International Journal of Drug Development and Research

Key words

Biginelli reaction, Tetrahydropyrimidines, Zone ofinhibition, Gram +ve bacteria, Gm –ve bacteria

Introduction

The treatment of many infectious diseases arechallenging due to resistance to antimicrobial agents.The emergence of resistance among bacteria to awide variety of structurally unrelated antibacterialagents such as 6-lactams, macrolides, tetracyclinesand fluoroquinolones as well as selected dyes anddisinfectants has become a serious public healthconcern so makes it necessary to continue the searchfor new antibacterial agents.

In recent scenario heterocycles plays a major rule indrug synthesis. In that respect pyrimidine plays asignificant rule among other heterocycles. From theliterature survey, in recent years 4,5-disubstituted-6-methyl-1,2,3,4-tetrahydropyrimidin-2(1H)-one haveattracted considerable interest because of theirtherapeutic and pharmacological properties. Severalof them have been found to exhibit a wide spectrumof biological effects including antimicrobial,antitumour, antiviral, antihypertensive, calciumchannel blocker, alpha-1a adrenergic antagonist, neuropeptide antagonist. So it was planed tosynthesize a novel series of 4,5-disubstituted-6-methyl-1,2,3,4-tetrahydropyrimidin-2(1H)-onederivatives and to check their activity asantimicrobial activity.1-2

Experimenta

The entire chemicals were supplied by S.D. Finechem. (Mumbai), Finar chem. Ltd (Ahmedabad) andLoba Chemie. Pvt. Ltd. (Mumbai). Melting points

Scheme of Synthesis

were determined by open tube capillary method andare uncorrected. Purity of compounds was checkedby thin layer chromatography (TLC) on silica gel G insolvent system hexane-ethyl acetate (1:2), the spotswere located under iodine vapours or UV light. IRspectra of all compounds were recorded on FT-IR8400S Shimadzu spectrophotometer using KBr.Mass spectra were obtained using 2010EV LCMSShimadzu instrument.

General Procedure for Ethyl 4-(4-substitutedphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 1-4

0.1mole (6gm) of urea, 0.1mole, substitutedbenzaldehyde and 0.1mole (12.6ml) of ethylacetoacetate were taken and refluxed with 2-3 dropsof Conc. HCl and sufficient quantity of ethanol at 70-80ºC temperature for 4-5 hrs. It was then allowed tocool and after addition of water, precipitate was obtained, which was filtered and recrystallized fromethanol. (4a-4b)

General procedure of 4-(4-substitutedphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid 5

Ethyl-4-(4-substitutedphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(0.01mole) was refluxed with 50 ml of 10% alcoholicNaOH for 1 hr and after cooling the reaction mixture and acidification with Conc. HCl precipitate of acidwas obtained, which was filtered, washed with waterand recrystallized from ethanol. (5a-5b)

General Procedure of Preparation of 4,5-disubstituted-6-methyl-1,2,3,4-tetrahydropyrimidin-2(1H)-one derivatives5

4-(4-substitutedphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid (0.01mole)was refluxed with 15ml of thionyl chloride for30mins. Unreacted thionyl chloride was removed byheating the reaction mixture on water-bath. Aftercooling the acid chloride product, 3 to 4 times ofdifferent amines and ethanol as reaction medium was added. Reaction mixture was stirred for 5 hrs thenadded cold water to the reaction mixture. Precipitatewas obtained, which was filtered and recrystallizedfrom ethanol. (6a-6h)

Physical Characteristics of SynthesizedCompounds

Spectral data of synthesized compounds

Spectral data of synthesized compounds

Antibacterial Activity6,7

The microbiological assay is based upon acomparison of inhibition of growth of microorganismsby measured concentrations of testcompounds with that produced by knownconcentration of a standard antibiotic ciprofloxacinusing microorganisms Staphylococcus aureus(MTCC No. 96) and Escherichia coli (MTCC No.521).

A filter paper sterilized disk saturated with measuredquantity of the sample was placed on plate containingsolid bacterial medium (nutrient agar broth) whichhas been heavily seeded with spore suspension of thetested organisms. After inoculation, the diameter ofthe clear zone of inhibition surrounding the samplehas been taken as measure of inhibitory power ofsample against the particular test organisms.

Results and Discussion

4,5-disubstituted-6-methyl-1,2,3,4-tetrahydropyrimidin-2(1H)-one derivatives havebeen synthesized by 3 steps. Reactions have beenmonitered by TLC. All synthesized derivatives havebeen confirmed by IR, Mass and H1NMR.Antibacterial activity has been carried out by thefilter disk method. All compounds showed activityagainst the gram negative E.coli and in higherconcentration activity has been found against grampositive S.aureus.

Tables at a glance

Table 1 Table 2 Table 3 Table 4 Table 5

References

1. Lanjewar KR, and Rahatgaonkar AM. Synthesis and Anti-microbial activity of 5-(2-aminothiazol-4-yl)- 3,4-dihydro-4-phenyl pyrimidine-2(1H)-one; Indian Journal of Chemistry, 2009, 48B, 1732- 1737.
2. Kumar DBA. et al. Microwave assisted facile synthesis of aminopyrimidines bearing benzofuran and investigation of their anti-microbial activity; Indian Journal of Chemistry, 2006, 45B, 1699- 1703.
3. Naik TA, and Chikhalia KH. Studies on synthesis of pyrimidine derivatives and their pharmacological evalution, E. Journal of Chemistry, 2007, 4(1), 60- 66.
4. Humle R. et al. Cyanamide a convenient building block to synthesis 4-aryl-2-cyanoimino-3,4- dihydro-1H-pyrimidine system via multicomponentreaction, Tetrahedron 2008, 64, 3372-3380.
5. Furniss B. S. et al. Vogel’s textbook of practical organic chemistry, An imprint of Addison, Wesley Longman, inc. 5thedition, 1998, 1166-1168.
6. Pelczar MJ, Chan ES, Pelczar JR, Krieg NR. Microbiology, McGraw-Hill Book company. 1997, 5, 73-98.
7. Mohamed NR et al. Utility of 6-amino-2-thiouracil as a precursor for the synthesis of bioactive pyrimidine derivatives, Bioorganic and Medicinal Chem. 2007, 15, 6227-6235.