REGISTRATION OF SUBJECT FOR DISSERTATION

A PROTOCOL FOR THE PROJECT WORK ENTITLED

“STUDIES OF BIOLOGICALLY ACTIVE HETEROCYCLICS:-SYNTHESIS, CHARACTERIZATION, ANTIBACTERIAL, ANTIFUNGAL AND ANTI OXIDANT ACTIVITY OF SOME NOVEL TRIAZOLES”

By,

SURYA.P.S.

M.Pharm, Part- I

Department of Pharmaceutical Chemistry

N.G.S.M. Institute of Pharmaceutical Sciences

Paneer, Deralakatte

Mangalore – 574160

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE

KARNATAKA.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS / SURYA.P.S.
N.G.S.M INSTITUTE OF PHARMACEUTICAL SCIENCES, PANEER DERALAKATTE, MANGALORE – 574160.
2. / NAME OF THE INSTITUTION / N.G.S.M. INSTITUTE OF PHARMACEUTICAL SCIENCES, PANEER DERALAKATTE, MANGALORE – 574160.
3. / COURSE OF STUDY AND SUBJECT / M.PHARM
[PHARMACEUTICAL CHEMISTRY]
4. / DATE OF ADMISSION / JUNE 2008
5. / TITLE OF THE TOPIC :
“STUDIES OF BIOLOGICALLY ACTIVE HETEROCYCLICS :- SYNTHESIS,CHARACTERIZATION, ANTIBACTERIAL, ANTIFUNGAL AND ANTI OXIDANT ACTIVITY OF SOME NOVEL TRIAZOLES”
6.
/ Brief resume of the intended work :
6.1 Need for the study:
The recent literature is enriched with progressive findings about the synthesis and pharmacological action of fused heterocycles. Heterocycles bearing a symmetrical triazole moiety are reported to show a broad spectrum of biological and pharmacological properties.
Heterocycles bearing three nitrogen moieties constitute the core structure of a number of biologically interesting compounds.
The efficiency of azole derivatives as chemotherapeutic agent is well established and their chemistry has been extensively studied.
Various, 1, 2, 4 –triazole derivatives have been reported to possess anticancer1, antibacterial2, antifungal2, anti inflammatory3, analgesic3, anticonvulsant4 , anti tubercular 5 activity etc.
The 1, 2, 4- triazole nucleus has been incorporated in to a wide variety of therapeutically interesting molecules to transform them in to better drugs. Some of the present day drugs such as Ribavirin (antiviral agent), Rizatriptan (anti migraine agent), Alprazolam (anxiolytic agent), Fluconazole and Itraconazole (antifungal agent) are the best examples of potent molecules possessing triazole nucleus.
1, 2, 4 – triazole nucleus has been incorporated into a wide variety of therapeutically interesting drug candidates including H1 /H2 histamine receptor blockers , cholinesterase active agents , CNS stimulants, antianxiety and sedative agents.
Mannich bases of 1, 2, 4 –triazoles carrying N-methyl piperazine moiety are reported to possess protozocidal and antibacterial activity. The drugs such as Prazosin, Lidoflazine and Urapidil carrying Piperazine nucleus are good cardiovascular drugs.
A number of pyridine derivatives are known for their varied biological and pharmacological activities. In the present work, pyridine-3-carboxylic acid [nicotinic acid] has taken as the starting material to prepare the title compounds, by condensing substituted hydrazides [R-CONHNH2].
In light of such stimulating properties, it was contemplated to synthesize some newer congeners of Triazoles containing nicotinic acid moiety with a view to explore their potency as better chemotherapeutic agents.

6.2 Review of Literature:
1.  Yadav LDS, et al. (1983)6 Synthesized 5-aryl-1, 2, 4 –triazolo [3, 4-c]-1, 2, 4-dithiazole -3- thiones and 5-aryl-3- arylimino-1, 2, 4-triazolo [3, 4-c]-1, 2, 4 –dithiazoles by the reaction of 5-aryl-3-phenacylthio-1, 2, 4-triazoles with carbon disulphide and aryl isothiocyanates respectively. 5-aryl-3-phenacylthio-1, 2, 4-triazoles was obtained by the phenacylation of 5-aryl-3-mercapto-1, 2, 4 –triazoles. 5-aryl-3- arylimino-1, 2, 4-triazolo[3, 4-c]-1, 2, 4 –dithiazoles on refluxing with carbon disulphide yielded 5-aryl-1, 2, 4 –triazolo[3, 4-c]-1, 2, 4-dithiazole -3- thiones which, when heated with aryl isothiocyanates, regenerated 5 -aryl-3- arylimino-1, 2, 4-triazolo[3, 4-c]-1, 2, 4 –dithiazoles .5-aryl-3-phenacylthio-1, 2, 4-triazoles and 5 -aryl-3- arylimino-1, 2, 4-triazolo[3, 4-c]-1, 2, 4 –dithiazoles were compared with Dithane M-45 for their fungi toxicity against Helminthosporium oryzae and Fusarium oxysporium.The screening results have been correlated with the structural features of the tested compounds.
2.  Sattur PB, et al. (1984)7 Synthesized a series of s-triazolo [3, 4-b]-1, 3, 4-thiadiazoles carrying aryl or aralkyl group at 2-position and aryl, aralkyl or diaralkyl group at 5-position and evaluated for their biological activities. Some of the compounds exhibited strong CNS depressant and mild to moderate anti inflammatory action in experimental animals.
3.  Nizamuddin, et al. (1988)8 Synthesized 6-Arylamino-1,2,4-triazolo[3,4-b] [1,3,4] thiadiazoles by cyclo-dehydro sulphurization of corresponding thio- ureas, which in turn were prepared by the condensation of N-amino-3-mercapto-1,2,4-triazoles and aryl isothiocyanates in dry dimethyl formamide. These triazolo thiadiazoles were screened for their fungicidal activities of A.niger and H.oryzae.
4.  Kalluraya Balakrishna, et al. (1996)9 Synthesized 3-(2-isopropyl-5-methyl) phenoxymethyl – 4-amino-5-mercapto-1, 2, 4-triazole and 1, 3, 4- oxadiazole were synthesized from Thymol. This triazole was then employed in the synthesis of some N-bridged heterocycles and oxadiazole was employed in the preparation of Mannich bases. All the newly synthesized compounds were characterized by analytical, NMR and mass spectral studies. Some of the newly synthesized compounds were screened for their antibacterial and antifungal properties.
5.  Udupi RH, et al. (1999)10 Synthesized 4-(4-pyridoyl)-3-substituted- 5- phenylazo-1, 2, 4-triazolo [3, 4-b] [1, 3, 4] thiadiazolidines and 1, 2, 4-triazolo Mannich bases and screened for biological activities.
6.  Shivarama Holla B, et al. (2000)11 Synthesized a series of 3- substituted -4-[5-(2,4-dichlorophenyl) -2-furfurylidine] amino -5-mercapto-1, 2, 4-triazoles.Aminomethylation of 3- substituted -4-[5-(2,4-dichlorophenyl )-2-furfurylidine ]amino -5-mercapto-1, 2, 4-triazoles with formaldehyde and a primary /secondary amine furnished Mannich bases 1-arylaminomethyl-3-substituted -4-[5-(2, 4-dichlorophenyl) -2-furfurylidene ]amino-5-mercapto-1, 2, 4-triazoles and 4-methyl-piperazin-1-yl-methyl-3-substituted -4-[5-(2, 4-dichlorophenyl)-2-furfurylidene]amino -5-mercapto-1,2,4-triazoles, were characterized on the basis of IR,1H NMR, mass spectral data and elemental analysis. All the newly synthesized compounds were tested for their antibacterial activities. Some of the selected compounds were also tested for their fungicidal and herbicidal properties.
7.  Shivarama Holla B, et al. (2001)12 Synthesized a series of 7-arylidene -6-(2,4-dichloro-5-fluorophenyl)-3-substituted -1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazines by the condensation of 4-amino-5- mercapto-3substituted -1, 2, 4 –triazoles and 3-aryl-1-(2, 4 –dichloro-5-fluorophenyl)-2-bromo-2-propen-1-one.The newly synthesized compounds were characterized on the basis of N-analyses, IR,1 H NMR and mass spectral data. Some of the newly synthesized compounds were tested for their antibacterial activities against Gram positive and Gram negative bacteria. Some of the newly synthesized compounds were also screened for their anticancer activities.
8.  Karthikeyan SM, et al. (2008)13 Synthesized Dichloro fluorophenyl containing aminotriazolothiadiazines by the initial condensation of 2-chloro –N-(substituted phenyl)acetamides with triazole and further cyclization using POCl3 .The structures of newly synthesized compounds were confirmed by IR, NMR, mass and elemental analysis. All the compounds were screened for their antibacterial and antifungal activities.

6.3 Objectives of the study:
The present studies were performed with the following objectives.
1.  Nicotinic hydrazide upon reaction with potassium hydroxide and carbon di sulphide yields the potassium dithiocarbazinate salt.
2.  The potassium dithiocarbazinate upon reaction with substituted hydrazide compounds yields the title compounds, 1, 2, 4- triazole derivatives.
3.  The final synthesized compounds were evaluated for their antimicrobial activity against Gram positive and Gram negative organisms.
4.  Evaluation for antifungal activity by using C. albicans and A.niger organisms.
5.  Antioxidant evaluation by using DPPH method.

Materials and methods:
7.1 Sources of data.
·  Journals and publications.
·  CD ROM and internet.
·  Laboratory based studies.
7.2 Methods of collection of data.
·  From available literature.
·  From library based books.
·  Websites.
-www.pubmed.com
-www.google.com
-www.sciencedirect.com

7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals?
If so please describe briefly
No.

7.4 Has ethical clearance been obtained your institution in case of 7.3?
Not applicable

LIST OF REFERENCE:-
1.  Bekircan Olcay, Kahvecl Bahittin, Kucuk Murat. Synthesis and anticancer evaluation of some new unsymmetrical 3, 5-diaryl-4H-1, 2, 4-triazole derivatives. Turk J Chem. 2006 Jan; 30 : 29-40.
2.  Ashok Mithun, Shivarama Holla B, Poojari Boja. Convenient one pot synthesis and antimicrobial evaluation of some new Mannich bases carrying 4-methylthiobenzyl moiety. Eur J Med Chem. 2007 Jan; 42 : 1095-1101.
3.  Keshavayya J, Mathew V, Vaidya VP. Heterocyclic system containing bridgehead nitrogen atom: Synthesis and pharmacological activities of some substituted 1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazoles. Eur J Med Chem. 2006 Jan; 41: 1048-58.
4.  Kalluraya B, Chimbalkar RM, Hegde JC. Anticonvulsant activity of nicotinyl /isonicotinyl substituted 1, 2, 4-triazol-5-thione Mannich bases. Ind J Het Chem. 2005 July-Sept; 15 : 15-8.
5.  Joshi HS, Dave TK, Purohit DH, Akbari JD. Synthesis and pharmacological study of thiazolidinones and Mannich bases of 4-amino-3-mercapto-5-pyridin-3’-yl-[1, 2, 4]-triazole. Ind J Chem. 2007 Feb; 46B : 352-6.
6.  Yadav LDS, Singh H , Sharma KS. 1, 3 –Cycloaddition of cyclic isothioureas to heterocumulenes and fungi toxicity of the resulting 1, 2, 4- triazolo [3, 4-c]-1, 2, 4-dithiazoles. Agric Biol Chem. 1983 October; 47(5) : 1017-20.
7.  Sattur PB, Deshmukh AA, Ramalingam T, Mody MK. Synthesis and pharmacology of 2-aryl/aralkyl-5-aryl/aralkyl/diaralkyl-s-triazolo [3, 4-b]-1-3, 4-thiadiazoles. Ind J Chem. 1984 Aug; 23B : 793-5.
8.  Nizamuddin, Chaturvedi B, Tiwari Nirupama. A convenient and novel synthesis of 1, 2, 4 –triazolo [3, 4 –b][1, 3, 4 ]-thiadiazoles as potential pesticides. Agric Biol Chem. 1988 Nov; 52(5) : 1229-32.
9.  Kalluraya B, Chimbalkar RM, Gunaga Prashantha. Synthesis and biological activities of some 1, 2, 4- triazole and 1, 3, 4 –oxadiazoles. Ind J Het Chem. 1996 Oct-Dec; 6 : 103-6.
10. Udupi RH, Kushnoor Ashok, Bhat AR. Synthesis and biological evaluation of of some substituted 1, 2, 4 –triazoles. J Ind Chem Soc. 1999 Sept; 76 : 461-2.
11. Shivarama Holla B, Sooryanarayana Rao B, Shridhara K, Akberali PM. Studies on aryl furan derivatives part XI. Synthesis, characterization and biological studies on some Mannich bases carrying 2, 4 –dichlorophenylfurfural moiety. IL Farmaco. 2000 March; 55 : 338-44.
12. Shivarama Holla B , Sarojini BK , Sooryanarayana Rao B, Akberali PM, Kumari Suchetha N, Shetty Veena. Synthesis of some halogen-containing 1, 2, 4 –triazolo-1, 3, 4 -thiadiazines and their antibacterial and anticancer screening studies-part I. IL Farmaco. 2001 Jan; 56 : 565-70.
13. Karthikeyan SM, Shivarama Holla B, Kumari Suchetha N.Synthesis and antimicrobial studies of novel dichlorofluorophenyl containing aminotriazolo thiadiazines. Eur J Med Chem. 2008 March; 43 : 309-14.

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