The document discusses the synthesis of novel oxime ether substituted oxazolidinone derivatives and their evaluation for antibacterial activity. It provides background on oxazolidinone antibacterial agents and mechanisms of bacterial resistance. The objective was to synthesize oxazolidinone intermediates and oxime ether intermediates, and couple them to generate novel derivatives. Various intermediates and final derivatives were synthesized and characterized using spectroscopy. All final derivatives showed antibacterial activity comparable to or better than the drug linezolid.

1. Undertheguidanceof
Dr. SandeepKanwar
AssistantGeneralManager
PanaceaBiotec
Undertheco-guidanceof
Dr. SrinivasNanduri
AssociateProfessor
NIPER-HYD
Presentation By
Ayla Mounika
MC/2013/02
National Institute of Pharmaceutical Education and Research
Dept. of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India NIPER HYDERABAD

2. • Introduction
• Literature review
• Objective of work
• Work done
• Supporting information
• Conclusion
• References
FLOW OF PRESENTATION
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3. INTRODUCTION
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION
Fig 1: Various classes of antibacterials and their targets
Antibacterial agents are chemical substances derived from biological source or
produced by chemical synthesis that kill or inhibit the growth of microorganisms.
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4. Resistance to Antibacterial agents:
• They employ several mechanisms in attaining multidrug resistance.
• Multidrug-resistance organisms (MDRO) are defined as microorganisms
resistance to two or more classes of antibacterial agents.
• Three most common MDRO’S are
1. Methicillin Resistant Staphylococcus aureus [MRSA]
2. Vancomycin Resistant Enterococci [VRE]
3. Extended Spectrum Beta –Lactumase producing Enterobacteriaceae
[ESBLS]
Strategies to overcome Bacterial resistance:
• Short term efforts : Chemical modification of existing agents to improve potency
or spectrum.
• Long term approaches : Use of microbial genomic sequencing techniques to
discover novel agents against potentially new bacterial targets.
• The ultimate solution of emerging resistance is to provide novel agents unaffected
by existing resistance mechanisms.
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION
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5. Novel Antibacterial Agents:
• To combat resistance, new antibiotics with new mechanisms or new classes of
compounds that bind to new binding sites of the established targets are needed.
• Novel Ribosome Inhibitor (NRI) class exhibits selective and broad-spectrum
antibacterial activity.
• Compounds in the NRI series appear to inhibit bacterial ribosomes by a new
mechanism, because NRI-resistant strains are not cross-resistant to other
ribosome inhibitors.
• The NRIs are a promising new antibacterial class with activity against all major
drug-resistant respiratory pathogens.
Oxazolidinone Antibacterial agents:
• The Antibacterial properties of oxazolidinones were discovered by E.I. DuPont de
Nemours in 1970’s.
• They are active against MRSA, VRE and Penicillin resistant streptococci.
• Oxazolidinone class of anti-bacterials have novel mechanism of action.
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION
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6. INTRODUCTION
LITERATURE
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION Mechanism of Oxazolidinone Antibacterials:
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7. INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION
Pharmacological
activities of
oxazolidinones
Anti-
bacterial
Antifungal
Anticonvuls
ant
Anticancer
Anti-
tuberculosis
Anti-HIV
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8. Linezolid: [ZYVOX]
• First commercially available 1,3-oxazolidinone.
• Treatment of gram positive infections.
• In 2000 linezolid was introduced into clinical practice.
Prolonged use of linezolid results in various side effects like
• myelosupression, anemia, leucopenia, pancytopenia, thrombocytopenia, non-
reversible peripheral neuropathy, optic nerve damage, acidosis etc.
• The emergence of early resistance and safety concerns in terms of
myelosupression has initiated the need for the development of more effective
oxazolidinones.
INTRODUCTION
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION
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9. INTRODUCTION
LITERATURE
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
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INTRODUCTION
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Phase III clinical trials
for acute skin infections
Phase II clinical trials
for community acquired pneumonia
Phase II
for treatment of tuberculosis
Phase I clinical trials
for treatment of tuberculosis
Linezolid Hybrids
(6 & 7)
TR-701 (Tedizolid), Rib-X (Radezolid), PNU-100480 (Sutezolid)

10. INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
INTRODUCTION
Oxime ethers:
• Oxime-ether derivatives have drawn much attention in medical research due to their
Anti-bacterial, Anti-tumour and Anti-fungal bioactivities.
• Oxime-ether compounds represent new structure scaffolds that can be optimized to
give new antibacterial agents with structures significantly different from those of
existing class of antibacterials.
• Some of the commercially available drugs with oxime-ether moiety are Ceftizoxime
(8), Strobilurins, Oxiconazole (9), Fenpyromate etc.
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11. From Epoxides:
Scheme-1
Scheme 2:
LITERATURE REVIEW
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
LITERATURE
REVIEW
Oxazolidinones can be synthesized by following methods
Madusudan G; et al.,Indian J. Chem. 2005, 44B, 1236.
Madhusudhan G; et al., Der Pharma Chemica. 2012, 4(1), 266.
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12. INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
LITERATURE
REVIEW
From Epoxides:
Scheme-1
SAR of Oxazolidinone type Antibacterial agents:
Four types of chemical modifications of oxazolidinone type antibacterial agents
include modification of A-ring (oxazolidinone), B-ring (phenyl), C-ring (morpholine)
ring as well as the C5- side chain of the A-ring sub-structure.
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13. C-5 side chain modification:
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
LITERATURE
REVIEW
Yan S; et al. Bioorg. Med. Chem. Lett. 2010, 21, 1302.
Takhi M et al., Bioorg. Med. Chem. Lett. 2006,
16, 2391.
Kamal A; et al.,Eur. J. Med. Chem. 2011, 46, 893e900.
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• Yan et al reported C-5 linked heterocyclic analogues having bicyclic oxazine
functionalities with modification of C-ring with thiomorpholine showed more potent
antibacterial activity (21).
• Takhi et al reported N-or O-linked alkyl substituents at the C-5 position of A-ring has
excellent antibacterial activity (gr +ve and gr –ve) (MIC=0.25-0.5 µg/mL and
MIC=0.5-4 µg/mL), C-5 thiocarbonyl compounds having difluoro substitution to the
phenyl ring were more active (22).
• Kamal et al synthesized aryl sulphonamido conjugates with oxazolidinones having
superior activity (23).

14. B-ring modification:
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
LITERATURE
REVIEW
Vara Prasad et al., Bioorg. Med. Chem. Lett. 2006, 16, 5392.
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Vara Prasad and co-workers reported the synthesis and antibacterial activities of
benzenoheptanone moiety substituted on the phenyl ring of oxazolidinone (26),
showed the better antibacterial activity.
A-ring modification:
Rakesh et al., Eur. J. Med. Chem. 2009, 44, 460.
Rakesh and co-workers reported the synthesis of a series of isoxazoline compounds
(25) with appreciable anti-tuberculosis activity.

15. INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
LITERATURE
REVIEW
Researchers from Panacea Biotec described piperazinyl-phenyloxazolidinone
connected with an additional ring (imidazopyrimidine) via 2-oxo-ethylformamide as
a spacer. This analog has displayed activity with MIC = 0.125 µg/mL against S.
aureus and E. faecalis.
Jain R; et al., PCT WO2010058423, 2010.
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C-ring modification:
Barbachyn M.R; et al. ,Angew. Chem., Int. Ed. 2010, 42, 143.
Das B; et al. Bioorg. Med. Chem. Lett. 2005, 15, 4261.
Ranbaxy has reported synthesis of oxazolidinone modified at C-region, which is a
potent compound (RBx-7644) and it is under clinical development (28).

16. • Present work involved Synthesis of Novel Oxime-ether substituted Oxazolidinone
compounds of formula (30) and their analogues (A, B, C, D).
OBJECTIVE OF WORK
INTRODUCTION
LITERATURE
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
OBJECTIVE
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17. General Scheme:
Synthesis of Intermediates:
WORK DONE
INTRODUCTION
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
WORK DONE
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18. Synthesis of Acetamide Derivative of Oxazolidinone : (42a)INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
WORK DONE
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19. INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
WORK DONE
Synthesis of Triazole Derivatives of Oxazolidinone: (44a, 45b)
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20. INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
WORK DONE
Synthesis of Oxime ether Derivatives: (49 a, b, c)
Compound 46, 47, 49 48
Ar R2 Ar R2 R3
a
b
c
C6H5
C6H5
H
CH3
CH3
C6H5
C6H5
H
CH3
CH3
C2H5
CH3
CH3
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21. INTRODUCTION
LITERATURE
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
WORK DONE
Amide Coupling: (I)
Compound Ar R2 X R1
A C6H5 H H -NHCOCH3
B C6H5 H H
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22. INTRODUCTION
LITERATURE
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
WORK DONE
Amide Coupling: (II)
Compound Ar R2 X R1
C C6H5 CH3 F
D CH3 F
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23. INTRODUCTION
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
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SPECTRAL DATA
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33a

24. 7/5/2015
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34a

25. 7/5/2015
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35a

26. 7/5/2015
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36a

27. 7/5/2015
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37a

28. MS (ESI): m/z 395.8 [M+1].
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29. 7/5/2015 29
39a

30. 7/5/2015
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40a

31. 7/5/2015
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41a

32. 7/5/2015 32
43a

33. 7/5/2015 33
37b

34. 7/5/2015
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37b

35. 7/5/2015
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43b

36. 7/5/2015 36
47a

37. 7/5/2015 37
48a

38. 7/5/2015 38
49a

39. 7/5/2015 39
49b

40. MS (ESI): m/z 192.7 [M-1].
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41. 7/5/2015 41
49c

42. 7/5/2015 42
A

43. MS (ESI): m/z 520.2 [M+23], 498.2 [M+1].
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44. 7/5/2015 44
B

45. MS (ESI): m/z 530.2 [M+23], 508.2 [M+1].
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46. 7/5/2015 46
C

47. MS (ESI): m/z 562.8 [M+23], 540.6 [M+1].
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48. • Oxazolodinone intermediates and oxime ether intermediates were successfully
synthesized and coupled to give a novel oxime ether substituted oxazolidinone
derivatives and evaluated for Anti-bacterial activity.
• They are confirmed by NMR, Mass, IR spectroscopy and purity is evaluated by
HPLC techniques.
• All the oxazolidinones synthesized have antibacterial activity either comparable to
linezolid or better than linezolid.
CONCLUSION
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
CONCLUSION
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49. REFERENCES
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
REFERENCES
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1. Perrin, D.D.; Armarego, W.L.F. Purification of Laboratory Chemicals, Pergamon Press: Oxford,
1988.
2. Gadwood ,R.C.; Carcanague, D.; Shales, D.; Levi, S.; Archer, G.; Zhang,.S.; Huband, M.D. J.
Antibac. Agents. 1991, 57, 455.
3. Richarel ,B.; Noel, M.; Jan V.; Doucette, A.; Kern ,G.; Brown, A.P.; J. Antibac. Agents. 2000, 16,
51.
4. Slee, A. M.; Wuonola, M. A.; Mc Ripley R. J.; Zajac, I.; Zawada, M. J.; Bartholomew ,P. J. Med.
Chem. 1987, 31, 1791.
5. Lin, A.H.; Murray, R.W.; Vidmar, T.J.; Marotti, K.R. Int. J. Antibac. Agents. 1997, 41, 2127.
6. Shinabarger, D.L.; Marotti , K.R.; Murray, R.W.; Lina, A.H.; Melchior, E.P.; Swaney S. J.
Antimicrob Chemother. 1997, 41, 2132.
7. Swaney, S.M.; Aoki, H.; Ganoza, M.C.; Shinabarger, D.L. J. Antimicrob Chemother. 1998, 42,
3251.
8. Brnardic, E.J.; Fraley, M.E.; Garbaccio, R.M.; Layton , M.E.; Sanders , J.M.; Culberson, E.;
Bioorg. & Med. Chem. Lett. 2010, 20, 312.
9. Michalska, K.; Karpiuk, I.; Król, I.; Tyski, S.; Mathur. Bioorg. & Med. Chem. 2013, 21, 577e591.
10. Diekema, D.J.; Jones, S. ; Fluit, A.C.; Hollis, R.J.;. Eur. J. Pharmacol. 2000, 59 (1), 7.
11. Wilcox, M. H.; J. Antibac. Agents. 2005, 6, 2315.
12. Stevens D.L; Dotter B; Madaras-Kelly K. J. Antibiot. 2004, 2, 51.
13. Villemagne, B.; Crauste, C.; Flipo, M.; Baulard ,A.R.; Déprez, B.; Willand, N.; Eur. J. Med. Chem.
2012, 51, 1.
14. Carter, P.H.; LaPorte, J.R.; Scherle, P.A.; Decicco, C.P.; Bioorg. Med. Chem. Lett. 2003, 13, 1237.
15. Hayden, F. G.; Gawaltney, J. M.; J. Antibac. Agents 1982, 21, 892.
16. Madusudan , G.; Om Reddy, G.; Ramanatham , J.; Dubey, P.K.;. Indian J. Chem. 2005, 44B, 1236.

50. INTRODUCTION
LITERATURE
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OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
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ACKNOWLEDGE
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REFERENCES
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17. Madhusudhan, G.; Venkanna, G.; Nagender, D.; Mukkanti ,K.; Der Pharma Chemica. 2012, 4(1),
266.
18. Alouane, A.; Catherine, J.; Silvestre; Raphael ,L.; Molecules. 2014, 19, 7429.
19. Zappia, G.; Cancelliere, G.; Gacs-Baitz, E.; DelleMonache, J.; Misiti ,D.; Nevola, L.; Botta, B.C.;
Tetrahedron Lett. 2007, 4, 238.
20. Yan, S.; Miller, M.J.; Wencewicz ,T.A.; Mollmann, U.; Bioorg. Med. Chem. Lett. 2010, 21, 1302.
21. Takhi, M.; Murugan, C.; Munikumar, M.; Baskarreddy, K.M.; Singh, G.; Srinivas, K.;
Sitaramkumar, M.; Selvakumar ,N.; Das, J.; Trehan, S.; Iqbal, J. Bioorg. Med. Chem. Lett. 2006,
16, 2391.
22. Kamal, A.; Shetti, R.V.C.R.N.C.; Azeeza, S.; Swapna, P.; Khan, M.N.A.; Reddy, A.M.; Khan, I.A.;
Sharma, S.; Abdullah , S.T.; Eur. J. Med. Chem. 2011, 46, 893e900.
23. Shiau, T. P.; Turtle, E. D.; Francavilla, C.; Alvarez, N. J.; Zuck, M.; Friedman, L.; O’Mahony, D. J.
R.; Low, E.; Anderson, M.B.; Najafi, R.; Jain, R. K.; Bioorg. Med. Chem. 2011, 21, 3025.
24. Rakesh Sun, D.; Lee, R. B.; Tangallapally, R. P.; Lee, R. E.; Eur. J. Med. Chem. 2009, 44, 460.
25. Ippolito, J.K.; Kanyo, Z.F.; Wang, D.; Franceschi, F.J.; Moore, P.B.; Steitz, T.A.; Duffy, E.M.; J.
Med. Chem. 2008, 51, 3353.
26. Vara Prasad , J.V.N.; Boyer, F.E.; Chupak ,L.; Dermyer, M.; Ding ,Q.; Gavardinas, K.; Hagen, S.E.;
Huband, M.D.; Jiao, W.; Kaneko, T.; Maiti, N.; Melnick, M.; Romero, K.; Patterson, M.; Wu X.
Bioorg. Med. Chem. Lett. 2006, 16, 5392.
27. Barbachyn ,M.R.; Ford, Ch. W. Angew. Chem., Int. Ed. 2010, 42, 143.
28. Das, B.; Rudra, S.; Yadav, A.; et al. Bioorg. Med. Chem. Lett. 2005, 15, 4261.
29. Jain, R.; Trehan, S.; Das, J.; Kanwar, S.; Magadi, S.K.; Sharma, S.K.; PCT WO2010058423, 2010.

51. ACKNOWLEDGEMENTS
INTRODUCTION
LITERATURE
REVIEW
OBJECTIVE
WORK DONE
SPECTRAL DATA
CONCLUSION
REFERENCES
ACKNOWLEDGE
MENT
ACKNOWLEDGEMENT
Dr.Ahmad Kamal Sir (Project Director)
Dr.N.Satyanarayana Sir (Registrar)
Dr.Srinivas Nanduri (Co-Guide)
Dr.B.Nagendra Babu (Course Coordinator)
All NIPER Faculty and
All My Friends.
My Sincere Thanks to
Dr. Jagattaran Das (Supervisor)
Dr. Sandeep Kanwar (Guide)
Sukhpreet Deo
Mohan Sharma
J. Vidya Sagar
Deepshika Patle
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52. T
H
A
N
K
Y
O
U
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