International Journal of Pharma and Bio Sciences ISSN … · the synthesis of dihydropyrimidinones...

Int J Pharm Bio Sci 2015 April; 6(2): (B) 522 - 543

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Research Article Bioinformatics

International Journal of Pharma and Bio Sciences ISSN

0975-6299

SYNTHESIS, CHARACTERIZATION, EVALUATION OF ANTIMICROBIAL

PROPERTIES AND QUANTUM CHEMICAL CALCULATIONS OF 3, 4-

DIHYDROPYRIMIDIN-2(1,H)-ONES

T.K.SHABEER* AND A.SUBRAMANI

P.G. and Research Department of Chemistry, The New College, Chennai, Tamilnadu, INDIA.

ABSTRACT

The purpose of this study was to synthesize substituted 3,4-dihydropyrimidin-2(1H)-ones (DHP) and to evaluate them for their antibacterial and antifungal activities. These compounds were synthesized by cyclocondensation reaction between substituted aromatic aldehyde i.e.,p-anisaldehyde, active methylene compounds (ethyl acetoacetate/acetylacetone), urea in the presence of CuCl2.2H2O and few drops of Con.HCl by grindstone technique. The products are obtained in good yield under mild, solvent free and ecofriendly conditions. The structures of these compounds have been confirmed on the basis of their IR and NMR spectral data. The structural parameters like bond distances and bond angles for the optimized structures of the compounds were evaluated by abinitio Hartree-Folk level and B3CYP methods using the basis sets 6-31h(d,p) and CC-PUDZ to determine the exact geometry of the synthesized compound. The dihydropyrimidinone derivatives synthesized have been tested for antibacterial activity against Micrococcus luteus, Escherichia coli & Pseudomonas aeruginosa, and for antifungal activity against Aspergillus niger, Candida albicans & Candida kefyr. KEYWORDS: 3,4-dihydropyrimidin-2(1H)-ones, Biginelli reaction, grindstone chemistry, antimicrobial activity, antifungal activity and quantum chemical calculation.

*Corresponding author

T.K.SHABEER

P.G. and Research Department of Chemistry, the New

College, Chennai, Tamilnadu, INDIA.



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INTRODUCTION

MULTICOMPONENT REACTIONS Multicomponent reactions (MCRs) are of increasing importance in organic and medicinal chemistry for various reasons1. In MCRs, “three or more reactants come together in a single reaction vessel to form products that contain portions of all the components2. In times where a premium is put on speed, diversity and efficiency in the drug discovery process3, MCR strategies offer significant advantages over conventional linear-type syntheses. The Passerini, Ugi and Biginelli are some of the multicomponent reactions. GREEN CHEMISTRY The development of new strategies for the preparation of complex molecules in neat conditions is a challenging area of organic synthesis. For instance, a large number of organic reactions are typically carried out under anhydrous conditions, using volatile organic solvents like benzene, which are the cause of environmental problems the solvents are also potentially carcinogenic. Hence, it is required to develop safe, practical and environment friendly processes. One promising approach to environmentally consciousness in chemical research and industry augments to minimize or completely eliminate the use of harmful organic solvents in organic syntheses is grindstone chemistry. This is because organic reactions run under solvent-free conditions are advantageous because of their enhanced selectivity, efficiency, ease of manipulation, and cleaner product formation4. Thus, a paradigm shift from using solvents toward solvent-free

reactions not only simplifies organic synthesis but also improves process conditions for large-scale synthesis. GRINDSTONE CHEMISTRY The pioneering work of Toda et al5 has shown that many exothermic reactions can be accomplished in high yield by just grinding solids together using mortar and pestle, a technique known as ‘Grindstone Chemistry’ which is one of the ‘Green Chemistry Techniques’. Reactions are initiated by grinding, with the transfer of very small amounts of energy through friction6. In addition to being energy efficient grindstone chemistry also results in high reactivity and less waste products. This work focuses on the synthesis of Biginelli compounds using the grindstone technique. BIGINELLI REACTION In 1893, the Italian Chemist Pietro Biginelli reported on the acid-catalysed cyclocondensation reaction of an aldehyde, a β-ketoester, and urea (or thiourea), a procedure known as the Biginelli reaction, which is receiving increased attention. More than a century ago, Biginelli intuitively anticipated the synthetic potential of multicomponent reactions by combining in a single flask the reactants of two different reactions having one component in common7,8. The result of the three-component reaction was a new product that was correctly characterized as a substituted 3,4-dihydropyrimidin-2(1H)-one (DHPM).



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IMPROVED REACTION CONDITONS The discovery of milder and practical routes for the synthesis of dihydropyrimidinones continues to attract the attention of researchers. Several improved procedures for the preparation of DHPMs have recently been reported, including traditional Bronsted Acids9, pleothra of Lewis acids10, ionic liquids11, microwave irradiation12, solid phase reagents13, polymer-supported catalysts14, heteropoly acids15, heterogeneous catalysts16, and organo acids17. Subsequently reported multi-step protocols afford somewhat higher yields but these do not have the simplicity of the original one-pot Biginelli protocol18. However, some of the newer reported methods also suffer from drawbacks such as unsatisfactory yields, cumbersome product isolation procedures and environmental pollution19. Several groups have demonstrated that chemical synthesis may be dramatically accelerated using microwave irradiation. The conditions caused by this kind of heating lead directly to acceleration in the reaction times compared with conventional reflux conditions. Reactions carried out in dry media offer a number of advantages, considering solvents are often expensive, toxic and in the case of aprotic solvents with high boiling point, difficult to remove20. Microwave irradiation can be applied to synthesis of a number of 3,4-dihydropyrimidinones, via a simple and fast procedure based on the reaction of EAA, aldehydes and urea or thiourea in solvent-free conditions21. Ionic liquids are environmentally benign alternative solvents for various chemical processes. They have attracted the attention of chemists owing to their unique physical and chemical properties22. Because of their low vapour pressure, ionic species do not contribute to volatile organic compound emission. They have also been referred to as ‘designer solvents’23, since their properties can be altered by the fine tuning of parameters such as the choice of the organic cation, inorganic anion and alkyl chain attached to the organic cation these structural variations provide an opportunity to devise the most idealized solvent needed for a particular chemical process. Several reactions have been carried out in ionic liquids24, including the

Biginelli reaction. RECENT LITERATURE In recent years, ferric chloride hexahydrate has emerged as an efficient catalyst in carbon-carbon bond-forming reactions. In 2004, Mirza-Aghayan et.al25 reported simple but effective modification of the bignelli reaction using ferric chloride hexahydrate under solvent-free conditions using microwave irradiation that produces good yields of the desired DHPMs while preserving the original one-pot strategy. Solvent free reactions26 in fine chemical synthesis are of increasing interest to synthetic organic chemists and industrialists. The development of solvent-free synthesis using microwave irradiation technique has contributed significantly to the eco-friendly synthesis due to the increasing environmental consciousness worldwide. I.T. Phucho et al27, reported a three-component cyclocondenstion of N-aryl-3-oxobutanamide/acetophenone, aldehyde and urea/ thiourea to synthesize pyrimidinone derivatives using inexpensive p-toluenesulphonic acid as catalyst under solvent-free condtions and microwave irradiation,which is an efficient and environmentally friendly method.The condensation of aldehydes, diketones and urea/thiourea (carrying both electron-withdrawing and electron-donating groups in aldehydes), in presence of 5-sulphosalicylic acid as a catalyst under solvent free conditions yielded desired Dihydroprimidinone derivatives in purity with good to excellent yields28. BIOLOGICAL ACTIVITIES The exploitation of some molecules with different functionalities is a worthwhile contribution in the chemistry of heterocycles. DHPMs, are well known to posses varied pharmacological and biological activities29 and hence their synthesis has always been of attraction to organic chemists. As early as in 1930 simple derivatives were patented as agents for the protections of wool against moths30. Later, there was development of nitractin, which showed excellent activity against the viruses of the trachoma group31 and also exhibited antibacterial activity. They have



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emerged as the integral backbones of several calcium channel blockers32, anticancer33, antihypertensive34, antiviral35, alpha-la-antagonists, antitumour, antiinflammatory36, analgesic, cardiovascular activities37. Recently, several isolated marine alkaloids with interesting biological activities were also found to contain the dihydropyrimidinone-5-carboxylate core38. Most notably among them are the batzelladine alkaloids, which have been found to be potent human immunodeficiency virus (HIV) gp-120-CD4 inhibitors39. The scope of this pharmacopore has been further increased by the identification of the 4-(3-hydroxyphenyl)-2-thione derivative (±)- 4i called monastrol40, as a novel cell-permeable lead molecule for the development of new anticancer drugs. DHPMs and their appropriately functionalized derivatives have interesting pharmalogical profiles. They potent mitotic kinesin inhibitors, neuropeptide y-antagonists, antimalarial agents, etc. Parlato et al41 synthesized various DHPMs derivarives by modification of the substituents in virtually all the six positions of the pyrimidine nucleus which provided with interesting activity against HIV, ASFV, Sendai virus and Rubella virus.

MATERIALS AND METHODS

All chemicals used were of AR grade. The reaction were monitored by TLC using silica gel of 60-120 mesh. Melting points was recorded by open capillary method and are uncorrected. IR spectra were recorded on Perkin-Elemer FTIR-240C spectrophotometer on KBr disc.1H-NMR spectra were recorded on 300 MHz make spectrometer in CDCl3 using TMS as internal standard. GENERAL PROCEDURE FOR SYNTHESIS OF DIHYDROPYRIMIDINONES A mixture of a substituted aromatic aldehyde i.e., p-anisaldehyde (10 mmol), ethyl acetoacetate /acetylacetone (10 mmol), urea (20 mmol) , CuCl2.2H2O (5 mmol) and few

drops of Con.HCl was ground together for 2-5 mins using a mortar and pestle of appropriate size. The initial syrupy reaction mixture solidifies within 5-20 mins. The solid mass was left overnight, then washed with cold water and purified by recrystallization from ethanol to afford the desired dihydropyrimidinones (A1&A2).The obtained products were characterized by means of spectral (IR & 1H-NMR) data and their melting points. ANTIMICROBIAL ACTIVITY In this work, we report in vitro study of antimicrobial activity of dihydropyrimidinones against Gram +ve bacterium (M.leteus), Gram –ve bacteria (E.coli and P.aeruginosa),fungus (A.niger) and yeast fungi (C.albicans and C.kefyr). ANTIMICROBIAL ASSAY Antibacterial analysis was followed using standard agar well diffusion method to study the antimicrobial activity of compounds 42-44. Each bacterial and fungal isolate was suspended in Brain Heart infusion (BHI) broth and diluted to approximately 105colony forming unit (CFU) per mL. They were flood-inoculated onto the surface of BHI agar and then dried. Five-millimeter diameter wells were cut from the agar using a sterile cork-borer and 30 µL (5µg compound in 500 uL DMSO) of the sample solution were poured into the wells. The plates were incubated for 18 h at 37 oC for bacteria and at room temperature for fungi. Antimicrobial activity was evaluated by measuring the zone of inhibition in mm against the test microorganisms. DMSO was used as solvent control. Ciprofloxacin was used as reference antibacterial agent. Ketoconazole was used as reference antifungal agent. The tests were carried out in triplicates. The results of in vitro study of antimicrobial activity of DHP against each of the three bacterial species (M.leteus, E.coli and P.aeruginosa) and three fungal species (A.niger, C.albicans and C.kefyr) are reported the tables II & III.



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BRAIN HEART INFUSION (BHI) AGAR Composition Calf brains (infusion from 200g) 12.5 Beef heart (infusion from 250g) 5.0 Proteose peptone 10.0 Sodium chloride 5.0 D(+)-Glucose 2.0 Disodium hydrogen phosphate 2.5 Agar 10.0 Final pH 7.4 + /- 0.2 at 37oC Store prepared media below 8oC, protected from direct light. Store dehydrated powder in a dry place in tightly –sealed containers at 2-25oC. Directions The above ingredients were suspended in 1 litre of distilled water and boiled to dissolve the medium completely. Distribute into tubes, plates or flasks and sterilized by autoclaving at 121oC for 15 minutes. The cytotoxicity of DHP was compared with ciprofloxacin for antibacterial study and ketoconazole for antifungal study. The zone of inhibition was expressed in mm and compared with standard drugs used. COMPUTATIONAL DETAILS Studies of intermolecular associations, dichroic absorption, and band contour of the vapour spectra, measurements of integrated intensities of the absorption bands and theoretical ab initio and normal coordinate analysis give information regarding the nature of the functional groups, orbital interactions and mixing of skeletal frequencies. In order to analyse the structural and vibrational characteristics of the compounds the LCAO-MO-SCF restricted Hartree-Fock (HF) level ab initio calculations have been carried out. However, the use of post-HF level calculations, which include electronic correlation to the calculations, is necessary to get more reliable results on the structural parameters and vibration properties. The density functional theory (DFT) is a popular post-HF approach for the calculation of

molecular structures, vibrational frequencies and energies of molecules. Unlike the HF and MP2 theory, DFT recovers electronic correlation in the self-consistent Kohn–Sham procedure through the functions of electron density and gives good descriptions for systems which require sophisticated treatments of electronic correlation in the conventional ab initio approach, so it is considered as an effective and reliable method. Density functional theory has proved to be an extremely useful in treating electronic structure of molecules. The combination of spectroscopic methods with DFT calculations are powerful tools for understanding the fundamental vibrations and the electronic structure of the compounds. The most stable geometry of the compound was established by optimization of the structure. The structural parameters of the stable molecular structure of the compounds have been computed by utilizing Becke’s three parameter hybrid functional (B3) 45, 46 combined with gradient corrected correlation functional of Lee–Yang–Parr (LYP)47 with STO–3G and the standard split–valence polarised 6-31G**48

basis sets on a Intel core–i5 processor using Gaussian 03W program49 to characterize all stationary points as minima. Gauss View 5.0.8 visualization program50 has been utilized to construct the optimized geometry of the compounds.



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RESULTS

Where, R = C2H5O or CH3

Table 1

Spectroscopic data A1:Ethyl-4(4- methoxyphenyl)-6-methyl-2-oxo-3,4-dihydroprimidine-5-carboxylate NMR (CDCl3): 1.2-t, (3H,CH3 of C2H5O), 2.3-s, (3H,CH3 at C6),3.2-s, (3H,-OCH3),4.1-q,(2H,CH2 of C2H5O),5.3-d, (1H, -CH), 5.8-d,(2H, Ar-H),6.8-d,(2H,Ar-H),7.3s, (1H,NH),8.3,s,(1H,NH).IR (KBr, cm-1): (N-H)3243, (C-H)2956, (C=O)1705, (C=N)1513, (C=C)1385, (C-O)1224, A2:5-Acetyl-4(4-methoxyphenyl)-6-methyl-2-oxo-3,4- dihydroprimidine. NMR (CDCl3): 2.1s, (3H, CH3 at C6) 2.4-S, (3H, CH3 of acetyl), 3.9-s, (3H, CH3O), 5.4-d, (1H, CH), 5.9-d, (2H,Ar-H), 6.8-d, (2H,Ar-H), 7.2-s,(1H, NH), IR (KBr, cm-1): (N-H) 3229, (C-H) 2954, (C=O) 1700, (C-N) 1509, (C=C) 1455, (C-O) 1249.

Table-II ANTIBACTERIAL DATA

Entry R M.P. (0C) Yield (%)

A1 C2H5O 201-2020C 92.0

A2 CH3 192-1940C 87.8

S.No Organisms (Bacteria) Zone of Inhibition (mm)

A1 A2 Ciprofloxacin

1 Micrococcus luteus 19 16 20

2 Escherichia coli 12 19 19 3 Pseudomonas

aeruginosa 7 10 15



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Table-III ANTI FUNGAL DATA

S.No Organisms (Fungus) Zone of Inhibition (mm)

A1 A2 Ketoconazole

1 Aspergillus niger 11 - 15 2 Candida albicans 19 23 19 3 Candida kefyr 23 23 16



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Figure 1 The optimised structure of A1 with the

scheme of atom numbering

Figure 2 The optimised structure of A1



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Figure 3 The optimised structure of A1 which has planar benzene ring

Figure 4 The optimised structure of A1 which has non-planar

Heterocyclic ringEnergy = -980.1429 a.u



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Figure 5 The optimised structure of A2 with the scheme of numbering of atoms

Figure 6 The optimised structure of compound A2



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Figure 7 The aromatic ring of the compound A2 is planar.

Figure 8 The heterocyclic ring of the compound A2 is non-planar.



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Figure 9 The optimised structure of the compound A2 in B3LYP/6-31G**

method and the energy is -878.3365 a.u

DISCUSSION

Antibacterial activity Table (II) shows that compound A1 has poor sensitivity against pseudomonas aeruginaosa and good sensitivity against Escherichia coli compared to standard ciprofloxacin. But in the case of A1 it has very good sensitivity against micrococcus luteus. Compound A2 shows moderate sensitivity against pseudomonas aeruginosa & micrococcus luteus and very good sensitivity against Escherichia coli.

Antifungal activity Compound A1 shows good sensitivity against aspergillus niger and very good sensitivity against candida albicans and high sensitivity against candida kefer fungal species compared to standard ketocknazole. Compound A2 shows greater sensitivity against candida kefer and candida albicans than strandard ketoconazole and no sensitivity against aspergillus niger.



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Structural properties The optimized structural property, bond length and bond angle for the thermodynamically structures of A1 and A2 found by B3LYP-STO-3G and B3LYP-6-31-G** methods are presented in tables (IV & V), in accordance with the atom numbering scheme of the compound given in the figure (1 & 5 ).From the structural data given in the table (IV & V ), it was observed that various ring C-C bond distances, C-H, C-O, C-N, N-H bond distances calculated by two methods are found to be almost same at all levels of calculations. Similarly the bond angles calculated by the two methods are almost same at all levels of calculations.The general molecular structures of the compound A1 and A2 are represented figures (2 & 6). From figures (3 & 4), it was observed that the optimized structure A1 as a planar benzene and non-planar heterocyclic ring with an energy of -980.14 au. Similarly from figures (7 & 9), it was observed that the optimized structure A2 as a planar benzene and non-planar heterocyclic ring with an energy of -778.33 au. Moreover in the structures of both A1 and A2, the aromatic ring is perpendicular to the heterocyclic ring. The structure A1 predicts the formation of a hydrogen bond between oxygen atoms attached to C-7 and the hydrogen atom at C-8. Similarly A2 predicts the formation of hydrogen bond between oxygen atom attached to C-7 and the hydrogen atom at C-8.

CONCLUSION

In summary, we have developed a simple, efficient and more eco-friendly grinding technique for the synthesis of 3,4-dihydropyrimidinone using p-anisaldehyde, acetoacetic ester/ acetylacetone & urea. The notable advantages of this method include no usage of solvent (except for recrystallisation), simple reaction profile, shorter reaction time(4-5mins) and high yields(87-94%).The antimicrobial study suggests that all the newly synthesized Biginelli compounds showed moderate to very good activity against the tested organisms. Among the compounds, A2 showed the most promising antibacterial and antifungal activity, suggesting further work with similar analogues. The structural parameters like bond distances and bond angles for the optimized structures of the compounds were evaluated by abinitio Hartree-Folk level and B3CYP methods using the basis sets 6-31 h (d,p) and CC-PUDZ it as the exact geometries of the synthesized compounds was determined.

ACKNOWLEDGEMENT

Author is thankful to Dr. V. ARJUNAN, Kanchi Mamunivar Centre for Post Graduate Studies, Puducherry, for his help in the quantum chemical calculation.

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