Synthesis and Antimicrobial Evaluation of Some Novel Mercapto Pyrimidine via Pyrrole Chalcone

 

Pankaj Kumar¹, Abhishek Kumar¹*, Prashant Nayak², Geena³, Bhashini³

¹Assistant Professor, Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences Paneer, Deralakatte, Mangalore 575018, Karnataka, India.

²Department of Pharmaceutics Nitte (Deemed to be University) Paneer, Deralakatte-575018, Mangalore, Karnataka.

³NGSM Institute of Pharmaceutical Sciences Nitte (Deemed to be University) Paneer, Deralakatte-575018, Mangalore, Karnataka.

 

ABSTRACT:

In an effort to develop antimicrobial agents, a series of mercaptopyrimidines were prepared by condensation of appropriate 3 Acetyl-2,4-dimethyl pyrrole with appropriate aromatic aldehydes in the presence of H₂SO₄ at room temperature. The final synthesized mercapto pyrimidine derivatives is prepared by the cyclization of pyrrolylchalcones with thioureain presence of KOH as base The synthesized compounds were characterized by means of their IR, Mass ¹H-NMR spectral data. All the compounds were tested for their antibacterial and antifungal activities by the cup plate.

 

 

 

INTRODUCTION:

Chalcones are well known intermediates for synthesizing various heterocyclic compounds. The compounds with the backbone of chalcones have been reported to possess various biological activities such as antimicrobial¹, anti-inflammatory², analgesic³, antiplatelet⁴ , antiulcerative⁵ , antimalarial⁶ , anticancer⁷, antiviral⁸ activities. The presence of a reactive α,β-unsaturatedketo function in chalcones is found to be responsible for their antimicrobial activity. To the best of our knowledge, there has been no previous reports of analogous mercaptopyrimidines and pyrroles as antimicrobialagents. However, there are numerous examples of nitrogen containing heterocyclic being used to treat antimicrobial agent for example clofazimine, Isoniazid and pyrazinamide.

 

 

These compounds provide structural precedence that our pyrrole and mercaptopyrimidine analogues may lead to the generation of novel anti-microbial agent. Herein the synthesis and in vitro antimicrobialactivity of novel mercaptopyrimidine derivatives are described.

 

MATERIALS AND METHODS:

All the chemicals were of analytical grade: 3 Acetyl-2,4-dimethyl pyrroleand, substituted benzaldehyde, thioureaand 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 were checked on silica gel-G coated plate by using ethyl acetate: 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 was 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) was added to a solution of 30% sulfuric acid with constant stirring of the reaction flask. The reaction mixture was stirred for 1 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 productchalcones.

2.      A mixture of 0.01 mol of the above synthesized chalcone 0.01 molthiourea 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-dihydropyrimidine-2-thiol (PKS4a)

IR (KBr) cm^-1: 1550 (C=C ring skeleton Ar. moiety), 1412 (C=C ring skeleton pyrimidine moiety), 1320 (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),1.5 (1H, s, Mercapto SH) 2.04-2.14 (3H, d, CH₃).

MS m/z (M⁺) 284.

 

4-(3,5-dimethyl-1H-pyrrol-2-yl)-6-(4-fluorophenyl)-1,6-dihydropyrimidine-2-thiol (PKS4c)

IR (KBr) cm^-1: IR (KBr) cm^-1: 1545 (C=C ring skeleton Ar. moiety), 1410(C=C ring skeleton pyrimidine moiety), 1320 (N-H), 3202 (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) 1.6 (1H, s, Mercapto SH)

MS m/z (M⁺)302.

 

4-(3,5-dimethyl-1H-pyrrol-2-yl)-6-(4-methoxyphenyl)-1,6-dihydropyrimidine-2-thiol (PKS4f)

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), 2.30 (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) 1.5 (1H, s, Mercapto SH).

MS m/z (M⁺)314.

 

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	PKS4a	C16H17N3S	283	241-243	0.42 CH3COOC2H5:C6H12 20:80	Reddish Crystal	71
2	PKS4b	C16H16ClN3S	317	262-264	0.46 CH3COOC2H5:C6H12 20:80	Light red Crystal	70
3	PKS4c	C16H16FN3S	302	251-253	0.32 CH3COOC2H5:C6H12 20:80	Pale Yellow Crystal	74
4	PKS4d	C17H19N3S	297	240-242	0.36 CH3COOC2H5:C6H12 95:5	Pale orange Crystal	68
5	PKS4f	C17H19N3OS	313	255-257	0.42 CH3COOC2H5:C6H12 95:5	Light orange Crystal	65

 

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
PKS4a	14	11	10	10
PKS4b	16	11	13	14
PKS4c	20	18	15	14
PKS4d	19	17	8	9
PKS4e	13	10	9	9
Ampicillin	23	20	19	18

 

Antimicrobial activity:

Among the screened compounds, PKS4c and PKS4d 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 mercapto pyrimidine derivatives via pyrrolylchalcones with 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 31.05.2018       © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(7): 2765-2767