The chemistry of coordination compounds with heterocyclic ligands containing oxygen and nitrogen as donor atoms has attracted the attention of chemists in recent years. It is well known that such ligands coordinate to metal atom in different ways in different media. Transition metal complexes with Schiff base have played an important role in much biological system in nature [13-15]. The chelating properties of Schiff base display manifold applications in medicine and industry. Pyridine moieties have been reported to possess antimicrobial [16], anti-inflammatory [17] and anticonvulsant [18] etc.

Schiff base metal complexes based research works have been widely carried out from 1930 because of their biological and industrial application [19-22], In organic chemistry Schiff bases are most widely used as pigments and dyes, catalysts, intermediate in organic synthesis, and as a polymer stabilizer [23]. Schiff bases and their metal complexes are also well known to have pronounced biological activity [24-25] and form an important class of compounds in medicine and pharmaceutical field also showed some degree of antibacterial ,antifungal, antitumor, anticancer and anti-inflammatory activity [26-34] ,the azo-methine linkage are responsible for the biological activity of Schiff bases.

Heterocyclic compounds are abundant in nature and are of great significance to life because their structural subunits exist in many natural products such as vitamins, hormones, and antibiotics [35,36]. Hence, they have attracted considerable attention in the design of biologically active molecules [37,38] and advanced organic chemistry [39,40]. Also in the family of heterocyclic compounds nitrogen containing Heterocycles are an important class of compounds in the medicinal chemistry and also contributed to the society from biological and industrial point which helps to understand life processes

[41]. A totally unsaturated six membered -ring containing nitrogen is known as azine [42] or pyridine (1); with two nitrogen atoms it is known as diazine [43]. and with a nitrogen at 1,2-position, it is known as pyridazine, at 1,3-position as Pyrimidine and at 1,4-position as pyrazine (Figure2). However, the current review focus on the significance of Pyrimidines class of antimicrobial agents along with clinical and in vitro applications of pyrimidine derivatives to facilitate the development of more potent as well as effective antimicrobial agents.

Figure-2 Structures of Pyridazine, Pyrimidine, Pyrazine

Quinazoline [44] are the heterocyclic aromatic compounds similar to benzene and pyridine containing two nitrogen atoms at positions 1 and 3 of the six membered rings. Heterocycles containing pyrimidine moiety are of great interest because they constitute an important class of natural and non natural products, many of which exhibit useful biological activities and clinical applications [45, 46]. Substituted purines and pyrimidines occur vary widely in living organisms and were some of the first compounds studied by the organic chemists [47].

The aim of this study was to make Schiff bases of 4-phenyl pyrimidine-2-carbohydrazide and their complexes, followed by characterization and antimicrobial activity determination of the schiff bases and metal complexes.

In view of these findings we have synthesized some metal complexes with a new Schiff base bis ((4-phenylpyrimidin-2-yl)(((2-thioxo-1,2-dihydroquinolin-3-yl)methylene)hydrazono)methoxy) which was prepared by the reaction between 4-phenyl pyrimidine-2-carbohydrazide and 2-thioxo-1,2-dihydroquinoline-3carbaldehyde.

MATERIALS AND METHODS:

All the chemicals used were of analytical grade and were used without further purification.

EXPERIMENTAL SECTION:

All reagents and solvents used in this work were analytical grade and used directly. The melting points were determined in open glass capillaries tubes. Purity of the compounds was checked by thin layer chromatography (TLC) on silica gel G plates and spots were located by using iodine chamber. Elemental analysis (C, H, N) of all the synthesized compounds were determined by Perkin-Elmer 2400 elemental analyzer. The IR spectra were recorded on a Beckman Acculab-10 spectrometer (ν max in cm^-1) and the ¹H NMR spectra were recorded by Brucker DPX300 MHz using CDCl₃ as solvent.

SYNTHESIS:

Synthesis of 2-methyl-4-phenyl pyrimidine(3):

A mixture of 3-phenylpropiolaldehyde (0.01 mol) and acetimidine hydro chloride (0.01 mol) was stirred in dry aceto nitrile(10 ml) and dry Na₂CO₃ (0.02mol) was added to it. The stirring was continued for 0.5 hr under Micro Wave conditions at 90^Oc .Reaction progress was monitored by TLC.After completion of reaction cool to RT. Then concentrated under reduced pressure by using rota evaporator and Purified by column chromatography(100-200 mesh size silica) with elution of 10% Ethyl acetate to get pure yellow solid yield:47 % mp: 130^Oc-132^Oc.

Synthesis of 4-phenylpyrimidine-2-carboxylic acid (4):

A mixture of compound (3) (0.01 mol), selenium di oxide (0.05 mol), and pyridine (10 ml) was refluxed for 2 hours. Reaction progress was monitored by TLC. after completion of compound 3, concentrated under reduced pressure, then added water (10 ml),acidified with Conc.HCl, white solid was formed, filter off, dried, to get 75 % yield. M.P.: 187-189^OC.

Synthesis of Schiff base (8):

The Schiff base (ligand) was prepared by the reaction of 4-phenylpyrimidine-2-carbohydrazide (0.6gm, 0.00280 mol) and 2-thioxo-1, 2dihydroquinoline-3-carbaldehyde (0.530gm, 0.0028 mol) in the presence of catalytic of glacial acetic acid (1-3 drops) under reflux for 7-8 h on the water bath. The reaction mixture was cooled at room temperature. The precipitate was then removed from the reaction mixture by filtration, washed with ethanol, dried and recrystallized from appropriate solvent. The synthesis of Schiff base have been shown in scheme 1

Synthesis of complexes

Schiff base (Z)-4-phenyl-N'-((2-thioxo-1,2-dihydroquinolin-3-yl)methylene)pyrimidine-2-carbohydrazide (0.77 gm, 0.002 mol) in ethanol (30 ml) and stirred gently for one hour to give homogeneous solution and added Ethanolic solution (10 ml) of respective metal chlorides (0.002 mol). The resulting solution was refluxed for 5 h on steam bath and then sodium acetate (0.5 gm) was added to it and refluxed for 2 h. It was poured into distilled water. The solid complexes were collected by filtration, washed with distilled water and dried in a vaccum over anhydrous calcium chloride in a desicater. The synthesis of metal complexes is given in scheme 2 and physical analytical data of ligand and its complexes are given in table 1.

IR, ¹HNMR Spectra of Ligand

The IR spectrum of ligand showed peak at 1635 cm^-1 due to imine group and three absorption band at 3115 and 3060 cm^-1 due to amide NH and NH of quinolone moiety. The bands observed at 1635, 1562 and 1161 cm^-1 are due to carbonyl C=O, azomethene C=N and C=S function at 2-position of quinoline moiety respectively. The ¹HNMR spectra of the Schiff base in d₆ DMSO at room temperature showed signal at δ 9.6 (s,1H, quinoline NH), δ 11.4 (s, 1H, CONH), δ 8.82 (s, 1H, N=CH) and δ 7.40-7.94 (m, 10H, Ar-H) due to protons of benzene ring aromatic protons, 8.4(1H,d),8.86(1H,d)due to protons of Pyrimidine ring protons, 6.92-7.16(8H,m) due to protons of quinoline ring protons respectively.

IR Spectral data of the complexes of ligand

IR spectral data of ligand. and its complexes are given in table 2. The IR spectrum of ligand was compared with those of the complexes of metal ions Co (II), Ni (II) and Zn (II) in order to study the binding mode of schiff base to the metal ions. In the IR spectra of ligand the band appeared at 1635 cm^-1 assigned to carbonyl group (C=O) has disappeared in its complexes the above metal ions suggesting the involvement of carbonyl oxygen atom in coordination by the deprotonation after its enolization. All the complexes except Zn (II) complex of the ligand under the present study displayed broad bands in the region 34253410 cm^-1 indicating the presence of lattice or coordinated water molecules. The peak observed at 3060 cm^-1 due to quinolone NH has appeared at about the same region 3020-3075 cm^-1 in all the complexes indicates the non-involvement of quinolone NH in complexation. Absorption band at 1562 cm^-1 in case of ligand due to C=N of azomethine function has been found to be shifted towards the lower frequency side 1536-1515 cm-1 in all the complexes indicates the metal ions have coordinated to azomethine nitrogen. A band at of all the complexes indicating the coordination of metal ions with sulfur of C=S function. The bands of weak intensity in the region 545-505 cm^-1 in case of all the complexes of the ligand are assigned M-O vibrations and the bands in the region 457-410 cm-1 to M-N vibration.

Table 1: Physical and analytical data of ligand and its complexes:

Compounds	Molecular formula	Mol.wt	M.P.(^OC)	Elemental analysis (%) Calculated (Found)
				M	C	H	N
Ligand	C₂₁H₁₅N₅OS	385.442	342-346	---	65.44	3.92	18.17
Co- complex	Co[C₄₂H₂₆N₈O₂S₂]2H₂O	863.285	364-366	6.82 (6.80)	58.40 (58.35)	3.73 (3.77)	16.21 (16.26)
Ni- complex	Ni[C₄₂H₃₀N₁₀O₂S₂]H₂O	845.591	370-372	6.80 (6.78)	58.41 (58.34)	3.73 (3.71)	16.22 (16.20)
Zn- complex	Zn[C₃₄H₂₈N₈O₂S₂]	832.113	346-349	7.84 (7.82)	60.47 (60.45)	3.38 (3.35)	16.79 (16.74)

Table 2: IR data of ligand and its complexes

Compound	ν_H2O	Amide NH	Quinoline NH	ν _C=O	ν _C=S	ν _C=N	ν _M-O	ν _M-N
Ligand	---	3112	3045	1655	1160	1562	---	---
Co- complex	3410	---	3020	---	1135	1536	515	467
Ni- complex	3425	----	3028	---	1145	1542	526	465
Zn- complex	---	---	3075	---	1164	1515	534	430

PHARMACOLOGICAL STUDIES:

Antibacterial Activity

All the newly synthesized metal complexes were tested for their antibacterial activity. Antibacterial activity was determined by agar cup plate method [48] against the following organism- Staphylococcus aureus, Escherichia coli and Proteus vulgaris. The zone of inhibition of each strain was recorded. Antibacterial activity of the ligand and its metal complexes was compared with the standard drug ciprofloxacin. The variation in the activity of different metal complexes against different micro-organism depends on their impermeability of the cell or the differences in ribosomes in microbial cell. The lipid membrane surrounding the cell favours the passage of any lipid soluble materials and it is knows that lipo solubility is an important factor controlling antibacterial activity.

Table 3: Antibacterial activity of ligand and its complexes:

Compounds	Bacterial inhibition zone/mm
	*S. aureus*	*E. coli*	*P. vulgaris*
Ligand	13	16	14
Co- complex	19	20	19
Ni- complex	14	13	18
Zn- complex	12	18	19
Ciprofloxacin	20	22	20

RESULTS AND DISCUSSION:

Synthesis:

2methyl-4-phenyl Pyrimidine (3) was synthesized according to the reported procedure [49]. The reaction of 2-methyl- 4-phenyl pyrimidine with selenium di oxide in pyridine to afford the corresponding 4-phenyl pyrimidine-2carboxylic acid(4) as per the reported procedure[50], which was reacted with methanol as per the reported procedure[51] to afford methyl 4-phenylpyrimidine-2-carboxylate (5), which was reacted with hydrazine hydrate in Ethanol as per the reported procedure[51] to afford 4-phenylpyrimidine-2-carbohydrazide (6).Compound (6) reacts with 2-thioxo-1,2-dihydroquinoline-3-carbaldehyde (6) to form (Z)-4-phenyl-N'-((2-thioxo-1,2-dihydroquinolin-3-yl)methylene)pyrimidine-2-carbohydrazide [Schiff base] (8) as per the reported procedure [52].

The results showed (table-3) that ligand exhibits moderate activity against all tested bacteria. Co (II) complex showed high antibacterial activity against S. aureus, E. coli and P. vulgaris. Ni complex exhibited moderate activity against S. aureus and E. coli but highly effective against P. vulgaris. Zn complex exhibited moderate activity against S. aureus but showed good activity against E. coli and P. vulgaris microorganism. Antibacterial activity of the ligand and its metal complexes is compared with the standard drug ciprofloxacin. The variation in the activity of different metal complexes against different micro-organism depends on their impermeability of the cell.

CONCLUSION:

Based on overall study it was concluded that metal complexes of schiff bases are more efficient antimicrobial agent than its native form. However the antimicrobial potentiality is of metal complex is highly dependent in the metal ion used for formation of metal complex. A new ligand (Z)-4-phenyl-N'-((2-thioxo-1,2-dihydroquinolin-3-yl)methylene)pyrimidine-2-carbohydrazide and its complexes have been synthesized and characterized by IR and ¹HNMR spectral data which includes that all the complexes exhibited octahedral geometry. Some of these complexes have exhibited good antibacterial activity.

REFERENCES:

[1]. Anand P., Patil V.M., Sharma V.K., Khosa R.L. and Masand N., Schiff bases: A Review on Biological Insights Biological activities of Schiff bases, Int. J. Drug Des. Discov., 3, 851–866 (2012)

[2]. Yang Z. and Sun P., Compare of three ways of synthesis of simple Schiff base., Molbank, 12–14 (2006)

[3]. Savalia R.V, Patel A.P., Trivedi P.T., Gohel H.R. and Khetani D.B., Rapid and Economic Synthesis of Schiff Base of Salicylaldehyde by Microwave Irradiation., Res. J. Chem. Sci., 3, 97–99 (2013)

[4]. Kumar N. and Sharma P., Synthesis of New Schiff-Base Complexes and Their Applications, Int. J. Appl. Res. study, 2, 1–6 (2013)

[5]. Somani R. et al., Optimization of Microwave Assisted synthesis of some Schiff ’ s bases, Int. J. ChemTech Res., 2, 172–179 (2010)

[6]. Kulshrestha A. and Baluja S., Microwave Promoted Synthesis of Some Schiff Bases, Sch. Res. Libr. 2, 221– 224 (2010)

[7]. Mohanambal D. and S A.A., Synthesis , Characterization and Antimicrobial activity of some novel schiff Base 3d Transition Metal Complexes Derived from Di hydro pyrimidinone and 4- Amino antipyrine, Res. J. Chem. Sci., 4, 11–17 (2014).

[8]. Girgaonkar, M. V and Shirodkar, S. G. Synthesis, characterization and Biological studies of Cu (II) and Ni(II) complexes with New Bidentate Shiff’s base ligands as 4-hydroxy-3-(1-(acrylimino)ethyl)chromen-2-one. Res. J. Chem. Sci. 1, 110–116 (2012).

[9]. Bader, N. R. applications of Schiff ’s bases chelates in quantitative analysis : a review RASAYAN J. Chem. 3, 660–670 (2010).

[10]. Satyanarayana, V. S. V, Sreevani, P., Sivakumar, A. and Vijayakumar, V. Synthesis and antimicrobial activity of new Schiff bases containing coumarin moiety and their spectral characterization. Arkivoc 2008, 221–233 (2008).

[11]. Patel, V., Trivedi, P., Gohel, H. and Khetani, D. Synthesis and Characterization of Schiff Base of p - chloro aniline and their Metal Complexes and their evaluation for Antibacterial Activity. Int. J. Adv. Pharmacy, Biol. Chem. 3, 999–1003 (2014).

[12]. Ashraf, M. A., Mahmood, K., Wajid, A., Maah, M. J. and Yusoff, I. Synthesis , Characterization and Biological Activity of Schiff Bases. Int. Conf. Chem. adn Chem. Process 10, 1–7 (2011).

[13]. Mohmoud WH, Mohamed GG and ElDessouky MMI. Synthesis, characterization and in vitro biological activity of mixed transition metal complexes of lornoxicam with 1,10phenanthroline. Inter J Electrochem Sci. 2014;9:1415-1438.

[14]. Eissa HH. Synthesis, characterization and antibacterial activity of macrocyclic Schiff bases based on 1,3-docarbonyl phenyl dehydrazide 1,4-docarbonyl phenyl dehydrazide. Organic Chemistry Current Research. 2013;2(3):1-8.

[15]. Bhagat SM and Deshpande MM. Synthesis and antimicrobial activity of some transition metal ion chelates of 2-(cinnamyl)-4-bromo-6-methyl benzothiazolyl hydrazones. Journal of Chemical and Pharmaceutical Research. 2012;4(3):1454-1456.

[16]. Patel NB, Agraval SN and Shaikh FM. Synthesis and antimicrobial activity of new pyridine derivatives. Med. Chem. Research. 2011;20: 1033-1041.

[17]. Al-Omar MA, Amr A-G and Al-Salahi RA. Antiinflammatory, analgesic, anticonvulsant and antiparkinsonian activities of some pyridine derivatives using 2,6-disubstituted isonicotinic acid hyrazides. Arch Pharm. 2010;343(11-12):648-656.

[18]. Pattan SR, Dighe NS, Musmade DS, Tambe SK, Kale SH, Craware VM and Chavan PA. Synthesis and evaluation of some new substituted 1,4 dihydropyridine derivatives and their anticonvulsant activity. J Chem Parm Res. 2010;2(1):246-252.

[19]. M.A.Ali,S.E. Livingstone and D.J. Philips, Inorganic Chimica Acta., 1973, 7, 179.

[20]. M.A. Ali and R. N. Bose, Polyhedron, 1984, 3(35), 517.

[21]. S. Kumar, D.N. Dhar, and P. N. Saxena, Applications of metal complexes of Schiff bases a review, Journal of Scientific and Industrial Research., 2009, 68(3), 181-187.

[22]. T. Punniyamurthy, S. J. S. Kalra, and J. Iqbal., Tetrahedron Letters, 1995, 36, 8497.

[23]. D.N. Dhar, C.L. Taploo, Schiff bases and their application, J.Sci. Ind. Res. 1982, 41(8), 501

[24]. L. Messori, F.Abbate, G. Marcon et al, Journal of Medicinal Chemistry., 2000, 43, (19), 3541

[25]. Md.Kudrat-E-Zahan and M. S. Islam, Russian Journal of General Chemistry., 2015, 85 (4), 979.

[26]. Dr.A. Xavier, N. Srividhya, 2014, 2278-5736, 7, 11, 06-15.

[27]. R.R Gupta, Kumar, V. Gupta, Heterocyclic chemistryI, 1998.

[28]. D.Worku, M Negussie, V. J.T. Raju, S. Theodros, J.A. Jonson, Bull. Chem. Soc.Ethiop. 2002,29.

[29]. D.Worku, M Negussie, V. J.T. Raju, R. Negussie, Bull.Chem.Soc.Ethiop. 2002., 17, 30.

[30]. D.N. Dhar, C.L. Taploo, Schiff bases and their applications. J Sci Ind Res 1982, 41(8):501.

[31]. G.Bringmann, M. Dreyer, J.H. Faber, Dalsgaard, D Pw,Staerk, J.W. Jaroszewski, et al. Ancistrotanzanine C and related 5,1/Jaroszewski JW, et al. Ancistrotanzanine C and related 5,1/ and 7,3/ coupled naphthylisoquinoline alkaloids from Ancistrocladus tanzaniensis. J Nat prod 2004. 67(5), 743. [32]. P.Przybylaki, A.Huxzynaki, K. Pyta B. Brzenzinski, F. Bartl, Biological properties of Schiff basess and azo derivatives of phenols, Curr. Org. Chem. 2009; 13(2):124-48.

[33]. A.O. de Souza, F.C.S0 Galetti, C.L. Silva, B. Bicalho, M.M.Pharma, S.F. Fonseca, et al. Antimycobacterial and cytotoxicity activity and natural compounds. Quim Nova 2007; 30(7):1563-6.

[34]. Z. Guo, R. Xing, S. Liu, Z. Zhong, X. Ji, L. Wang et al. Antifungal properties of Schiff bases of chitosan, N-substituted chitosan and quaternized chitosan. Carbohydrate Res 2007; 342(10); 1329-32.

[35]. Y. Ju and R. S. Varma, “Aqueous Nheterocyclization of primary amines and hydrazines with dihalides: microwaveassisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives,” Journal of Organic Chemistry, vol. 71, no. 1, pp. 135–141, 2006

[36]. Y. Ju, D. Kumar, and R. S. Varma, “Revisiting nucleophilic substitution reactions: microwave-assisted synthesis of azides, thiocyanates, and sulfones in an aqueous medium,” Journal of Organic Chemistry, vol. 71, no. 17, pp. 6697–6700, 2006.

[37]. P. D. Lokhande, B. Y. Waghamare, and S. S. Sakate, “Regioselective one-pot synthesis of 3,5-diarylpyrazoles,” Indian Journal of Chemistry B, vol. 44, no. 11, pp. 2338–2342, 2005.

[38]. G. J. Reddy, D. Manjula, K. S. Rao, M. Khalilullah, and D. Latha, “A Direct single step synthesis of 1,3-diaryl-4-cyanopyrazoles and their conversion to 1,3-diaryl-4-(4,6-diamino 1,3,5-triazin-2-yl)pyrazoles,” Indian Journal of Chemistry B, vol. 44, pp. 2412–2415, 2005.

[39]. C. A. Zificsak and D. J. Hlasta, “Current methods for the synthesis of 2-substituted azoles,” Tetrahedron, vol. 60, no. 41, pp. 8991– 9016, 2004.

[40]. T. Haino, M. Tanaka, K. Ideta, K. Kubo, A. Mori, and Y. Fukazawa, “Solid-phase synthesis of liquid crystalline isoxazole library,” Tetrahedron Letters, vol. 45, no. 11, pp. 2277– 2279, 2004.

[41]. M. García-Valverde and T. Torroba, “Special issue: sulfur-nitrogen heterocycles,” Molecules, vol. 10, no. 2, pp. 318–320, 2005.

[42]. D. W. Hopper, A. L. Crombie, J. J. Clemens, and S. Kwon, “Six-membered ring systems: pyridine and benzo derivatives,” Progress in Heterocyclic Chemistry, vol. 21, pp. 330–374, 2009.

[43]. A. Manlove and M. P. Groziak, “Six-membered ring systems: diazines and benzo derivatives,” Progress in Heterocyclic Chemistry, vol. 21, pp. 375–414, 2009.

[44]. A. D. Russell, “Mechanisms of bacterial insusceptibility to biocides,” The American Journal of Infection Control, vol. 29, no. 4, pp. 259–261, 2001.

[45]. D. J. Brown, Comprehensive Heterocyclic Chemistry, vol. 14, Pergamon Press, Oxford, UK, 1984. [46]. R. C. Elderfield, Heterocyclic Compounds, vol. 6, John Wiley and Sons, New York, NY, USA, 1957. [47]. P. Y. Bruice, Organic Chemistry, Pearson Education, Singapore, 3rd edition, 2007.

[48]. Smith QE. In pharmacological screening tests progress in medicinal chemistry. Butterworths London. 1960;1:1-33.

[49]. Bagley, Mark C.; Hughes, David D.; Taylor, Paul H.Synlett, 2003 , # 2 p. 259 – 261 [50].Sakamoto; Sakasai; Yamanaka Chemical and Pharmaceutical Bulletin, 1980 , vol. 28, # 2, p. 571 – 577

[51]. Wu, Jiahui; Zhang, Dengyou; Chen, Lei; Li, Jianneng; Wang, Jianling; Ning, Chengqing; Yu, Niefang; Zhao, Fei; Chen, Dongying; Chen, Xiaoyan; Chen, Kaixian; Jiang, Hualiang; Liu, Hong; Liu, Dongxiang Journal of Medicinal Chemistry, 2013, vol. 56, # 3 p. 761 – 780.

[52]. Li, Huan-Qiu; Li, Dong-Dong; Lu, Xiang; Xu, Yun-Yun; Zhu, Hai-Liang Bioorganic and Medicinal Chemistry, 2012, vol. 20#1 p. 317-323.

INTRODUCTION: