Jamonline / 2(4); 2012 / 273281 Research Article

Sambhaji P. Vartale et al

Journal of Atoms and Molecules

An International Online Journal
ISSN 2277 1247

SYNTHETIC APPROACH TOWARDS PYRIMIDO [4, 5-B] QUINOLINE WITH 2-SUBSTITUTED DERIVATIVES AND STUDY OF ANTIMICROBIAL ACTIVITY

Sambhaji P. Vartale*, Nilesh K. Halikar, Prashant N. Ubale and Niwrati S. Pawar P.G. Research centre, Department of chemistry, Yeshwant Mahavidyalaya, Nanded-431602(MS) India. Received on: 01-07-2012 Abstract: 2-Amino-8-nitropyrimido[4,5-b]quinoline (1) and ethyl 2-cyano-3,3-bis(methylthio)acrylate (2) were refluxed in N,N-dimethyl formamide (DMF) in presence of catalytic amount of anhydrous potassium carbonate to afforded 3-cyano-8-nitro-2- (methylthio) -4-oxo- 4H- pyrimido [2,1-b] pyrimido [4,5-b] quinoline (3). The latter were further reacted with different substituted aniline, phenol, hetryl amine and compound containing active methyl groups. Afforded to 3-cyano-8-nitro4- oxo- 4H- pyrimido [2, 1-b] pyrimido [4, 5-b] quinoline and their 2-substuited derivatives (4a-7c). All these newly synthesized compounds were characterized by elemental analysis and spectral data, and screened for their antimicrobial activities. Keyword N,N-Dimethyl formamide, potassium carbonate, ethyl 2-cyano-3,3-bis (methylthio) acrylate. Introduction: * Corresponding author Sambhaji P. Vartale, Email: spvartale@gmail.com Phone: +91- 9822430549 Among various heterocyclic compounds, quinoline, pyrimido quinoline derivative have been prepared and evaluate their pharmacological properties. Have been studied for over a century because of a variety All rights reserved 2011 www.jamonline.in 273 Revised on:02-08-2012 Accepted on: 25-08-2012

Jamonline / 2(4); 2012 / 273281 of chemical and biological significance. They have been reported as antibacterial1, antifolate3 calcium
9

Sambhaji P. Vartale et al reaction with different substituted anilines, substituted phenols, active methylene

Antiasthmatic, tyrosine
7

antiallergic2 antimicroibial5
8

compounds and hetryl amines in presence of N,N-dimethyl formamide and catalytic

kinase4

channel antagonists6 anti-inflammatory and analgesic antihypertensive tuberculostatic10, antileishmanial anticonvulsants11,

amount of potassium carbonate obtained product was characterized on the basis of elemental analysis. Materials and Methods Melting points were determined by in an open capillary method and are uncorrected. The chemicals and solvents used for

In

outlook of these valied observations stimulate us to synthesize such quinoline fused with pyrimidine ring would exhibit some

interesting pharmacological activities further, the ring anellation to amino groups containing nitrogen
13

heterocycles

with
12-

laboratory grade and were purified. IR spectra were recorded (in KBr pallets) on Shimadzu spectrophotometer.
1

ketene dithioacetals as reagent has reported

. Recently we report one pot synthesis of 3-

H NMR spectra were

cyano-8-nitro-2-(methylthio)-4-oxo-4Hpyrimido[2,1-b] pyrimido[4,5-b] quinoline

recorded (in DMSO-d6) on Avance-300 MHz spectrometer using TMS as an internal standard. The MASS was recorded on EIShimadzu GCMS spectrometer. Elemental analyses were performed on a Heraeus CHNO rapid analyzer. General procedure for the preparation of 3-cyano-8-nitro-2-(methylthio)-4-oxo-4Hpyrimido [2,1-b] pyrimido[4,5-b] quinoline (3) A mixture of 2-amino-8-nitropyrimido [4,5b]quinoline (1) (2.58g, 0.01 m mol) and ethyl 2-cyano-3,3-bis(methylthio)acrylate (2) (1.70 g, 0.01 m mol) was refluxed in the presence of N, N-dimethyl formamide catalytic

and its reaction with selected nucleophiles. In continuation of this additional development of milder condition with better yields. The compound (3) was prepared by the reaction of 2-amino-8-nitropyrimido [4,5-b]quinoline (1) reaction with ethyl 2-cyano-3,3-bis (methylthio) acrylate (2) in presence of N,Ndimethyl formamide and catalytic amount of potassium carbonate scheme-1. Compound (3) possesses an active methylthio group at the 2-position that is activated by the ring 1nitrogen atom and the electron withdrawing 3cyano group. Compound (3) was reacted with selected N-, O-, and C-nucleophiles like aryl amines, substituted phenols, heteryl amines and compound containing active methylene group. Hence compound (3) independently All rights reserved 2011

amount of anhydrous Potassium carbonate for 5 hrs. The reaction mixture was cooled to room temperature and poured in to ice cold www.jamonline.in 274

Jamonline / 2(4); 2012 / 273281 water. The separated solid was filtered, washed with water and recrystallized from N, N dimethyl formamide-ethanol mixture to afford compound (3). Brown powder, (92% yield), M.P.: 210 oC; EI-MS (m/z-RA%) : 364 (M+), IR (cm-1, KBr) : 2206(CN), 1642(CO), 1H NMR (DMSO-d6, ppm): 2.4 (s, 3H, SCH3), 4.5(s,1H,-CH-) 7.38.8 (m, 5H, Ar-H), C NMR (DMSO13

Sambhaji P. Vartale et al : 2212 (CN), 1630(CO), 1H NMR (DMSO-d6, ppm): 4.3 (s,1H,-NH), 4.3 (s,1H,-CH-) 6.58.9 (m, 9H, Ar-H), Anal. Calcd. For: C21H10ClN7O3 ; C, 56.83; H, 2.27; N, 22.09; Found: C, 56.42; H, 2.12; N, 21.98. 3-Cyano-8-nitro-2-(4methoxy oxo-4H-pyrimido[2,1-b] quinoline (4b) Brown powder, (87% yield), M.P.: 310 oC; EI-MS (m/z-RA%) : 439 (M+) ,IR (cm-1, KBr) : 2210 (CN), 1648(CO), 1H NMR (DMSO-d6, ppm): 3.7 (s,3H,OCH3), 4.4 (s,1H,-NH), 4.6 (s,1H,-CH-) 6.4-8.7 (m, 9H, Ar-H), Anal. anilino)-4-

pyrimido[4,5-b]

d6, ppm) 16, 70, 78, 114,116, 123, 124,125, 128, 136, 148, 149, 159, 167, 169,179; Anal. Calcd. For: C16H8N6O3S; C, 52.75; H, 2.21; N, 23.07; Found: C, 52.24; H, 2.01; N, 22.96. 3-Cyano-8-nitro-2-(4-chloro aniline / 4methoxy aniline / 4-methyl aniline)-4-oxo4H- pyrimido [2,1-b] pyrimido [4, 5-b] quinoline (4a-c) A mixture of compound (3) (3.83 g, 0.01 mol), in N, N-dimethyl formamide and catalytic amount anhydrous potassium

Calcd. For: C22H13N7O4; C, 60.14; H, 2.98; N, 22.31; Found: C, 60.02; H, 2.79; N, 22.16. 3-Cyano-8-nitro-2-(4methyl anilino)4-

oxo-4H-pyrimido[2,1-b] pyrimido [4, 5-b] quinoline (4c) Brown powder, (77% yield), M.P.: 308 oC; EI-MS (m/z-RA%) : 423 (M+), IR (cm-1, KBr) : 2214(CN), 1652(CO),
1

carbonate and appropriate substituted anilines (0.01m mol) was refluxed for 4 hrs. The reaction mixture was cooled to room

H NMR (DMSO-d6,

ppm) : 2. 4 (s,3H,CH3), 4.1 (s,1H,-NH), 4.4 (s,1H,-CH-), 6.6-8.7 (m, 9H, Ar-H), Anal. Calcd. For: C22H13N7O3; C, 62.41; H, 3.09; N, 23.16; Found: C, 62.32; H, 2.98; N, 23.08. 3-Cyano-8-nitro-2-(4-chloro phenol/4-

temperature and poured into ice cold water. The products 4a-c thus obtained were recrystallized from N, N -dimethyl

formamide-ethanol solvent. 3-Cyano-8-nitro-2-(4-chloro anilino)-4-

methoxy phenol /2-chloro phenol)-4-oxo4H- pyrimido [2,1-b] pyrimido [4, 5-b] quinoline (5a-c) A mixture of compound (3) (3.83 g, 0.01 mol), in N, N dimethyl formamide and www.jamonline.in 275

oxo-4H- pyrimido [2,1-b] pyrimido [4, 5-b] quinoline (4a) Brown powder, (81% yield), M.P.: 314 oC; EI-MS (m/z-RA%) : 443 (M+), IR (cm-1, KBr) All rights reserved 2011

Jamonline / 2(4); 2012 / 273281 catalytic amount anhydrous Potassium

Sambhaji P. Vartale et al Brown powder, (76% yield), M.P.: 318 oC; EI-MS (m/z-RA%) : 445 (M+1), IR (cm-1, KBr) : 2216 (CN), 1648(CO),
1

carbonate and appropriate substituted phenol (0.01m mol) was refluxed for 5 hrs. The reaction mixture was cooled to room

H NMR

(DMSO-d6, ppm) : 4.2 (s,1H,-CH-), 7.4-8.8 (m, 9H, Ar-H), Anal. Calcd. For:

temperature and poured into ice cold water. The products 5a-c thus obtained were recrystallized from N, N-dimethyl

C21H9ClN6O4; C, 56.71; H, 2.04; N, 18.89; Found: C, 56.58; H, 2.01; N, 18.65. 3-Cyano-8-nitro-2-

formamide-ethanol solvent. 3-Cyano-8-nitro-2-(4-chloro phenol)-4-

(pyrrolidino/piperidino/morpholino)-4-oxo4H-pyrimido[2,1-b] quinoline (6a-c) A mixture of compound (3) (3.83 g, 0.01 mol), in N, N dimethyl formamide and catalytic amount anhydrous Potassium pyrimido[4,5-b]

oxo-4H-pyrimido[2,1-b] pyrimido [4, 5-b] quinoline (5a) Brown powder, (72% yield), M.P.: 315 oC; EI-MS (m/z-RA%) : 444 (M+), IR (cm-1, KBr) : 2216 (CN), 1648(CO), 1H NMR (DMSO-d6, ppm) : 4.2 (s,1H,-CH-), 7.4-8.8 (m, 9H, ArH), Anal. Calcd. For: C21H9ClN6O4; C, 56.71; H, 2.04; N, 18.89; Found: C, 56.58; H, 2.01; N, 18.65. 3-Cyano-8-nitro -2-(4-methoxy phenol)-4oxo-4H-pyrimido[2,1-b]pyrimido[4,5-b] quinoline (5b) Brown powder, (80% yield), M.P.: 310oC; EIMS (m/z-RA%) : 441 (M+ +1), IR (cm-1, KBr) : 2212 (CN), 1652(CO), 1H NMR (DMSO-d6, ppm) : 3.7 (s,3H,OCH3), 4.0 (s,1H,-CH-), 7.28.9 (m, 9H, Ar-H), Anal. Calcd. For: C22H12N6O5; C, 60.00; H, 2.75; N,

carbonate and appropriate substituted hetryl amine (0.01m mol) was refluxed for 4 hrs. The reaction mixture was cooled to room temperature and poured into ice cold water. The products 6a-c thus obtained were recrystallized from N, N dimethyl

formamide-ethanol solvent. 3-Cyano-8-nitro-2-(pyrrolidino)-4-oxo-4Hpyrimido [2,1-b] pyrimido [4, 5-b] quinoline (6a) Brown powder, (88% yield), M.P.: 319 oC; EI-MS (m/z-RA%) : 387 (M+), IR (cm-1, KBr) : 2212 (CN), 1644(CO), 1H NMR (DMSO-d6, ppm) : 1.6 (t,4H, CH2 ), 2.7 (t,4H, -NCH2_), 4.1 (s,1H,-CH-), 7.4-8.8 (m, 5H, Ar-H), Anal. Calcd. For: C19H13N7O3; C, 58.91; H, 3.38; N, 25.31; Found: C, 58.86; H, 3.21; N, 25.20.

19.08;Found: C, 59.81; H, 2.63; N, 18.98. 3-Cyano-8-nitro -2-(2-chloro phenol)-4oxo-4H-pyrimido [2,1-b]pyrimido [4,5-b] quinoline (5c)

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Jamonline / 2(4); 2012 / 273281 3-Cyano-8-nitro -2-(piperidino)- 4-oxo-4Hpyrimido [2,1-b] pyrimido [4, 5-b]

Sambhaji P. Vartale et al temperature and poured into ice cold water. The products 7a-c thus obtained were recrystallized from N, N-dimethyl

quinoline (6b) Brown powder, (74% yield), M.P.: 314 oC; EI-MS (m/z-RA%) : 401 (M+) ,IR (cm-1, KBr) : 2213 (CN), 1644(CO), 1H NMR (DMSO-d6, ppm) : 1.3 (t,6H, three -CH2 ), 2.6 (t,4H, twoNCH2 ), 4.3 (s,1H,-CH-),7.4-8.6 (m, 5H, ArH), Anal. Calcd. For: C20H15N7O3; C, 59.85; H, 3.77; N, 24.43 Found: C, 59.74; H, 3.52; N, 24.23. 3-Cyano-8-nitro -2-(morpholino)- 4-oxo4H- pyrimido[2,1-b] pyrimido [4, 5-b] quinoline (6c) Brown powder, (78% yield), M.P.: 310oC; EIMS (m/z-RA%) : 403 (M+ ), IR (cm-1, KBr) : 2196 (CN), 1646(CO),
1 _ _

formamide-ethanol solvent. 3-Cyano-8-nitro-2-(-ethylacetoacetyl)-4oxo-4H-pyrimido[2,1-b]pyrimido[4,5b]quinoline (7a) Brown powder, (85% yield), M.P.: 310 oC; EI-MS (m/z-RA%) : 446(M+), IR (cm-1, KBr) : 2196 (CN), 1640(CO), 1H NMR (DMSO-d6, ppm) : 1.3 (s,3H,-CH3), 2.1 (s,3H,COCH3), 3.8 (s,1H,-CH),4.1 (s,2H,-CH2), 4.5 (s,1H,CH-),7.5-8.8 (m, 5H, Ar-H), Anal. Calc. For: C21H14N6O6; C, 56.51; H, 3.16; N, 18.83; Found: C, 56.42; H, 3.04; N, 18.76. 3-Cyano-8-nitro-2-(-ethylcyanoacetyl)-4oxo-4H-pyrimido[2,1-b]pyrimido[4,5b]quinoline (7b) Brown powder, (83% yield), M.P.: 312 oC; EI-MS (m/z-RA%) : 429 (M+), IR (cm-1, KBr) : 2218 (CN), 1640(CO), 1H NMR (DMSO-d6, ppm) : 1.2 (s,3H,-CH3), 3.8 (s,1H,-CH), 4.2(s,

H NMR (DMSO-d6,

ppm) : 2.6 (t,4H, -NCH2), 3.7(t,4H, OCH2 ), 4.2 (s,1H,-CH-), 7.6-8.7 (m, 5H, Ar-H), Anal. Calcd. For: C19H13N7O4; C, 56.58; H, 3.25; N, 24.31; Found: C, 56.47; H, 3.10; N, 24.20. 3-Cyano-8-nitro-2-(-ethylacetoacetyl /ethylcyanoacetyl /-malononitriyl)-4-oxo4H- pyrimido [2,1-b] pyrimido [4, 5-b] quinoline (7a-c) A mixture of compound (3) (3.83 g, 0.01 mol) in N, N-dimethyl formamide and catalytic amount anhydrous Potassium carbonate and appropriate substituted active methylene

2H,-OCH2-), 4.3 (s,1H,-CH-),7.4-8.9 (m, 5H, Ar-H), Anal. Calc. For: C20H11N7O5; C, 55.95; H, 2.58; N, 22.84; Found: C, 55.74; H, 2.46; N, 22.67. 3-Cyano-8-nitro-2-(-malononitriyl)-4-oxo4H- pyrimido[2,1-b] pyrimido [4, 5-b] quinoline (7c) Brown powder, (89% yield), M.P.: 318oC; EIMS (m/z-RA%) : 382 (M+ ), IR (cm-1, KBr) : www.jamonline.in 277

groups (0.01m mol) was refluxed for 5 hrs. The reaction mixture was cooled to room All rights reserved 2011

Jamonline / 2(4); 2012 / 273281 2214 (CN), 1647(CO),

1

Sambhaji P. Vartale et al aniline)- 4-oxo-4H- pyrimido[2,1-b] pyrimido [4, 5-b] quinoline (4a-c) respectively.

H NMR (DMSO-d6,

ppm): 4.3 (s,2H,-CH), 7.4-8.7 (m, 5H, Ar-H), Anal. Calc. For: C18H6N8O3; C, 56.55; H, 1.58; N, 29.31; Found: C, 56.48; H, 1.40; N, 29.02. Result and Discussion In the present investigation, we have developed new methodology towards the synthesis of 3-Cyano-8-nitro -2-(methylthio)4-oxo-4H- pyrimido[2,1-b] pyrimido [4, 5-b] quinoline and their 2-substituted derivatives. (3) Our method gives

Scheme-2 3-Cyano-8-nitro -2-(4-chloro phenol/4methoxy phenol /2-chloro phenol)- 4-oxo4Hpyrimido[2,1-b] pyrimido [4, 5-b]

quinoline (5a-c) respectively scheme-3 were obtained by condensation of (3) with p-chloro phenol, p-methoxy phenol, o-chloro phenol in N, N dimethyl formamide and catalytic amount anhydrous potassium carbonate. Under similar experimental condition compound (3) reacted independently with hetryl amines like pyrolidine, piperidine, morpholine to yield 3-Cyano-8-nitro -2(pyrrolidino / piperidino / morpholino)- 4oxo-4H- pyrimido[2,1-b] pyrimido [4, 5-b] quinoline (6a-c) respectively scheme-4 Compounds on reaction with ethyl acetoacetate, ethyl cyano acetate, malanonitrile in presence of N, N dimethyl formamide and catalytic amount anhydrous Potassium carbonate yielded compounds 3Cyano-8-nitro -2-(-ethylacetoacetyl /-

single product with high yield. The reaction started with 2-Amino-8-nitropyrimido[4,5b]quinoline (1) and ethyl 2-cyano-3,3-

bis(methylthio) acrylate (2) were refluxed in N, N dimethyl formamide and catalytic amount anhydrous potassium carbonate to afford (3) scheme-1. Compound 3 posses a replaceable active methylthio group at 2- position which is activated by ring 1-nitrogen atom and electron withdrawing group 3-cyano group.

Compound (3) reacted with selected N-,O-, Cnucleophiles like aryl amines hetryl amines, substituted phenols and compounds

ethylcyanoacetyl /-malononitriyl) - 4-oxo4Hpyrimido[2,1-b] pyrimido [4, 5-b]

containing an active methylene group. The compound (3) on independently reaction with p-chloro aniline, p-methoxy aniline, p-methyl aniline in N, N dimethyl formamide and catalytic amount anhydrous potassium

quinoline (7a-c) respectively scheme-5. Compounds 4a-c, 5a-c, 6a-c, 7a-c show

absorption bands in their IR spectra in the range of 2190 cm-1 to 2230 cm-1 due CN and 1630-1660 cm-1 due to CO stretching respectively, 1H NMR and Mass spectral data www.jamonline.in 278

carbonate, afforded 3-Cyano-8-nitro-2-(4chloro aniline/4-methoxy aniline/4-methyl All rights reserved 2011

Jamonline / 2(4); 2012 / 273281 are also in agreement with structures of newly synthesized compounds 4a-c, 5a-c, 6a-c, 7a-c. The structures of these newly synthesized compounds were established on the

Sambhaji P. Vartale et al coli and B. Subtilis by paper disc diffusion method14. Control for fungal and bacterial species using Disc diffusion method, solvent DMSO was used, Fungi- Czapeks dox agar, Bacteria- Nutrient agar. Incubation period for fungi 4 days (24+/- 2 0C) and for bacteria 24 hrs (37
0

basis of elemental analysis, IR, PMR and MA SS spectral data, spectral studies of all

compounds shows that compounds are stable & do not exhibit any tautomerism. Antimicrobial activity All the compounds evaluate their antifungal and antibacterial activity against species Aspergillus flavus, Aspergillus Niger and E.
Sr. No code

C). The synthesized compounds

exhibited zone of inhibition of 10-31 mm in diameter, where as standard Fluconazole exhibited zone of inhibition of 26 mm. Streptomycin exhibited zone of inhibition of 25 mm in diameter against E. coli and B. Subtilis respectively.
Zone of inhibition in mm

Fungal species Af 1 2 3 4 5 6 7 8 9 10 11 12 13 Positive control 3 4a 4b 4c 5a 5b 5c 6a 6b 6c 7a 7b 7c 12 15 12 11 16 18 -10 11 20 08 18 17 26 Fluconazole An 10 -11 17 15 13 17 07 02 09 11 12 11

Bacterial species Ec 11 16 12 10 05 12 11 10 05 10 18 17 12 25 Streptomycin Bs 15 12 14 17 12 10 13 14 10 08 07 15 18

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Jamonline / 2(4); 2012 / 273281 Conclusion In conclusion, we highly have described a and V.

Sambhaji P. Vartale et al Acknowledgements The authors are grateful to Dr. N. Kalyankar, Principal, Nanded, for Yeshwant providing

convenient,

efficient,

environmentally benign procedure for the preparation of structurally diverse pyrimido [4,5-b] quinoline derivatives by the one pot synthesis. The products were milder reaction conditions, simple workup, environmental friendly, and good yields are the most significant advantages of this new procedure in the synthesis of these potential biologically active compounds.
N O2N N 1 N NC NH2 H3CS 2 COOC2H5

Mahavidyalaya,

laboratory facilities, To UGC New Delhi for financial assistance under major research project (F.N 39-834/2010 SR) and Director, Indian Institute of Chemical Technology, Hyderabad, for providing spectra and also thanks Principal Dr. Kalamse, Science College Nanded, providing biological activity.

N O2N N 3 O CN N N SCH3

DMF/Anhy.K2CO3

SCH3

N O2N N O CN 5a 5b 5c 4'-Cl 4'-OCH3 2'-Cl

R OH

N N R O
DM h An F/

O2N
.K 2
3 CO

N
NH2 R

N O

N R CN N H

4hrs

DM

An F/

hy

O 2N
CO .K 2 hy
3

y. CO K2
3

4hrs

4a 4b 4c

4'-Cl 4'-OCH3 2'-CH3

N N O 3 N CN 4hrs X Y N N SCH3
DM F/A

DM

An F/

CO 3 y. K 2 nh

N O2N N O CN N 6a N 6b N 6c O N N N

4hrs

N O2 N N O N N X X COCH3 CN CN Y Y CN COOC2H5 COOC2H5 CN

7a 7b 7c

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Jamonline / 2(4); 2012 / 273281 References

Sambhaji P. Vartale et al

[1]L.V.G. Nargund, Y.S.R. Reddy, R. Jose, Indian Drugs 29 (1991) 45. [2] K. Furukawa, T. Hasegawa, Can. Pat. 2151971; Chem. Abstr. 124 (1996) 289568c. [3] A. Rosowsky, C.E. Mota, S.F. Queener, J. Heterocycl. Chem. 32 (1995) 335. [4] A.M. Thompson, A.J. Bridges, D.W. Fry, et al. J. Med. Chem. 38 (1995) 3780. [5] I.O. Donkor, C.L. Klein, L. Liang, et al. J. Pharm. Sci. 84 (1995) 661. [6] A. Pastor, R. Alajarin, J.J. Vaquero, et al. Tetrahedron 50 (1994) 8085. [7] V.E. Kolla, A.B. Deyanov, F.Y. Nazmetdinov, et al. Khim-Farm. Zh. 27 (1993) 29. [8] J.W. Ellingboe, US Pat. 5,466,692; Chem. Abstr. 124 (1996) 176134q. [9] N.K. Satti, K.A. Suri, O.P. Sun, et al. Indian J. Chem. Sect. B 32B (1993) 978. [10] I.D. Bystryakova, I.A. Burova, G.M. Chelysheva, et al. Khim-Farm. Zh. 25 (1991) 31. [11] A.B. Deyanov, R.K. Niyazov, F.Y. Nazmetdivov, et al. Khim-Farm. Zh. 25 (1991) 26. [12] Sambhaji P. Vartale, Nilesh K. Halikar, Nagesh D. Kalyankar and Avinash V. Pawde, IJPIs Journal of Medicinal Chemistry, ISSN 2229 6875. Vol. 1;4 2011[1-9]. [13] Sambhaji P. Vartale, Vijay N. Bhosale, Sandeep V.Khansole, Ramdas N.Katapalle, Lett.in Org.Chem.2009,6,544-548. [14] Ananthanarayan R& Panikar J C K, Textbook of microbiology (orient Longman), 1999, 578.

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