Synthesis and Biological Evaluation of Pyrimidine Derivatives Via Pyrrolyl Chalcones

 

Pankaj Kumar, Abhishek Kumar*, Jean Sandra pinto, Akshata G, Bhashini,

Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte University, Paneer, Deralakatte-575018, Mangalore, Karnataka.

 

ABSTRACT:

The appearance to antimicrobial resistance to the antimicrobial agent has become a matter of high concern for health care professionals since last ten years. It will an effort to establish new pyrimidine derivatives as improved antimicrobial agent. In this particular series of novel substituted pyrimidine derivatives (PK1-PK5) were synthesized by simple condensation reaction between different substituted aldehydes and 3 acetyl -2,4-dimethyl pyrrole in presence of a strong ethanolic base to yield the pyrrolyl chalcones. The final synthesized pyrimidine derivative is prepared by the cyclization of pyrrolyl chalcones with urea in presence of KOH as base.

The structures of the final synthesized compounds were characterized by IR, mass and ¹H NMR spectra. The synthesized compounds were screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosaby cup plate method. Most of the compounds exhibited promising antibacterial activity.

 

 

 

 

INTRODUCTION:

Chalcones have various biological activities such as cytotoxic, antimalarial,¹ antioxidant,²tyrosinase Inhibitory,³ anti-inflammatory,⁴ cancer chemo preventive  and antibacterial⁵. Several pyrimidine derivatives have wide varieties of usages and its nucleus is also present in vitamin B2 and folic acid. Pyrimidine heterocycles possessing hydroxyl group has a unique place in medicinal chemistry ⁶ and also plays a vital role in biological processes well as synthetic drugs⁷.Pyrimidines are associated with various therapeutic activities e.g., anti-HIV, anti-tubercular, antitumor, antineoplastic, anti-inflammatory, diuretic, antimalaria, cardiovascular⁸.

 

To the best of our knowledge, there have been no previous reports of analogous pyrimidines and pyrroles as chalcones antimicrobial agents. However, there are numerous examples of nitrogen containing heterocycles being used to treat antimicrobial agent for example Clofazimine, Isoniazid and Pyrazinamide. These compounds provide structural precedence that our chalcone and pyrimidine analogues may lead to the generation of novel anti-microbial agent. Herein the synthesis and in vitro antimicrobial activity of novel pyrimidine derivatives are described.

 

MATERIALS AND METHODS:

All the chemicals were of analytical grade: 3 Acetyl -2,4-dimethyl pyrrole and, substituted benzaldehyde, urea and potassium hydroxide. Melting points were determined by open capillary method and are uncorrected. The purity of the compounds was monitored by thin layer chromatography (TLC) using silica gel G plates. The spots were visualized under UV light and by the exposure to iodine vapors. The homogeneity of the compounds was checked on silica gel-G coated plate by using Ethylacetate: n-hexane as solvent. IR spectra were recorded in Alpha Bruker using ATR method. ¹H NMR spectra were recorded on Bruker spectrophotometer (400 MHz) in DMSO-d₆ solvent using tetra methyl silane (TMS) as an internal standard. Mass spectra were recorded by LCMS method.

 

General Procedure:

The synthesis consists of the two major steps which are as follows:

1.        To a mixture of ethyl 3 Acetyl -2, 4-dimethyl pyrrole(0.01 mol) and the substituded aldehyde (0.01 mol) in oxygen-free ethanol was added to a solution of 40% sodium hydroxide in distilled water with constant stirring of the reaction flask. The reaction mixture was stirred for 24 hours on a magnetic stirrer and poured on to crushed ice. The solid mass that separated out was filtered, washed with water and crystallized from ethanol to furnish the desired product chalcones.

2.        A mixture of 0.01 mol of the above synthesized chalcone 0.01 mol urea and KOH in 20 ml ethanol was heated under reflux for 10 hours, then cooled and poured onto crushed ice. The so obtained solid product was filtered and recrystalized from ethanol⁹.

 

SCHEME

 

R=Phenyl, 2-cloro phenyl, 2-flouro phenyl, 2-methyl phenyl, 2-methoxy phenyl

 

Spectral Data:

4-(3,5-Dimethyl-1H-pyrrol-2-yl)-6-phenyl-1,6-dihydropyrimidin-2-ol (PK1A):

IR (KBr) cm^-1: 1550 (C=C ring skeleton Ar. moiety), 1412(C=C ring skeleton pyrimidine moiety), 13220 (N-H), 3302(OH).

¹H NMR (d) in ppm 6.0 (1H, s, NH -2-Pyrrole),2.35 (1H, s, Pyrimidine NH), 4.36 (1H, d, Pyrimidine,7.23-7.33 (5H, d, Ar-H), 2.04-2.14 (3H, d, CH₃).

MS m/z (M⁺) 268

 

4-(3,5-Dimethyl-1H-pyrrol-2-yl)-6-(2-fluorophenyl)-1,6-dihydropyrimidin-2-ol (PK 1C):

IR (KBr) cm^-1: IR (KBr) cm^-1: 1550 (C=C ring skeleton Ar. moiety), 1412(C=C ring skeleton pyrimidine moiety), 13220 (N-H), 3302(OH) 760 (C-F).

 

¹H NMR (d) in ppm 6.0 (1H, s, NH -2-Pyrrole), 2.35 (1H, s, Pyrimidine NH), 4.36 (1H, d, Pyrimidine, 7.23-7.33 (4H, d, Ar-H), 2.04-2.14 (3H, d, CH₃).MS m/z (M⁺) 286.

 

4-(3,5-dimethyl-1H-pyrrol-2-yl)-6-(2-methoxyphenyl)-1,6-dihydropyrimidin-2-ol (PK 1E):

IR (KBr) cm^-1: IR (KBr) cm^-1: 1550 (C=C ring skeleton Ar. moiety), 1412(C=C ring skeleton pyrimidine moiety), 13220 (N-H), 3302(OH).

 

¹H NMR (d) in ppm 6.0 (1H, s, NH -2-Pyrrole), 2.35 (1H, s, Pyrimidine NH), 4.36 (1H, d, Pyrimidine,7.23-7.33 (4H, d, Ar-H), 3.69 (s, 3H, OCH3),2.04-2.14 (3H, d, CH₃).

MS m/z (M⁺)298.

 

Antimicrobial Activity:

Microbial growth inhibitory properties of test substances were determined by cup plate method. The drugs were initially dissolved in H₂O₂/DMSO and tested at concentrations of 100μg/ml against all the microorganisms. Sterile nutrient agar plates were prepared and 0.1 ml of the innoculum from standardized culture of test organism was spread uniformly. Wells were prepared by using a sterile borer of diameter 10 mm and 100μl of the test substance, standard antibiotic and the solvent control were added in each well separately. Standard antibiotic, ampicillin was tested against gram negative, gram positive bacteria respectively. The plates were placed at 4ºC for 1 h to allow the diffusion of test solution into the medium and plates were incubated at a temperature optimal for the test organism and for a period of time sufficient for the growth of at least 10 to 15 generations (usually 24 h at 37ºC). The zone of inhibitions of microbial growth around the well was measured in mm.

RESULTS AND DISCUSSION:

Table 1: Physicochemical data of synthesized compounds

S. No	Comp. Code	Mol. Formula	Mol. Wt	M.P0C	Rf value (solvent system)	Physical Nature	% Yield
1	PK1 A	C16H17N3O	267	221-223	0.30 CH3COOC2H5:C6H12 20:80	Yellow Crystal	65
2	PK1 B	C16H16ClN3O	301	252-254	0.34 CH3COOC2H5:C6H12 20:80	Light Green Crystal	67
3	PK1 C	C16H16FN3O	285	230-232	0.28 CH3COOC2H5:C6H12 20:80	Pale Yellow Crystal	65
4	PK1 D	C17H19N3O	281	236-238	0.32 CH3COOC2H5:C6H12 95:5	Pale Yellow Crystal	74
5	PK1 F	C17H19N3O2	297	244-246	0.38 CH3COOC2H5:C6H12 95:5	Light Yellow Crystal	62

 

 

Table 2: Antimicrobial activity data of synthesized compounds.

Comp Code	Anti-bacterial activity (Zone of inhibition in mm)
	B.subtilis	S.aureus	E.coli	P.aeruginosa
PK  1 A	13	10	10	9
PK  1B	15	11	12	13
PK  1C	17	14	13	14
PK1D	10	9	8	9
PK 1E	12	9	8	9
Ampicillin	20	16	17	18

 

Antimicrobial Activity:

Among the screened compounds, PK1A and PK1B have shown good antibacterial activity against gram +ve and gram -ve bacteria compared to the standard drug.

 

CONCLUSION:

This study reports the successful synthesis of substituted pyrimidine derivatives via pyrrolyl chalconeswith moderate yields and most of the synthesized compounds showed promising antimicrobial activity.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Nitte University for providing the necessary facilities to carry out this research. The authors are grateful to Sequent Research Ltd, Mangalore and Central Instrumentation Facility, MIT Manipal for providing spectroscopic data.

 

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Accepted on 28.03.2017           © RJPT All right reserved