HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 4, 2013, pp. 841-851
Received, 8th January, 2013, Accepted, 30th January, 2013, Published online, 13th February, 2013.
DOI: 10.3987/COM-13-12663

■ Synthesis and Biological Evaluation of Some New Pyrimidine Derivatives

Kamelia M. El-mahdy and Azza M. El-Kazak*

Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

Reaction of 2-mercaptopyrimidine 1 with ethyl chloroacetate afforded isomeric pyrimidines 2 and 3. Interaction of 3 with bifunctional nitrogen nucleophiles yielded pyrimidotriazine 5 and 7. Hydrazinolysis of 2 by hydrazine hydrate afforded hydrazinopyrimidine 8. Treatment of 8 with acetophenone gave 9. Cyclization of 9 with Vilsmeier reagent afforded the pyrazole carbaldehyde 10. Interaction of 8 with benzylidenemalononitrile and/or ethyl ethoxymethylene- cyanoacetate afforded the pyrazoles 11 and 12. The reaction of 8 with p-chlorobenzaldehyde yielded 13, which was cyclized with thioglycolic acid to give thiazolidinone 14. The biological activity of selected compounds was investigated.

The synthesis of dihydropyrimidine derivatives have been attracting extensive attention as a wide range of such compounds played an important role in the field of medicinal chemistry as antiviral,1 antibacterial,2 antimalarial,3 antihypertensive4 and anti-inflammatory agents.5 In addition, pyrimidine derivatives form the basis of a large number of pharmacological products with anticancer and protein kinase inhibitory activity.6,7 The Biginelli reaction8 is a simple one-pot condensation of an aldehyde, keto ester, and urea or thiourea in the presence of catalytic amount of acid to produce 3,4-dihydropyrimidin-2(1H)-ones. Dihydropyrimidinones (DHPMs) and their derivatives exhibit wide range of biological activities such as antibacterial, antiviral, antitumour, and anti-inflamatory actions.9 Biginelli compounds exhibit pharmacological activities as calcium channel blockers, antihypertensive agents, α-1a–antagonists, and neuro peptide Y(NPY) antagonists.10-12 Biological activities of some marine alkaloids isolated were also found to contain the dihydropyrimidinone-5-carboxylate core.13-16
The versatile biological properties of pyrimidine derivatives prompted us to synthesize some novel pyrimidine and fused heterocyclic pyrimidine derivatives for biological screening.
On heating of ethyl 2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (1)17 under reflux with ethyl chloroacetate in ethanolic potassium hydroxide solution, ethyl 2-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (2) and ethyl 1-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (3) were obtained (Scheme 1).

As depicted in Scheme 1, the reaction proceeded through S-alkylation18 to give S-alkylated product 2 as the major reaction product in 75% yield. In addition, this reaction was accompanied by a second, minor product, 3, which was obtained in 10% yield. The structures of compounds 2 and 3 were confirmed on the basis of their elemental analysis, IR, 1H NMR and mass spectral analysis.
Treatment of compound 3 with ethyl carbazate, in refluxing ethanol in the presence of a catalytic amount of piperidine, furnished a single product identified as diethyl pyrimido[2,1-c][1,2,4]triazine-4,7-dicarboxylate 5. The formation of 5 may be attributed to the intermediacy of the non-isolable transamination adduct 4, which underwent cyclization via loss of ethanol molecule. Also, compound 3 was allowed to react with hydrazine hydrate in boiling ethanol, it yielded the respective pyrimido[2,1-c][1,2,4]triazine-7-carbohydrazide 7. The direct formation of 7 indicates that the initially formed product namely ethyl 1-(2-ethoxy-2-oxoethyl)-2-hydrazino-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (6) underwent in situ cyclization via loss of ethanol molecule to give pyrimido[2,1-c][1,2,4]triazine 7 (Scheme 2).

The structures of compounds 5 and 7 were characterized from their spectroscopic as well as elemental analytical data. Thus, compound 5 showed absorption bands at 3243, 1704 and 1648 cm-1 corresponding to NH and two C=O functions, respectively. Its 1H NMR spectrum revealed a triplet signal at δ 1.09 ppm with coupling constant (J = 6.6 Hz) due to CH3 protons, a quartet signal at δ 3.99 ppm with coupling constant (J = 6.9 Hz) due to CH2 protons, two D2O-exchangeable signals at δ 6.88 and 7.15 due two NH protons in addition to D2O-exchangeable signal at δ 9.13 corresponding to OH proton. The IR spectrum of compound 6 revealed bands at 3431, 3250 and 1632 cm-1 corresponding to NH2, NH and C=O groups, respectively. Its 1H NMR spectrum showed the absence of CH3 and CH2 protons of ethoxycarbonyl group and showed D2O-exchangeable signal at δ 3.39 ppm due to NH2 protons. It showed also three D2O-exchangeable signals at δ 7.65, 7.81 and 7.82 ppm corresponding to three NH protons, in addition to aromatic protons.

When the thioglycolate 2 was treated with hydrazine hydrate, it afforded 2-hydrazino-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide (8). 2-hydrazinopyrimidine carbohydrazide 8 could be used as versatile building blocks in the synthesis of new heterocyclic systems. Thus, condensation of 2-hydrazinopyrimidine 8 with acetophenone in boiling ethanol and few drops of acetic acid were added, it gave N-[(1-phenylethylidene)-2-[2-(1-phenylethylidene)hydrazino]-1,6-dihydropyrimidine 9, which on treatment with POCl3/DMF under Vilsmeier reaction condition yielded the final product 1-{5-[(4-formyl-3-phenyl-1H-pyrazol-1-yl)-carbonyl]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl}-3-phenyl-1H-pyrazole-4-carbaldehyde (10) (Scheme 3).

The structures of compounds 9 and 10 were characterized from their spectroscopic as well as elemental analytical data. The IR and 1H NMR spectrum of compound 9 lacked an absorption band and protons corresponding to NH2 groups. While, the IR spectrum of compound 10 showed bands at 1717 and 1680 due to formyl and exocyclic C=O groups, its 1H NMR spectrum were characterized by the appearance of single broad signal at 13 ppm attributed to formyl proton.
Furthermore, cyclocondensation of 2-hydrazinopyrimidine 8 with (p-methoxybenzylidene)malononitrile in pyridine gave the corresponding aminopyrazolecarbonitrile 11. Also, interaction of 8 with ethyl ethoxymethylenecyanoacetate in DMF led to the formation of the ethyl pyrazolecarboxylate 12. Finally, the amino functionality of 2-hydrazinopyrimidine carbohydrazide 8 was reacted with carbon electrophiles such p-chlorobenzaldehyde to afford 2-[2-(p-chlorobenzylidene)hydrazine]-N-[1-(p-chlorophenyl)- methylene]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide (13). Compound 13 was formed by nucleophilic attack of the amino group on the electronically deficient carbonyl carbon atom of the aldehyde followed by dehydration. It is of interest to investigate the behavior of 13 which contain an activated C=N bond towards aliphatic mercaptan. Thus, cyclocondensation of 13 with thioglycolic acid in dioxane gave the thiazolidinone derivative 14 (Scheme 4).

The structures of compounds 11 and 12 were confirmed on the basis of their elemental analysis, IR, 1H NMR, and the mass spectral data. The IR spectrum of compound 11 showed characteristic bands at 2208 attributed to C≡N group. While, the IR spectrum of compound 12 revealed absorption peaks at 1721 and 1693 cm-1 due to ester and exocyclic C=O group. The 1H NMR spectrum of compound 11 was characterized by the appearance of douplet douplet signals at δ 6.95 ppm with coupling constant (J = 8.7 Hz), 7 ppm with coupling constant (J = 8.4 Hz), 7.08 ppm with coupling constant (J = 6.9 Hz), 7.13 ppm with coupling constant (J = 6.9 Hz), 7.42 ppm with coupling constant (J = 8.4 Hz), and 7.75 ppm with coupling constant (J = 8.7 Hz), assignable to aromatic protons. While, the 1H NMR spectrum of compound 12 was characterized by the appearance of CH3 and CH2 protons of ethoxycarbonyl groups. The mass spectrum of compound 12 showed a molecular ion peak (M+) at m/z = 536 which is in an agreement with the molecular formula C25H28N8O6.
Also, the structures of compounds 13 and 14 were confirmed on the basis of their elemental analysis, IR, 1H NMR and mass spectral analysis. The IR and 1H NMR spectrum of compounds 13 and 14 lacked an absorption band and protons corresponding to NH2 group. 1H NMR spectrum of compound 13 revealed singlet signal at δ 8.71 assigned to the CH=N. The mass spectrum of 14 showed a molecular ion peak (M+) at m/z = 683 corresponding to a molecular formula C31H28Cl2N6O4S2.

EXPERIMENTAL
Melting points are uncorrected and were recorded in open capillary tubes on a Stuart SMP3 melting point apparatus. Infrared spectra were recorded on FT-IR Bruker Vector 22 spectrophotometer using KBr wafer technique. The 1H NMR and 13C NMR spectra were recorded in DMSO-d6 or CDCl3 on Gemini spectrometer (300 MHz for 1H NMR and 75 MHz for 13C NMR) and the chemical shift in δ downfield from TMS as an internal standard. Elemental microanalyses were performed at the Main Laboratories of the War Chemical. Mass spectra were obtained using gas chromatography GCMS qp-2010 plus Schimadzu instrument mass spectrometer (70 eV) were performed at the Cairo University Microanalytical Center.
Ethyl 2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (1). This compound was prepared according to the reported method.17
Ethyl 2-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (2) and ethyl 1-(2-ethoxy-2-oxoethyl)-2-mercapto-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxylate (3). A mixture of compound 1 (3 g, 0.01 mol) and ethyl chloroacetate (1.6 mL, 0.015 mol) in ethanolic potassium hydroxide solution (prepared by dissolving 0.56 g, 0.01 mol of KOH in 50 mL EtOH) was heated under reflux for 3 h and cooled. The solid obtained was filtered off and recrystallized from dilute dioxane to give compound 3 as yellow crystals (0.3 g, yield 10%): mp >300 °C; IR (ν cm-1) 3114 (CH aromatic), 2979, 2956 (CH aliphatic), 1704 (C=O), 1648 (C=O), 1611 (C=N); 1H NMR (DMSO-d6) δ 1.09 (t, 6H, CH2 CH3, J = 6.9 Hz), 2.23 (s, 3H, CH3), 3.35 (s, 2H, NCH2), 3.71 (s, 3H, OCH3), 3.96 (q, 4H, CH2 CH3, J = 6.9 Hz), 5.09 (s, 1H, pyrimidine-H-6), 6.86 (d, 2H, ArH’s, J = 9 Hz), 7.14 (d, 2H, ArH’s, J = 9 Hz), 9.16 (s, 1H, D2O-exchangeable, SH); MS m/z (%): [M+-CH2] 378 (5.8), 351 (21.8), 328 (28.8), 302 (25.3), 234 (20.2), 232 (4.2), 218 (18.9), 195 (19.9), 155 (100), 151 (20.8), 123 (9.3), 97 (8.9); Anal. Calcd for C19H24N2O5S (%): C, 58.15; H, 6.16; N, 7.14. Found C, 58.18; H, 6.16; N, 7.10%.
On the other hand, the filtrate of the above reaction was poured gradually onto crushed ice. The solid was filtered off and recrystallized from EtOH to give compound 2 as yellow crystals (2.25 g, yield 75%): mp 180-182 °C; IR (ν cm-1) 3114 (CH aromatic), 2979, 2956 (CH aliphatic), 1704 (C=O), 1648 (C=O), 1611 (C=N); 1H NMR (DMSO-d6) δ 1.09 (t, 6H, CH2CH3, J = 6.9 Hz), 2.23 (s, 3H, CH3), 3.35 (s, 2H, NCH2), 3.71 (s, 3H, OCH3), 3.96 (q, 4H, CH2CH3, J = 6.9 Hz), 5.09 (s, 1H, pyrimidine-H-6), 6.86 (d, 2H, ArH’s, J = 9 Hz), 7.14 (d, 2H, ArH’s, J = 9 Hz ), 9.16 (s, 1H, D2O-exchangeable, NH); MS m/z (%): [M+-CH2] 378 (22.4), 348 (5.5), 290 (21.2), 275 (11.8), 261 (100), 244 (20.2), 217 (63.5), 183 (42.1), 155 (39.1), 137 (43.1), 77 (42.6); Anal. Calcd for C19H24N2O5S (%): C, 58.15; H, 6.16; N, 7.14. Found C, 58.20; H, 6.14; N, 7.18%.
Diethyl 3-hydroxy-6-(p-methoxyphenyl)-8-methyl-1,6-dihydro-2H-pyrimido[2,1-c][1,2,4]triazine-4,7-dicarboxylate (5). A mixture of compound 3 (0.392 g, 0.001 mol) and ethyl carbazate (0.104 g, 0.001 mol) in EtOH (10 mL) and few drops of piperidine was refluxed for 2 h. The solid thus obtained was filtered off and recrystallized from EtOH to give compound 5 as yellow crystals (0.274 g, yield 70%): mp 248-250 °C; IR (ν cm-1) 3243 (NH), 3113 (CH aromatic), 2979, 2955 (CH aliphatic), 1704, 1648 (C=O), 1612 (C=N); 1H NMR (DMSO-d6) δ 1.09 (t, 6H, CH2CH3, J = 6.6 Hz), 2.23 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.99 (q, 4H, CH2CH3, J = 6.9 Hz), 5.08 (s, 1H, pyrimidine-H-6), 6.85 (d, 2H, ArH’s, J = 8.1 Hz), 7.12 (d, 2H, ArH’s, J = 9 Hz), 6.88, 7.15 (s, 2H, D2O-exchangeable, NH), 9.13 (s, 1H, D2O-exchangeable, OH); MS m/z (%): [M+] 416 (34.3), 415 (32.5), 403 (32.5), 373 (38.5), 340 (34.3), 308 (36.7), 284 (51.5), 274 (42), 183 (45), 137 (100), 84 (88.7), 58 (52.6); Anal. Calcd for C20H24N4O6 (%): C, 57.68; H, 5.81; N, 13.45. Found C, 57.70; H, 5.80; N, 13.50%.
6-(p-Methoxyphenyl)-8-methyl-3-oxo-1,3,4,6-tetrahydro-2H-pyrimido[2,1-c][1,2,4]triazine-7-carbohydrazide (7). A suspension of compound 3 (0.392 g, 0.001 mol) and hydrazine hydrate (4 mL, 99%) in EtOH (10 mL) was refluxed for 2 h and cooled. The solid separated was filtered off and recrystallized from dioxane to give compound 7 as yellow crystals (0.274 g, yield 70%): mp 258-260 °C; IR (ν cm-1) 3431, 3250 (NH2, NH), 3050 (CH aromatic), 2925 (CH aliphatic), 1632 (C=O); 1H NMR (DMSO-d6) δ 2.28 (s, 3H, CH3), 3.39 (brs, 2H, D2O-exchangeable, NH2), 3.77 (s, 3H, OCH3), 3.79 (s, 2H, CH2), 6.82 (s, 1H, pyrimidine-H-6), 7.03 (d, 2H, ArH’s, J = 8.7 Hz), 7.79 (d, 2H, ArH’s, J = 8.7 Hz), 7.65, 7.81, 7.82 (s, 3H, D2O-exchangeable, NH); MS m/z (%): [M+] 330 (55.3), [M++1] 331 (82.9), 302 (61.7), 286 (61.7), 274 (15), 252 (70.2), 206 (61.7), 172 (74.5), 92 (100), 78 (80), 58 (46.8); Anal. Calcd for C15H18N6O3 (%): C, 54.54; H, 5.49; N, 25.44. Found C, 54.60; H, 5.50; N, 25.40%.
2-Hydrazino-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide (8).
A mixture of compound 2 (0.392 g, 0.001 mol) and hydrazine hydrate (5 mL, 99%) was heated under reflux for 2 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from EtOH to give compound 8 as yellow crystals (0.31 g, yield 80%): mp 168-170 °C; IR (ν cm-1) 3243, 3139 (NH2, NH), 3034 (CH aromatic), 2981 (CH aliphatic), 1625 (C=O), 1602 (C=N); 1H NMR (DMSO-d6) δ 2.24 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 4.71 (s, 4H, D2O-exchangeable, NH2), 6.83 (s, 1H, pyrimidine-H-6), 7.02 (d, 2H, ArH’s, J = 8.4 Hz), 7.56 (s, 1H, D2O-exchangeable, NH), 7.59 (s, 1H, D2O-exchangeable, NH), 7.77 (d, 2H, ArH’s, J = 8.4 Hz), 8.20 (s, 1H, D2O-exchangeable, NH); MS m/z (%): [M++1] 291 (16.1), [M+] 290 (17.8), 275 (19.2), 264 (20.9), 234 (25.1), 219 (21.4), 172 (24.2), 135 (29.9), 134 (22), 75 (100), 60 (9.6), 52(8.4); Anal. Calcd for C13H18N6O2 (%): C, 53.78; H, 6.25; N, 28.95. Found C, 53.72; H, 6.20; N, 28.90%.
6-(p-Methoxyphenyl)-4-methyl-N-[(1-phenylethylidene)-2-[2-(1-phenylethylidene)hydrazino]-1,6-dihydropyrimidine-5-carbohydrazide (9). To a solution of 8 (0.29 g, 0.001 mol) in hot EtOH, acetophenone (0.22 mL, 0.002 mol) and few drops of acetic acid were added. The solid that separated on warming for 30 min on a water-bath was filtered off and recrystallized from MeOH to give compound 9 as yellow crystals (0.2 g, yield 72%): mp 128-129 °C; IR (ν cm-1) 3350 (NH), 3056 (CH aromatic), 2958 (CH aliphatic), 1679 (C=O), 1602 (C=N); 1H NMR (DMSO-d6) δ 2.22 (s, 3H, CH3), 2.27 (s, 6H, CH3C=N), 3.62 (s, 3H, OCH3), 7.45-7.91 (m, 15H, ArH’s and pyrimidine-H-6), 7.92, 7.93 (s, 3H, D2O-exchangeable, NH); MS m/z (%): [M+] 494 (28.7), [M+-1] 493 (3.9), 412 (44), 387 (31.1), 334 (18.8), 320 (41.5), 214 (42.5), 187 (28.7), 174 (36.1), 131 (83.6), 101 (100), 73 (29.7), 66 (34.1); Anal. Calcd for C29H30N6O2 (%): C, 70.42; H, 6.11; N, 16.99. Found C, 70.40; H, 6.10; N, 16.70%.
1-{5-[(4-Formyl-3-phenyl-1H-pyrazol-1-yl)carbonyl]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl}-3-phenyl-1H-pyrazole-4-carbaldehyde (10). To the Vilsmeier reagent [prepared from DMF (10 mL) and POCl3 (1.1 mL, 0.012 mol)], compound 9 (1.1 g, 0.004 mol) in DMF was added and then the reaction mixture stirred at 60-65 °C for 2 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from dilute dioxane to give compound 10 as yellow crystals (0.66 g, yield 60%): mp 288-290 °C; IR (ν cm-1) 3430 (NH), 3057 (CH aromatic), 2926 (CH aliphatic), 1717, 1680 (C=O), 1628 (C=N); 1H NMR (DMSO-d6) δ 2.23 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 6.68 (s, 1H, pyrimidine-H-6), 7.03-8.57 (m, 16H, ArH’s and pyrazole-H-5), 8.21 (s, 1H, D2O-exchangeable, NH), 13 (s, br, 2H, CHO); MS m/z (%): [M++1] 571 (0.71), [M+] 570 (0.20), 549 (6.50), 537 (8.87), 532 (6.63), 509 (5.57), 492 (2.72), 480 (3.09), 423 (3.97), 313 (14.62), 236 (21.37), 150 (100), 64 (43.14), 55 (38.83); Anal. Calcd for C33H26N6O4 (%): C, 69.46; H, 4.59; N, 14.73. Found C, 69.40; H, 4.54; N, 14.70%.
3-Amino-1-{(5-[(3-amino-4-cyano-5-(p-methoxyphenyl)-1H-pyrazol-1-yl)carbonyl]}-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)-5-(p-methoxyphenyl)-1H-pyrazole-4-carbonitrile (11). A mixture of 8 (0.29 g, 0.001 mol) and (p-methoxybenzylidene)malononitrile (0.368 g, 0.002 mol) in pyridine (10 mL) was heated under reflux for 3h. The reaction mixture was cooled, poured gradually onto crushed ice and neutralized with diluted HCl. The solid obtained was filtered off and recrystallized from MeOH to give compound 11 as brown crystals (0.17 g, yield 60%): mp 130-132 °C; IR (ν cm-1) 3320, 3205 (NH2, NH), 3006 (CH aromatic), 2930 (CH aliphatic), 2208 (C≡N), 1670 (C=O), 1603 (C=N); 1H NMR (DMSO-d6) δ 2.48 (s, 3H, CH3), 3.32 (s, br, 4H, NH2), 3.82 (s, 9H, OCH3), 6.75 (s, 1H, pyrimidine-H-6), 6.95 (d, 2H, ArH’s, J = 8.7 Hz), 7 (d, 2H, ArH’s, J = 8.4 Hz), 7.08 (d, 2H, ArH’s, J = 6.9 Hz), 7.13 (d, 2H, ArH’s, J = 6.9 Hz), 7.42 (d, 2H, ArH’s, J = 8.4 Hz), 7.75 (d, 2H, ArH’s, J = 8.7 Hz), 9.10 (s, 1H, D2O-exchangeable, NH); MS m/z (%): [M++1] 655 (56.7), [M+] 654 (61.2), 518 (80.1), 490 (73.8), 401 (75.6), 398 (72.9), 345 (66.6), 321 (100), 318 (59.4), 297 (70.2), 271 (81), 260 (88.2), 229 (65.7), 191 (63), 145 (70.2), 73 (63.9); Anal. Calcd for C35H30N10O4 (%): C, 64.21; H, 4.62; N, 21.39. Found C, 64.20; H, 4.60; N, 21.36%.
Ethyl 3-amino-1-(5-{[(3-amino-4-(ethoxycarbonyl)-1H-pyrazol-1-yl)carbonyl]}-6-(p-methoxy- phenyl)-4-methyl-1,6-dihydropyrimidin-2-yl)-1H-pyrazole-4-carboxylate (12). Equimolar mixture of compound 8 (0.29 g, 0.001 mol) and ethyl ethoxymethylenecyanoacetate (0.338 g, 0.002 mol) in DMF (10 mL) was refluxed for 4 h then cooled and diluted with cooled water. The solid obtained was filtered off and recrystallized from EtOH to give compound 12 as yellow crystals (0.17 g, yield 60%): mp 185-186 °C; IR (ν cm-1) ν 3392, 3279, 3124 (NH2, NH), 3090 (CH aromatic), 2933, 2904 (CH aliphatic), 1721, 1693 (C=O), 1635 (C=N); 1H NMR (DMSO-d6) δ 1.32 (t, 6H, CH2CH3, J = 6.9 Hz), 2.49 (s, 3H, CH3), 3.31 (s, 3H, OCH3), 4.24 (s, 2H, D2O-exchangeable, NH2), 4.31 (q, 4H, CH2CH3, J = 6.9 Hz), 4.39 (s, 2H, D2O-exchangeable, NH2), 5.20 (s, 1H, pyrimidine-H-6), 8.57-8.79 (m, 6H, ArH’s and pyrazole-H-5), 9 (s, 1H, D2O-exchangeable, NH); MS m/z (%): [M+] 536 (59.7), [M+-1] 535 (77.1), 515 (93.4), 499 (89.1), 465 (85.8), 429 (61,9), 381 (59.7), 355 (88), 307 (77.1), 284 (76), 241 (100), 201 (93.4), 155 (13), 101(80.4), 81 (46.7), 56 (28.2); Anal. Calcd for C25H28N8O6 (%): C, 55.96; H, 5.26; N, 20.88. Found C, 55.90; H, 5.24; N, 20.90%.
2-[2-(p-Chlorobenzylidene)hydrazine]-N-[1-(p-chlorophenyl)methylene]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carbohydrazide (13). A mixture of 8 (0.29 g, 0.001 mol) and p-chlorobenzaldehyde (0.28 g, 0.002 mol) in glacial acetic acid (10 mL) was heated under reflux for 2 h. The reaction mixture was cooled and poured gradually onto crushed ice. The solid obtained was filtered off and recrystallized from EtOH to give compound 13 as yellow crystals (0.26 g, yield 90%): mp 208-210 °C; IR (ν cm-1) 3429 (NH), 3027 (CH aromatic), 2931 (CH aliphatic), 1664 (C=O), 1624 (C=N); 1H NMR (DMSO-d6) δ 2.49 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 6.90 (s, 1H, pyrimidine-H-6), 7.56-7.89 (m, 12H, ArH’s), 7.91 (s, 3H, D2O-exchangeable, NH), 8.71 (s, 2H, CH=N); MS m/z (%): [M++2] 537 (62), [M+] 535 (21), 446 (86), 427 (73), 413 (54), 364 (78), 319 (86.), 309 (57), 294 (78), 226 (73), 157 (92), 117 (100), 68 (58), 55 (79); Anal. Calcd for C27H24Cl2N6O2 (%): C, 60.57; H, 4.52; N, 15.70. Found C, 60.54; H, 4.50; N, 15.78%.
N-[(4-(p-Chlorophenyl)-5-oxo-1,3-thiazolidin-3-yl)-2-[(4-(p-chlorophenyl)-5-oxo-1,3-thiazolidin-3-yl)amino]-6-(p-methoxyphenyl)-4-methyl-1,6-dihydropyrimidine-5-carboxamide (14). A mixture of 13 (0.535 g, 0.001 mol) and thioglycolic acid (0.69 mL, 0.01 mol) in dioxane (10 mL) was refluxed for 10 h. The solid obtained was filtered off and recrystallized from EtOH to give compound 14 as yellow crystals (0.48 g, yield 90%): mp 197-199 °C; IR (ν cm-1) 3434 (NH), 3090 (CH aromatic), 2981, 2925 (CH aliphatic), 1670, 1654 (C=O), 1624 (C=N); 1H NMR (DMSO-d6) δ 2.08 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.83 (s, 2H, NCH2S), 3.97 (s, 2H, NCH2S), 6.48 (s, 1H, pyrimidine-H-6), 7.38-7.89 (m, 14H, ArH’s and thiazolidinone-H-4), 7.92 (s, 3H, D2O-exchangeable, NH); MS m/z (%): [M++2] 685 (29.5), [M++1] 684 (39.5), [M+] 683 (28.6), 667 (25.9), 655 (30), 627 (35.4), 586 (42.7), 534 (35.4), 454 (44), 405 (46.3), 364 (45.4), 289 (40.9), 258 (14.1), 195 (46.8), 72 (100), 58 (14.5); Anal. Calcd for C31H28Cl2N6O4S2 (%): C, 54.46; H, 4.13; N, 12.29. Found C, 54.40; H, 4.10; N, 12.20%.

BIOLOGICAL ACTIVITIES
The results depicted in Table 1, showed various activities against all species of microorganisms which suggest that the variations in the structures affect on the growth of the microorganisms. Thus, we can conclude from these results that, some of the prepared compounds showed a low to high antimicrobial activity towards Gram positive bacteria, Gram negative bacteria and the fungal strain (Table 1).

References

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