Research Article
Synthesis and Anti-microbial Evaluation of Some 3, 4-Dihydro Pyrimidine-2-one Derivatives

Richa Mishra, Brijeshkunvar Mishra and N.S. Hari Narayana Moorthy

Trends in Applied Sciences Research, 2008, 3(2), 203-208.

Abstract

4-phenyl-5-carboxyethyl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-ones have been synthesized using the principle of Biginelli condensation from easily available starting materials. The carboethoxy group at the C₅ position of the pyrimidine ring is converted to corresponding hydrazide which in turn is condensed with cyclizing agents such as aromatic aldehyde, CS₂ to give fused heterocycles. The fused heterocycles are then subjected to substitution to give N₃-aryl/alkylpyrimido-heterocycles in excellent yields. The compounds were tested for antimicrobial action relative to Norfloxacin against Gram positive and Gram negative bacteria using serial dilution technique.

ASCI-ID: 95-170

Fig. 1) adapted from the schemes already reported (Padhy et al., 2003) and (Upadhyay and Ram, 1999).

Fig. 1:	Synthesis of pyrimidine derivatives

Synthesis of 4-Phenyl-5-Carboethoxy-6-Methyl-3, 4-Dihydropyrimidine-2- One
0.5 moles of urea (1), 0.75 moles of ethylacetoacetate (3) and 0.5 moles of benzaldehyde (2) were mixed in 25 mL of ethanol. Catalytic amount of concentrated hydrochloric acid (5 drops) was added to the mixture and the mixture was refluxed until the completion of the reaction (approximately 3 h). On cooling, a solid separated which was filtered and recrystallized using ethanol to give the product 4. Completion of the reaction was monitored by TLC, yield 83%; m.p.185-189°C; IR (5): 1570 (C-N), 1650 (amide), 1730 (ester), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.5 (s, CH₃), 1.8 (t, COOCH₂CH₃), 2.5 (q, COOCH₂CH₃), 3.4 (s, C-NH-CHO), 5.4 (s, Ar-NH-CO), 6.4 (s, Ar-CH), 7-8 (m, 5H, ArH); MS: m/z 260 (M⁺).

Synthesis of 4-Phenyl -5-Carboxyhydrazide-6-Methyl-3, 4-Dihydropyrimidine-2-One
To 0.1 mole of the product 4 in 20 mL ethanol, 0.1 mole of hydrazine hydrate was added. To the mixture, catalytic amount of concentrated sulfuric acid was added. The mixture was refluxed until the completion of the reaction (approximately 2 h). On cooling, a solid separated, which was recrystallized from ethanol to give the product V, yield 50%; m.p. 184-186°C; IR(KBr) cm^-1: 1570 (C-N), 1650 (amide), 3350 (N-H) cm^-1; ¹H NMR (CDCl₃): δ 2.5 (d, 2H, NHNH₂), 3.4 (s, C-NH-CO), 5.1 (s, CO-NH-CO), 4.1 (t, CONHN), 7-8 (m, 5H, ArH); MS: m/z 246 (M⁺).

Synthesis of 4- Phenyl -5-(2’-Substituted-1’, 3’, 4’-Triazolo)-6-Methyl-3, 4-Dihydropyrimidine-2-One
To 0.1 mole of product 5 in 20 mL acetic acid, a pinch of ammonium acetate was added, followed by the addition of 0.1 mole of Benzaldehyde/formaldehyde solution. The mixture was stirred for 24 h at room temperature. After 24 h, the reaction mixture was neutralized with ammonia solution, to give a solid, which was recrystallized from ethanol to give the product 6, yield 48%; m.p. 138-142°C; IR: 1650 (amide), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.4 (s, -CH₃), 5.2 (s, C-NH-CO), 7-8 (m, 9H, ArH).

Synthesis of 4-Phenyl -5-(1’, 3’, 4’-Thiadiazolo)-6-Methyl-3, 4-Dihydropyrimidine-2-One
To a solution of 0.15 moles potassium hydroxide in ethanol and 0.15 mole of the compound 5 was added 0.15 mole of carbon disulfide. The mixture was diluted with ethanol and stirred at room temperature for 12-16 h. The mixture was then neutralized with concentrated hydrochloric acid and the precipitated solid was filtered, washed with water and recrystallized from ethanol to give the product 7, yield: 52%; m.p. 146-148°C; IR(KBr) cm ^-1: 1570 (C-N), 1650 (amide), 2650 (SH), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.4 (s, 3H, CH₃), 3.2 (s, 6H, OCH₃), 6.4 (s, ArCH), 7-8 (m, 3H, ArH).

General Method of Synthesis of the N-Substituted Compound
A mixture of 2.17 nmoles of 6 or 7, 4.35 nmoles of K₂CO₃ and 4.48 nmoles of the alkyl or aryl halide in 6 mL of DMF was stirred for 4 h at room temperature. The mixture was then diluted with water and the solid was filtered off and was recrystallized from ethanol to give the final product 8 or 9.

Table 1 summarizes the various synthesized compounds and the percent yield of each relative to the compound 6. The physical properties of synthesized compounds (Table 2).

Synthesis of 4-Phenyl-5-2’-(1’,3’,4’-Triazolo-5’-Phenyl)-6-Methyl-3-N-Phenyl-Pyrimidine-2-One

To 2.17 nmoles of 6, 4.35 nmoles of K₂CO₃ and 4.48 nmoles of chlorobenzene in 6 mL DMF was stirred for 4 h at room temperature. The mixture was then diluted with water and the solid was filtered off and was recrystallized from ethanol to give the final product PYMTB 1, IR(KBr) cm^-1: 1570 (C-N), 1650 (amide), 2650 (SH), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.4 (s, 3H, CH₃), 3.2 (s, 6H, OCH₃), 6.4 (s, ArCH), 7-8 (m, 3H, ArH); MS: m/z 407 (M⁺); Found: N, 16.76%.

Table 1:	List of the synthesized compound

Table 2:	Physical properties of the synthesized compounds

Synthesis of 4-Phenyl-5-2’-(1’,3’,4’-Triazolo-5’-Phenyl)-6-Methyl-3-N-Methyl-Pyrimidine-2-One
To 2.17 nmoles of 6, 4.35 nmoles of K₂CO₃ and 4.48 nmoles of methyl chloride in 6 mL DMF was stirred for 4 h at room temperature. The mixture was then diluted with water and the solid was filtered off and was recrystallized from ethanol to give the final product PYMTB 2, IR (Kbr) cm^-1: 1570 (C-N), 1650 (amide), 2650 (SH), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.4 (s, 3H, CH₃), 3.2 (s, 6H, OCH₃), 6.4 (s, ArCH), 7-8 (m, 3H, ArH); MS: m/z 346 (M⁺); Found: N, 19.80%.

Table 3:	Antibacterial activity of the synthesized compounds

Synthesis of 4-Phenyl-5-2’-(1’,3’,4’-Thiadiazolo)-6-Methyl-3-N-Phenyl-Pyrimidine-2-One
To 2.17 nmoles of 6, 4.35 nmoles of K₂CO₃ and 4.48 nmoles of chlorobenzene in 6 mL DMF was stirred for 4 h at room temperature. The mixture was then diluted with water and the solid was filtered off and was recrystallized from ethanol to give the final product PYMTD -1, IR(KBr) cm^-1: 1570 (C-N), 1650 (amide), 2650 (SH), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.4 (s, 3H, CH₃), 3.2 (s, 6H, OCH₃), 6.4 (s, ArCH), 7-8 (m, 3H, ArH); MS: m/z 380 (M⁺); Found: N, 14.01%.

Synthesis of 4-Phenyl-5-2’-(1’,3’,4’-Thiadiazolo)-6-Methyl-3-N-Methyl-Pyrimidine-2-One
To 2.17 nmoles of 6, 4.35 nmoles of K₂CO₃ and 4.48 nmoles of methyl chloride in 6 mL DMF was stirred for 4 h at room temperature. The mixture was then diluted with water and the solid was filtered off and was recrystallized from ethanol to give the final product PYMTD 2, IR (KBr) cm^-1: 1570 (C-N), 1650 (amide), 2650 (SH), 3350 (NH) cm^-1; ¹H NMR (CDCl₃): δ 1.4 (s, 3H, CH₃), 3.2 (s, 6H, OCH₃), 6.4 (s, ArCH), 7-8 (m, 3H, ArH); MS: m/z 318 (M⁺); Found: N, 16.75%.

Antimicrobial Evaluation of the Synthesized Compounds
The antimicrobial activity of the synthesized compounds was tested against Proteus mirabilis, Pseudomonas aeruginosa (Gram negative), Bacillus subtilis, Staphylococcus aureus (Gram positive) bacteria (Table 3).

RESULTS AND DISCUSSION

Characterization of the synthesized compounds was carried out by determining their melting points, UV absorption maxima, IR spectra, H1 NMR and nitrogen content studies by Kjeldahl method. All the compounds were found to exhibit the amide, amine, aromatic hydrogen and methoxy group shifts in the 1H NMR spectra.

The yield of all the synthesized compounds is found to be significant. The structural confirmation of the compounds is done by IR spectra and the percentage nitrogen content found in the synthesized compounds. All the synthesized compounds show peaks in the IR spectrum at wave number (cm^-1) 3500, 3120, 2980, 1690, 756, 1370 and 1456. These peaks are characteristics of N—H, C—H (Aromatic), C—H, C = O stretching and C—H bending. Compounds PYMD-1 and PYMD-2 show peaks at 2525, which is the characteristic stretching of S—H group.

The compounds were evaluated for anti bacterial activity by serial dilution method. All the synthesized compounds possessed anti bacterial activity. MIC value of the compounds was deduced from the antibacterial assay method employed.

The results obtained led to the conclusion that the activity of the pyrimidine derivatives as anti microbial agents is affected by the type of the substituent at the 5-position of the pyrimidine nucleus. As envisaged from the literature review and SAR studies, the substitution of the nitrogen in pyrimidine ring led to significant anti microbial activity. It could also be concluded from the results that the substitution of the 5-position with a substitution on the substituent yielded better activity than a non substituted one. The substitution of the pyrimidine ring nitrogen with aryl groups yielded better activity than that obtained with alkyl substitution.

Similar Articles

Trends in Applied Sciences Research, 2011, 6(1), 19-33.

Trends in Applied Sciences Research, 2008, 3(2), 174-181.

Cited By

Monatshefte für Chemie - Chemical Monthly, 2010, 141(1), 75. DOI: 10.1007/s00706-009-0223-6

Tetrahedron, 2011, 67(6), 1294. DOI: 10.1016/j.tet.2010.11.075

Synthetic Communications, 2013, 43(22), 3072. DOI: 10.1080/00397911.2013.769604

Journal of the Iranian Chemical Society, 2014, 11(6), 1619. DOI: 10.1007/s13738-014-0438-2

Research Journal of Pharmacy and Technology, 2023, (), 2715. DOI: 10.52711/0974-360X.2023.00446

Journal of Chemical Research, 2012, 36(12), 718. DOI: 10.3184/174751912X13523931169712