68) 9.95 6.68) 9.96 9.62) 9.62 9.21) 10.54 10.07) 21.09 21.15) 18.47 18.54) 18.97 18.40) 18.37 18.39) 20.04 20.28) checked for homogeneity by TLC on silica gel-g. The IR spectra were recorded on FT-IR Thermo Nicolet Avatar 370 spectrophotometer using KBr disc method. The 1 H and 13 C NMR were recorded on Bruker Avance III 400 MHz FTNMR spectrometer using DMSO-d 6. Elemental analyses were recorded on Elemental Vario EL III instrument. The mass spectra were recorded on Joel GC-mate spectrometer. All compounds gave satisfactory micro analytical results. Pyrimidine 1 was prepared by reported method. General procedure for the synthesis of 5-(hydrazine carbothioamide)-3, 4-dihydro-6-methyl-4-phenylpyrimidin-2(1H)-one, 2a-j An equimolar mixture of compound 1 (0.01 mol) and thiosemicarbazide (0.01 mol) in acetone was refluxed for 10-12 hr and allowed to cool and the yellow crude solid was purified by recrystallization from alcohol. m.p.140 C. Yield 85%. 1 H NMR (DMSO-d 6 ): δ 2.251 (s, 3H, CH 3 ), 5.152 (J = 3.2 Hz, d, 1H, CH), 6.501 (s, 2H, NH 2 ), 7.213 7.336 (m, 5H, Ar-H), 7.702 (J = 2.8 Hz, d, 1H, NH), 8.175 (J = 6.4 Hz, d, 2H, NH 2), 9.149 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.72, 59.17, 99.33, 126.21, 127.23, 128.34,148.25, 151.71, 152.16, 165.33, 178.40; FT-IR (KBr): 3365, 3241, 3116 (NH), 3079 (Ar-H), 2978 (CH), 1724 (C=O), 1385 (C-N), 1219 (C=S), 1089 cm -1 (N-N); GCMS: m/z 305 M +. chlorophenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)- one, 2b: 1 H NMR (DMSO-d 6 ): δ 2.251 (s, 3H, CH 3 ), 5.146 (J = 3.6 Hz, d, 1H, CH), 6.530 (s, 2H, NH 2 ), 7.249 (J = 8.4 Hz, dd, 2H, Ar-H), 7.388 (J = 8.8 Hz, dd, 2H, Ar-H), 7.733 (J = 1.2 Hz, d, 1H, NH), 8.096 (J = 2 Hz, d, 2H, NH 2), 9.204(s,1H,NH); 13 C NMR(DMSO-d 6 ): δ 17.75, 59.22, 98.87, 128.15, 128.34, 131.74, 143.74, 148.64, 151.92, 165.18, 178.43; FT-IR(KBr): 3376, 3240, 3118 (NH), 3029(Ar-H), 2978(CH), 1724(C=O), 1340(C-N), 1220 (C=S), 1090 cm -1 (N-N); GCMS: m/z 339 M +. (dimethylamino)phenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)-one, 2c: 1 H NMR (DMSO-d 6 ): δ 2.226 (s, 3H, CH 3 ), 2.846 (s, 6H, N(CH 3 ) 2 ), 5.5036 (J = 3.2 Hz, d, 1H, CH), 6.130 (s, 2H, NH 2 ), 6.650 (J = 8.8 Hz, d, 2H, Ar-H),7.036 (J = 8.8 Hz, d, 2H, Ar-H), 7.534 (J = 2.8 Hz, d, 2H, NH 2), 9.036 (J = 1.2 Hz, d, 1H, NH), 9.866 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.67, 53.29, 59.06, 99.93, 112.20, 126.85, 132.61, 149.73, 151.27, 165.46, 178.43; FT-IR(KBr): 3365, 3241, 3116 (NH), 3053 (Ar-H), 1700 (C=O), 1340 (C-N), 1219 (C=S), 1089 cm -1 (N-N); GCMS: m/z 349 M +. Synthesis of 5-(hydrazine carbothioamide)-4-(3- nitrophenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)- one, 2d: 1 H NMR (DMSO-d 6 ): δ 2.276 (s, 3H, CH 3 ), 5.309 (J = 4 Hz, d, 1H, CH), 6.970 (s, 2H, NH 2 ), 7.656-7.760 (m, 4H, Ar-H), 7.826 (J = 3.7 Hz, d, 2H, NH 2), 9.345 (J = 2.4 Hz, d, 1H, NH), 9.872 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.81, 58.61, 98.35,

ANDREWS et al.: PYRIMIDINE BEARING 1,3,4-THIADIAZOLE DERIVATIVES 409 129.61, 130.19, 132.95, 147.65, 147.73, 149.36, 151.62, 151.73, 165.04, 178.44; FT-IR(KBr): 3377, 3239, 3117 (NH), 3029 (Ar-H), 2977 (CH), 1719 (C=O), 1365 (C-N), 1219 (C=S), 1091 cm -1 (N-N); GCMS: m/z 350 M +. hydroxyphenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H )-one, 2e: 1 H NMR (DMSO-d 6 ): δ 2.233 (s, 3H, CH 3 ), 5.049 (J = 3.2 Hz, d, 1H, CH), 6.176 (s, 2H, NH 2 ), 6.676-6.698 (J = 8.8 Hz, dd, 2H, Ar-H), 7.019-7.040 (J = 8.4 Hz, dd, 2H, Ar-H), 7.572 (J = 2.4 Hz, d, 2H, NH 2), 7.956 (s, 1H, OH), 9.065 (J = 1.2 Hz, d, 1H, NH), 9.868 (s, 1H, NH); 13 C NMR(DMSO-d 6 ): δ 17.69, 59.07, 99.80, 114.96, 127.37, 135.40, 151.66, 152.19, 156.50, 165.39, 178.43; FT-IR (KBr): 3515 (OH), 3377, 3234, 3151 (NH), 2997 (Ar-H), 2904 (CH), 1684 (C=O), 1367 (C-N), 1268 (C=S), 1098 cm -1 (N-N); GCMS: m/z 321 M +. Synthesis of 5-(hydrazine carbothioamide)- 3, 4-dihydro-6-methyl-4-phenylpyrimidin-2(1H)-thione, 2f: 1 H NMR (DMSO-d 6 ): δ 2.292 (s, 3H, CH 3 ), 5.176 (J = 3.6 Hz, d, 1H, CH), 6.681 (s, 2H, NH 2 ), 7.211-7.366 (m, 5H, Ar-H), 7.981 (J = 4 Hz, d, 2H, NH 2), 9.887 (J = 1.2 Hz, d, 1H, NH), 10.308 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.47, 59.54, 100.75, 126.35, 127.62, 128.50, 143.47, 144.95, 165.10, 178.47, 183.94; FT-IR (KBr): 3328, 3172, 3106 (NH), 2979 (Ar-H), 2936 (CH), 1669 (C=O), 1327 (C-N), 1283 (C=S), 1117 cm -1 (N-N); GCMS: m/z 321M +. chlorophenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)- thione, 2g: 1 H NMR (DMSO-d 6 ): δ 2.296 (s, 3H, CH 3 ), 5.174 (J = 2 Hz, d, 1H, CH), 7.023 (s, 2H, NH 2 ), 7.209-7.243 (J = 13.6 Hz, dd, 2H, Ar-H), 7.413-7.503 (J = 9.8 Hz, dd, 2H, Ar-H), 8.295 (J = 0.8 Hz, d, 2H, NH 2), 9.648 (J = 2.8 Hz, d, 1H, NH), 10.363 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.48, 59.63, 100.34, 128.27, 128.52, 142.33, 145.28, 164.96, 178.43, 183.89; FT-IR (KBr): 3377, 3327, 3236 (NH), 3158 (Ar-H), 2996 (CH), 1731 (C=O), 1335 (C-N), 1281 (C=S), 1041 cm -1 (N-N); GCMS: m/z 355M +. (dimethylamino)phenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)-thione, 2h: 1 H NMR (DMSO-d 6 ): δ 2.277 (s, 3H, CH 3 ), 2.855 (s, 6H, N(CH 3 ) 2 ), 5.048 (J = 4 Hz, d, 1H, CH), 6.305 (s, 2H, NH 2 ), 6.663 (J = 8.8 Hz, d, 2H, Ar-H), 7.016 (J = 8.8 Hz, d, 2H, Ar-H), 9.509 (J = 1.6 Hz, d, 2H, NH 2), 9.887 (s, 1H, NH), 10.197 (J = 0.8 Hz, d, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.48, 53.53, 59.43, 101.27, 112.16, 127.08, 131.19, 149.93, 151.56, 165.25, 178.47, 183.93; FT-IR (KBr): 3377, 3356, 3168 (NH), 3105 (Ar-H), 2981 (CH), 1669 (C=O), 1366 (C-N), 1285 (C=S), 1117 cm -1 (N-N); GCMS: m/z 364M +. Synthesis of 5-(hydrazine carbothioamide)-4-(3- nitrophenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)- thione, 2i: 1 H NMR (DMSO-d 6 ): δ 2.498 (s, 3H, CH 3 ), 4.931 (J = 1.2 Hz, d, 1H, CH), 6.557 (s, 2H, NH 2 ), 7.540-7.817 (m, 4H, Ar-H), 8.178 (J = 0.8 Hz, d, 2H, NH 2), 8.566 (J = 2.4 Hz, d, 1H, NH), 9.855 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.49, 60.26, 98.35, 122.96, 123.05, 129.73, 135.27, 141.64, 149.51, 151.64, 168.09, 175.39, 183.85; FT-IR (KBr): 3379, 3273, 3175 (NH), 3088 (Ar-H), 2982 (CH), 1727 (C=O), 1315 (C-N), 1233 (C=S), 1117 cm -1 (N-N); GCMS: m/z 366 M +. hydroxyphenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H)-thione, 2j: 1 H NMR (DMSO-d 6 ): δ 2.277 (s, 3H, CH 3 ), 5.063 (J = 3.6 Hz, d, 1H, CH), 6.120 (s, 2H, NH 2 ), 6.699-6.720 (t, 2H, Ar-H), 6.999-7.070 (q, 2H, Ar-H), 7.500 (s, 1H, Ar-H), 7.965 (J = 3.5 Hz, d, 2H, NH 2), 9.528 (J = 1.6 Hz, d, 1H, NH), 9.883 (s,1h,nh); 13 C NMR (DMSO-d 6 ): δ 17.50, 59.47, 101.12, 115.17, 127.61, 134.08, 144.42, 151.68, 165.18, 178.38, 183.83; FT-IR (KBr): 3429 (OH), 3245, 3179, 3079 (NH), 3036 (Ar-H), 2988 (CH), 1715 (C=O), 1314 (C-N), 1259 (C=S), 1082 cm -1 (N-N); GCMS: m/z 337 M +. General procedure for synthesis of 5-(5-amino- 1, 3, 4-thiadiazole-2-yl)-3, 4-dihydro-6-methyl-4-phenylpyrimidin-2(1H)-one, 3a-j Hydrazine carbothioamide 2 (0.01mol) was dissolved in 5 ml conc. H 2 SO 4. This solution was stirred at RT and left overnight. It was then poured in crushed ice. The resulting suspension was kept in ammonical water for 2 hr, filtered and purified by recrystallization from alcohol as white crystals. m.p.175 C. Yield 92%. 1 H NMR (DMSO-d 6 ): δ 2.258 (s, 3H, CH 3 ), 4.004 (s, 2H, NH 2 ), 5.159 (J = 3.2 Hz, d, 1H, CH), 7.227 7.347 (m, 5H, Ar-H), 7.701 (J = 2 Hz, d, 1H, NH), 9.151 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.03, 59.15, 99.30, 126.20, 127.20, 128.34, 144.82, 148.27, 152.10, 165.32; FT-IR (KBr): 3354, 3227, 3110 (NH), 3027 (Ar-H), 2976 (CH), 1689 (C=O), 1460 (C=N), 1225 (C-S),1378 (C-N), 1098 cm -1 (N-N); GCMS: m/z 287 M +. (4-chlorophenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H)-one, 3b: 1 H NMR (DMSO-d 6 ): δ 2.257 (s, 3H, CH 3 ), 4.003 (s, 2H, NH 2 ), 5.154 (J = 3.2 Hz, d, 1H, CH), 7.247 7.274 (J = 10.8 Hz, dd, 2H, Ar-H), 7.379-7.413

410 INDIAN J. CHEM., SEC B, MARCH 2015 (J = 13.6 Hz, dd, 2H, Ar-H), 7.738 (J = 3.2 Hz, d, 1H, NH), 9.209 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17. 75, 59.21, 98.88, 126.15, 128.33, 131.78, 143.75, 148.63, 151.93, 165.18; FT-IR (KBr): 3542, 3242, 3114 (NH), 3037 (Ar-H), 2977 (CH), 1713 (C=O), 1529 (C=N), 1290 (C-N), 1223 (C-S), 1089 (N-N), 1011 cm -1 (Cl-C); GCMS: m/z 322 M +. (4-(dimethylamino)phenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)-one, 3c: 1 H NMR (DMSO-d 6 ): δ 2.238 (s, 3H, CH 3 ), 2.856 (s, 6H, N(CH 3 ) 2 ), 3.996 (s, 2H, NH 2 ), 5.048 (J = 3.2 Hz, d, 1H, CH), 6.660 (J = 8.8 Hz, d, 2H, Ar-H), 7.048 (J = 8.4 Hz, d, 2H, Ar-H), 7.556 (J = 2.4 Hz, d, 1H, NH), 9.053 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.68, 53.30, 59.04, 99.94, 112.19, 126.85, 132.62, 147.46, 149.74, 152.27, 165.46; FT-IR (KBr): 3357, 3242, 3110 (NH), 3018 (Ar-H), 2977 (CH), 1721 (C=O), 1526 (C=N), 1221 (C-S), 1093 cm -1 (N-N); GCMS: m/z 331 M +. Synthesis of 5-(5-amino-1,3,4-thiadiazole-2-yl)- 4-(3-nitrophenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H)-one, 3d: 1 H NMR (DMSO-d 6 ): δ 2.066 (s, 3H, CH 3 ), 3.805 (s, 2H, NH 2 ), 5.098 (J = 3.2 Hz, d, 1H, CH), 7.036-7.802 (m, 4H, Ar-H), 8.482 (J = 3.2 Hz, d, 1H, NH), 9.126 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.81, 59.35, 98.35, 122.29, 123.87, 132.94, 133.40, 146.96, 147.73, 148.38, 149.36, 165.03, 178.39; FT-IR (KBr): 3429, 3396, 3245(NH), 3153 (Ar-H), 2980 (CH), 1705 (C=O), 1526 (C=N), 1348 (C-N), 1294 (C-S), 1094 cm -1 (N-N); GCMS: m/z 332 M +. (4- hydroxyphenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H)-one, 3e: 1 H NMR (DMSO-d 6 ): δ 2.237 (s, 3H, CH 3 ), 3.991 (s, 2H, NH 2 ), 5.051 (J = 3.2 Hz, d, 1H, CH), 6.887-7.115 (m, 4H, Ar-H), 7.563 (J = 1.6 Hz, d, 1H, NH), 9.074 (s, 1H, NH), 10.296 (br, 1H, OH); 13 C NMR (DMSO-d 6 ): δ 17.69, 59.08, 99.79, 114.97, 127.36, 129.67, 135.22, 147.65, 155.32, 156.51, 165.40; FT-IR (KBr): 3607 (OH), 3429, 3396, 3245 (NH), 3030 (Ar-H), 2980 (CH), 1705 (C=O), 1526 (C=N), 1348 (C-N), 1294 (C-S), 1094 cm -1 (N-N); GCMS: m/z 303M +. Synthesis of 5-(5-amino-1,3,4-thiadiazole-2-yl)-3,4- dihydro-6-methyl-4-phenyl pyrimidin-2(1h)-thione, 3f: 1 H NMR (DMSO-d 6 ): δ 2.301 (s,3h,ch 3 ), 4.030 (s, 2H, NH 2 ), 5.189 (J = 4 Hz, d, 1H, CH), 7.222-7.372 (m, 4H, Ar-H), 9.634 (J = 1.6 Hz, d, 1H, NH), 9.074 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.12, 59.57, 100.75, 126.35, 127.65, 128.51, 143.44, 144.95, 165.12, 174.23; FT-IR (KBr): 3328, 3174, 3106 (NH), 3033 (Ar-H), 2979 (CH), 1574 (C=N), 1384 (C-N), 1282 (C=S), 1195 (C-S), 1001 cm -1 (N-N); GCMS: m/z 303M +. (4-chlorophenyl)-3,4-dihydro-6-methyl pyrimidin- 2(1H)-thione, 3g: 1 H NMR (DMSO-d 6 ): δ 2.301 (s, 3H, CH 3 ), 4.027 (s, 2H, NH 2 ), 5.179 (J = 3.6 Hz, d, 1H, CH), 7.227-7.254 (J = 10.8 Hz, dd, 2H, Ar-H), 7.419-7.440 (J = 8.4 Hz, dd, 2H, Ar-H), 9.653 (J = 2 Hz, d, 1H, NH), 10.369 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.14, 59.62, 100.30, 128.28, 128.54, 132.24, 142.34, 145.32, 164.97, 174.24; FT-IR (KBr): 3327, 3174, 3104 (NH), 3030 (Ar-H), 2982 (CH), 1573 (C=N), 1380 (C-N), 1281 (C=S), 1196 (C-S), 1092 (N-N), 1014 cm -1 (Cl-C); GCMS: m/z 337M +. (4-(dimethylamino)phenyl)-3, 4-dihydro-6-methylpyrimidin-2(1H)-thione, 3h: 1 H NMR (DMSO-d 6 ): δ 2.284(s, 3H, CH 3 ), 2.864 (s, 6H, N(CH 3 ) 2 ), 4.018 (s, 2H, NH 2 ), 5.059 (J = 2.8 Hz, d, 1H, CH), 6.671 (J = 9.2 Hz, d, 2H, Ar-H), 7.024 (J = 8.8 Hz, d, 2H, Ar-H), 9.515 (J = 3.2 Hz, d, 1H, NH), 10.202 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.07, 53.48, 59.43,101.25, 112.16, 127.08, 131.18, 144.24, 149.93, 165.25, 173.84; FT-IR (KBr): 3326, 3164 (NH), 2982 (Ar-H), 2882 (CH), 1593 (C=N), 1360 (C-N), 1281 (C=S), 1191 (C-S), 1100 cm -1 (N-N); GCMS: m/z 346M +. Synthesis of 5-(5-amino-1,3,4-thiadiazole-2-yl)- 4-(3-nitrophenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H)-thione,3i: 1 H NMR (DMSO-d 6 ): δ 2.301 (s, 3H, CH 3 ), 4.027 (s, 2H, NH 2 ), 5.342 (J = 2.8 Hz, d, 1H, CH), 7.236 (J = 8.4 Hz, d, 2H, Ar-H), 7.429 (J = 8.4 Hz, d, 2H, Ar-H), 7.682-7.856 (J = 6.9 Hz, dd, 2H, Ar-H), 8.165 (J = 2.4 Hz, d, 1H, NH), 9.655 (s, 1H, NH); 13 C NMR (DMSO-d 6 ): δ 17.83, 59.35, 99.35, 123.87, 130.07, 133.04, 134.40, 136.16, 149.38, 151.06, 165.83, 178.39; FT-IR (KBr): 3424, 3326, 3176 (NH), 3016 (Ar-H), 2986 (CH), 1593 (C=N), 1343 (C-N), 1296 (C=S), 1193 (C-S), 1102 cm -1 (N-N); GCMS: m/z 348 M +. (4-hydroxyphenyl)-3, 4-dihydro-6-methylpyrimidin- 2(1H)-thione, 3j: 1 H NMR (DMSO-d 6 ): δ 2.229 (s, 3H, CH 3 ), 4.014 (s, 2H, NH 2 ), 5.075 (J = 8.4 Hz, d, 1H, CH), 7.386-8.051 (m, 4H, Ar-H), 8.562 (J = 5.2 Hz, d, 1H, NH), 10.224 (s, 1H, NH), 11.221 (s, 1H, OH); 13 C NMR (DMSO-d 6 ): δ 17.06, 59.32, 90.20, 115.11, 115.51, 125.42, 127.86, 129.00, 134.36, 152.51, 164.92; FT-IR (KBr): 3545 (OH), 3187, 3134 (NH), 3080 (Ar-H), 2980 (CH),1511 (C=N), 1329 (C-N),1285 (C=S), 1186 (C-S), 1113 cm -1 (N-N); GCMS: m/z 319M +. Antibacterial studies The newly synthesized pyrimidine derivatives were screened for their antibacterial activity in vitro against

ANDREWS et al.: PYRIMIDINE BEARING 1,3,4-THIADIAZOLE DERIVATIVES 411 Table III Antibacterial activity of compounds 3a-j Antibacterial activity (in mm) Std. Ciprofloxacin (25 mm) Compd Pseudomonas Staphylococcus Escherichia aeruginosa (-ve) aureus (+ve) coli (-ve) Control 0 0 0 3a 6 7 7 3b 5 7 8 3c 5 8 9 3d 5 5 8 3e 14 16 18 3f 5 5 6 3g 7 10 7 3h 5 5 6 3i 5 8 10 3j 10 11 14 Concentration was 10 µg/ml @ 10% DMSO; 0 no inhibition zone the species of Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli, using agar well disk diffusion method. The test compounds were dissolved in DMSO to get a solution of 10 µg/ml concentration. The inhibition zones were measured in millimeters at the end of an incubation period of 18 hr at 37 C. Ciprofloxacin was used as a reference standard and the results are shown in Table III. Most of the tested compounds showed antibacterial activity comparable with that of the standard drug ciprofloxacin. The investigation of antibacterial screening data revealed that all the tested compounds showed moderate to good inhibition at 10 µg/ml concentration. Especially, the compounds 3e and 3j showed very good activity in comparison to the others. However, the activity was less compared to the standard drug. Acknowledgement The authors are thankful to Principal and Research Department of Chemistry, Islamiah College, Vaniyambadi, Vellore district, Tamil Nadu for constant encouragement and providing necessary facilities. References 1 Kape C O, Tetrahedron, 49, 1993, 6937. 2 Ugi I, Domling A & Horl W, Endeavour, 18, 1998, 115. 3 Kape C O, Eur J Med Chem, 35, 2000, 1043. 4 Mannich C & Lammering D, Chem Ber, 55, 1922, 3510. 5 Manjula A, Rao B V & Neelakantam P, Synth Commun, 34, 2004, 2665. 6 Zych A, Wang H J & Sakwa S A, Tetrahedron Lett, 51, 2010, 5103. 7 Garima, Srivastava V P & Yadav D S, Tetrahedron Lett, 51, 2010, 6436. 8 Ryabukhin S V, Plaskon S, Bondarenko S, Ostapchuk E N, Grygorenko O, Shishkin V & Tolmachev A, Tetrahedron Lett, 51, 2010, 4229. 9 Tramontini M & Angiolini L, Mannich Bases: Chemistry and Uses (CRC Press, Boca Raton), 1994. 10 (a) Zang H, Vrang L, Bacbro K, Lind P, Sahlberg C, Unge & Oberg B, Antiviral Res, 28, 1995, 331; (b) Mishra V, Pandeya S N, Declereq E, Pannelouque & Witvouw M, Pharm Acta Helv, 73, 1998, 215. 11 Guo H M, Wu Y, Niu H Y, Wang D C & Qu G, J Org Chem, 75, 2010, 3863. 12 Hellmann H & Loschman I, Chem Ber, 87, 1954, 1684. 13 Moore M B & Rapela R T, J Am Chem Soc, 68, 1946, 1657. 14 Atkinson R O, J Chem Soc, 1954, 1329. 15 Varma R S, J Indian Chem Soc, 81, 2004, 627. 16 Narwade S K, Halnor V B, Dalvi N R, Gill C H & Karale B K, Indian J Chem, 45B, 2006, 2776. 17 Kidwai M, Venkataramanan R & Dave B, J Heterocycl Chem, 39, 2002, 1045. 18 Ross N A & Burtsch R A, J Heterocycl Chem, 38, 2001, 1255. 19 Singh V, Sapehiyia V & Kad G L, Synthesis, 2, 2003, 198. 20 Ojha S, Ameta U, Dhakar N & Talesara G L, Indian J Chem, 46B, 2007, 860. 21 Xiajuan Z & Guiyu J, J Heterocycl Chem, 38, 2001, 993. 22 Jagadhani S G, Kale S B, Dalvi N R, More M S & Karale B K, Indian J Heterocycl Chem, 15, 2006, 335. 23 Ravindra K C, Vaidya V P, Chandrashekhar C & Vagdevi M H, Indian J Heterocycl Chem, 15, 2006, 283. 24 Bhavsar A M, Shah M D, Saxena A K & Desai N C, Indian J Chem, 47B, 2008, 579. 25 Andrews B & Ahmed M, Asian J Chem, 25, 2013, 2070. 26 Andrews B & Ahmed M, J Chem Pharm Res, 4 (8), 2012, 3920.

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