RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCE, KARNATAKA BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE AND ADDRESS

Mr.PRAVEEN D.M.DEPT.OF PHARMACEUTICAL CHEMISTRYK.L.E.SOCIETY’S COLLEGE OF PHARMACY VIDYANAGARHUBLI-580031

2. NAME OF THE INSTITUTION K.L.E.SOCIETY’S COLLEGE OF PHARMACY VIDYANAGARHUBLI.-580031

3. COURSE OF STUDY AND SUBJECT MASTER OF PHARMACY IN PHARMACEUTICAL CHEMISTRY

4. DATE OF ADMISSION TO COURSE JUNE-2008

5. TITLE OF THE TOPIC

SYNTHESIS AND EVALUATION OF ANTI INFLAMMATORY ACTIVITY OF ETHYL- 2-(BENZILIDENE AMINO) SUBSTITUTED-3-PHENYL PROPIONATE

6.BRIEF RESUME OF INTENDED WORK6.1 Need for the study

Inflammation is the local response of living mammalian tissue to injury due to any

agent.1 Large number of non steroidal anti-inflammatory drugs (NSAIDs) are prescribed

throughout the world and used mainly for the treatment of pain, fever and inflammation

particularly for different types of arthritis.2

The pharmacological activity of NSAIDs is related in the suppression of prostaglandin

biosynthesis from arachidonic acid by inhibiting the enzyme prostaglandin endoperoxidase,

popularly known as cyclo-oxygenase.3 Cyclo-oxygenase exists in two isoforms, COX-1 and

COX-2, which are regulated and expressed differently. COX-1 provides cytoprotection in

the gastrointestinal tract (GIT), whereas inducible COX-2 selectively mediates

inflammatory signals.4

A Large number of conventional non steroidal anti-inflammatory drugs are available

clinically to treat acute and chronic inflammatory disorder. However, most of these drugs

cause gastrointestinal hemorrhage, ulceration5, renal disorders and other side effects. Even

though the days of selective COX-II inhibitor are quite bright but the gloomy face, cardiac

disorder are the major drawbacks.6

Because of these side effects of the existing NSAIDs a need for exploring newer

NSAIDs which are free from these side effects. Hence search for newer and safer anti-

inflammatory agent is still very active and essential. Literature survey reveals that different

amino acids and amino acid derivatives and Schiff base of different nucleus showed

significant anti-inflammatory activity.7, 8

Preparation of derivatives and evaluation of their activity is an interesting topic of

research in the field of Medicinal Chemistry. The word derivative is a broad term which

involves different kinds of modification in the existing drugs. Therefore the need for

synthesis of newer molecule consisting Schiff base with amino acid which may show better

pharmacological activity. Hence the present study has been design to synthesis and

evaluation of anti-inflammatory activity of amino acid Schiff base.

6.2 Review of Literature

Extensive literature survey was carried out in library of K.L.E.’S College of Pharmacy

Hubli. Karnataka University Dharwad and by visiting various web sites through internet the

relevant data has been collected.

Literature survey reveals that different amino acids and Schiff base of different nucleus

showed variety of biological activity. Several methods for the synthesis and pharmacological

properties of Schiff base reported in literature

Iffet Sakiyan. et. al. reported the synthesis characterization of Manganese-III

complexes of Schiff base derived from L-alanine, L-phenylalanine.9

Zahid H Chohan. et. al. reported the synthesis and characterization of Co(II), Cu(II),

Ni(II), Zn(II) metal complexes. The metal complexes were evaluated for anti-bacterial

and anti-fungal activity.10

M=Co(II),Cu(II), Ni(II) or Zn(II)

Gehad G. Mohamed. reported the synthesis and characterization of bis(phenylimine)

Schiff base ligands and their metal complexes. The metal complexes were evaluated

for anti-bacterial activity.11

M=Co(II),Cu(II), Ni(II) or Zn(II)

Massimo curini. et. al. reported the novel chiral Schiff base ligands from o-

phenylenediamine, aminoacid, salicylaldehyde.12

M.Sivasankaran Nair. et. al. reported the synthesis and characterization of Co(II),

Cu(II), Ni(II), Zn(II) complexes of tridentate Schiff base derived from vanilin and DL-

aminobyteric acid. The metal complexes were evaluated for anti-bacterial activity.13

M=Co(II),Cu(II), Ni(II) or Zn(II)

Mohammad shakir. et. al. reported the synthesis and characterization of Co(II), Cu(II),

Ni(II), Zn(II) complexes with 12 membered Schiff base tetraazamacrocyclic ligand.

The metal complexes were evaluated for anti-microbial activity.14

M=Co(II),Cu(II), Ni(II) or Zn(II)

Javed IQBAL. et. al. reported the biological properties of Chloro-salicylidene aniline

and its complexes with Co(II), Cu(II). The metal complexes were evaluated for anti-

bacterial activity.15

M=Co(II),Cu(II)

Jian Lv. et. al. reported the synthesis and biological properties of Co(II), Cu(II),

complexes of valine derived schiff base. The metal complexes were evaluated for anti-

bacterial, anti-fungal activity.16

N

N

O

N

OCu

O

Ina Bolz. et. al. reported the novel Schiff base derived from 5-amino barbituric acid.

These compounds have been investigated by means of solid state 13C{1H} NMR- and

FTIR-spectroscopy.18

F.M.Morad. et. al. reported the preparation and characterization of Ni(II) schiff base

complex. The metal complex were evaluated for anti-bacterial activity.19

Scott E. Harpstrite. et. al. reported the synthesis and characterization of novel schiff

base phenol. The compounds are evaluated for anti-microbial activity.20

US Patent. Edmundson et. al. reported the analgesic use of N-L-α-asparatyl-L-

phenylalanine-1-methyl ester deravitives.21

US Patent. Ketazawa et. al. reported the amino acid derivative and anti-inflammatory

agent. The anti-inflammatory agent of the invention inhibits expression of an

inflammatory protein and activation of a gene transcription control factor.22

.

Literature survey reveals that chronic use of non steroidal anti-inflammatory drugs

causes different side effects due to free carboxylic acid group. So still researchers focusing

on newer and safer anti-inflammatory agents by protecting free acid group. Earlier reports

reveals aminoacids, cystein, L-tryptophan and L-phenylalanine were reported to posses anti-

inflammatory activity. In view of above biological importance of amino-acid and different

Schiff base, we are aiming to synthesize amino-acid Schiff base with following objectives.

6.3 Objective of the study

The main objective of the present investigation is to synthesize substituted

benzilidine amino acid derivatives.

To characterize the structure of synthesized compounds by Physical and Spectral data

viz UV, IR, NMR and Mass spectra.

To screen the newly synthesized compounds for acute anti-inflammatory activity.

Compounds which are showing promising anti-inflammatory activity in acute model

will be further screened for chronic anti-inflammatory, analgesic, anti-pyretic and

ulcerogenic activities.

.

7. Material and methods

7.1 Source of Data

Data generated from laboratory experimentation techniques including,

(a) Synthesis of Amino acid Schiff base.

(b) Spectral studies of the newly synthesized compounds by UV, IR, NMR and Mass

spectral data.

(c) These newly synthesized compounds will be evaluated for anti- inflammatory activity.

7.2 Method of Collection of Data:

(Including sampling procedure if any)

Necessary data for synthesis and pharmacological evaluation will be collected by literature

survey and experimentation technique.

A] Synthetic studies

Amino acid Schiff bases will be synthesized as per the literature methods, the completion

of the reaction will be ascertained by thin layer chromatography. The new compounds will be

synthesized according to the following scheme. We are aiming to synthesize 12-15 different

target compounds.

(D&L) 2-amino-3-phenyl Ethyl-2-amino-3-phenyl

Propanoic acid propanoate + Substituted benzaldehyde

Schiff base derivatives of 2-amino 3-phenyl-Propanoic acid

B] Acute anti-inflammatory activity23

Anti-inflammatory study will be carried out by using Carrgeenin induced rat paw edema

method.

C] Analgesic activity24

Analgesic study will be carried out by using acetic acid induced writhing in mice method

D] Chronic anti-inflammatory activity25

Chronic anti-inflammatory activity study will be carried out by using Fruend’s adjuvant

model in rats

7.3 Does the study requires any investigation or interventions to be conducted on

patients or other humans/animals? If so please described briefly.

The above study requires investigation to be done on albino rats of wistar strains for the

determination of anti-inflammatory, and albino mice for determination of analgesic activity

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

Applied for ethical committee of the institution for clearance

8. List of Reference

1. Harsh Mohan. Text book of Pathology 4th ed. page no-114, Jaypee brothers

medical publishers (P) LTD New Delhi.

2. Loeb DS, Tally NJ, Ahlqist DA, Carpenter HA, Zinmeister AR. Long term non

steroidal anti-inflammatory drug use and gastroduodenal injury: the role of

Helicobacter pylori infection. Gastroenterol. 1992; 102:1899-05.

3. Warner TD, Giuliano F, Vaynovie I, Bukasa A, Mitchell JA, Vave JR. Proc. Natl

Acad Sci 1999; 96:7563–68.

4. Amgad GH, Praveen Rao PN, Edward EK. Design and Synthesis of 4, 5-

Diphenyl-4-isoxazolines:   Novel Inhibitors of Cyclooxygenase-2 with Analgesic and

Antiinflammatory Activity. J Med Chem. 2001; 44:2921-27.

5. MC Allison, AG Howatson, CJ Torrance, FD Lee, and RI Russell.

Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory

drugs. Engl J Med 1992; 327:749-54.

6. Bombardier C, Laine L, Reicin A. Comparison of upper gastrointestinal toxicity

of refecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2001;

343:1521-28.

7. Khanna NK. Amino acids as Antiinflammatory agents. Ind J Pharmcol. 1984;

16:122-23.

8. Shashikant VB, Kailash GB, Mayuresh KR, Ajit AP, Aniket PS Vinod JM.

Design, Synthesis and Evaluation of Antiinflammatory, Analgesic and Ulcerogenicity

studies of Novel S-Substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of

Diclofenac acid as Nonulcerogenic Derivatives. Bioorg Med Chem 2008; 16:1822–31.

9. Ankara University Project Report. İffet Şakıyan. Synthesis and characterization

of Manganese (iii) Complexes of schiff bases derived from amino acids and 2-

hydroxy-1-naphthaldehyde. 2003.

10. Zahid H. CM, Arif, M, Muhammad AA, Claudiu TS. Metal-Based Antibacterial

and Antifungal Agents Synthesis, Characterization, and In Vitro Biological Evaluation

of Co(II), Cu(II), Ni(II), and Zn(II) Complexes with Amino Acid Derived

Compounds. Bioinorg. Chem App.2006; 1–13.

11. Gehad G. Mohamed. Synthesis, characterization and biological activity of bis(phenylimine) Schiff base ligands and their metal complexes. Spectrochimica Acta Part A. 2006; 64:188–95.

12. Massimo Curini, Francesco Epifano, Federica Maltese, Maria C. Marcotullio. Novel chiral Schiff base ligands from amino acid amides

and Salicylaldehyde. Tetrahedron. Lett. 2002; 43:3821–23 .13. M. Sivasankaran Nair , R. Selwin Joseyphus. Synthesis and

characterization of Co(II), Ni(II), Cu(II) and Zn(II) complexes of tridentate Schiff base derived from vanillin and dl-aminobutyric acid. Spectrochimica Acta Part A 2008; 70:749–53.

14. Mohammad Shakir , Yasser Azim, Hamida-Tun-Nisa Chishti, Shama Parveen. Synthesis, characterization of complexes of Co(II), Ni(II),Cu(II) and Zn(II) with 12-membered Schiff base tetraazamacrocyclic ligand and the study of their antimicrobial and reducing power. Spectrochimica Acta Part A., 2006; 65:490–96.

15. Javed I, Syed Ahmad T, Feroza Hamid W, Muhammad I, Muhammad Hamid

Sarwar W, Shahida S, Shoomaila L Biological Properties of Chloro-salicylidene

Aniline and Its Complexes with Co(II) and Cu(II). Turk J Biol 2006; 30:1-4.

16. Jian Lv , Tingting Liu , Sulan Cai , Xin Wang , Lei Liu , Yongmei Wang.

Synthesis, structure and biological activity of cobalt(II) and copper(II) complexes of

valine-derived schiff bases. J Inor Biochem. 2006;100:1888–96

17. Ina Bolz, Claudia May, and Stefan Spange “Novel Schiff bases derived from 5-

aminobarbituric acid: synthesis and solid state structure” ARKIVOC 2007 (iii) 60-67.

18. F.M. Morad, M.M.EL.ajaily, S. Ben Gweirif. Preparation, physical

characterization and antibacterial activity of Ni (ii) Schiff base complex. J Sci App. 2007; 1:72-78,

19. Scott EH, Silvia DC, Ana Oksman, Daniel EG, Vijay Sharma. Synthesis, Characterization, and Antimalarial Activity of Novel Schiff- Base Phenol

and Naphthalene-Amine Ligands. Med Chem. 2008; 4:392-95

20. Allen B.Edmundson, Carl V. Manion, Analgesic use of N-L-α-Asparatyl-L-

Phenylalanine 1-Methyl ester. United States Patent, patent no-5654334, Aug. 5,

1997.

21. Manabu Kitazawa, Keiji Iwasaki, Shiojiri. Amino acid derivative and Anti-

inflammatorry agent. United States Patent, patent no-US 6552061 B1, Apr. 22,

2003.

22. Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the

rat as an assay for anti-inflammatory drugs. Proc Soc Exp Bio Med. 1962; 111:544-

47.

23. Vogel, Gerhard H, Wolfgand H vogel. Drug discovery and Evaluation, Newyork:

Springer-Velag Berlin Heidelberg; 1996.

24. Vogel, Gerhard H, Wolfgand H Vogel. Drug discovery and Evaluation. Newyork

Springer-Velag Berlin Heidelberg; 1996.

9 Signature of the Candidate

10Remarks of the Guide The above work which is assigned to

Mr. Praveen D.M is verified and found

correct. The present study will be carried out

under my supervision.

1111.1 Name and designation of Guide

Dr. V.S. MADDIPROFESSORDEPT. OF PHARMACEUTICAL CHEMISTRYK.L.E. SCOETY’S COLLEGE OF PHARMACYVIDYANAGAR, HUBLI-580031

11.2 Signature

11.3 Co-guide _ _ _ _

11.4 Signature _ _ _ _

11.5 Head of Department Dr. V.S. MADDIPROFESSORDEPT. OF PHARMACEUTICAL CHEMISTRYK.L.E. SCOETY’S COLLEGE OF PHARMACYVIDYANAGAR, HUBLI-580031

11.6 Signature

1212.1 Remarks of Principal The above mentioned information is correct

and I recommended the same for approval.

12.2 Signature

Dr. B. M. PATIL PRINCIPALK.L.E. SCOETY’S COLLEGE OF PHARMACYVIDYANAGAR, HUBLI-580031