RAJIVGANDHIUNIVERSITY 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 CHEMISTRY
K.L.E.SOCIETY’S COLLEGE OF PHARMACY VIDYANAGAR
HUBLI-580031
2. / NAME OF THE INSTITUTION / K.L.E.SOCIETY’S COLLEGE OF PHARMACY VIDYANAGAR
HUBLI.-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 WORK
6.1 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 inthe 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 abroad 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
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.
6.3Objective 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, TallyNJ, 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 useof nonsteroidal anti-inflammatory drugs. EnglJMed 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 asAntiinflammatory 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-Substitutedphenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of Diclofenacacid as Nonulcerogenic Derivatives. Bioorg Med Chem 2008; 16:1822–31.
9.AnkaraUniversity 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 andSalicylaldehyde.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 vanillinand 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 theirantimicrobial and reducingpower.Spectrochimica Acta Part A., 2006; 65:490–96.
15.JavedI, Syed Ahmad T, Feroza Hamid W, Muhammad I,Muhammad Hamid Sarwar W, Shahida S, Shoomaila LBiological Properties of Chloro-salicylidene Aniline and ItsComplexes 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) andcopper(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: synthesisand 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. JSci App. 2007; 1:72-78,
19.Scott EH, Silvia DC, Ana Oksman, Daniel EG, Vijay Sharma.Synthesis, Characterization, and Antimalarial Activity of Novel Schiff- BasePhenol 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 Hvogel. Drug discovery and Evaluation, Newyork: Springer-Velag Berlin Heidelberg; 1996.
24.Vogel, Gerhard H, Wolfgand HVogel. Drug discovery and Evaluation. Newyork
Springer-Velag Berlin Heidelberg; 1996.
9 / Signature of the Candidate
10 / Remarks 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.
11 / 11.1Nameand designation
of Guide / Dr. V.S. MADDI
PROFESSOR
DEPT. OF PHARMACEUTICAL CHEMISTRY
K.L.E. SCOETY’S COLLEGE OF PHARMACY
VIDYANAGAR, HUBLI-580031
11.2 Signature
11.3 Co-guide / _ _ _ _
11.4 Signature / _ _ _ _
11.5 Headof Department / Dr. V.S. MADDI
PROFESSOR
DEPT. OF PHARMACEUTICAL CHEMISTRY
K.L.E. SCOETY’S COLLEGE OF PHARMACY
VIDYANAGAR, HUBLI-580031
11.6 Signature
12 / 12.1 Remarks of Principal / The above mentioned information is correct and I recommended the same for approval.
12.2 Signature / Dr. B. M. PATIL
PRINCIPAL
K.L.E. SCOETY’S COLLEGE OF PHARMACY
VIDYANAGAR, HUBLI-580031