6. / BRIEF RESUME OF INTENDED WORK:
6.1: NEED FOR THE STUDY:
It is a well-known fact that Non-Steroidal Anti Inflammatory Drugs (NSAIDs) are associated with ulcerogenic effects especially in long term use. People suffering from chronic ailments like arthritis, which require constant medication through NSAIDs, may be subjected to ulcerogenic adverse effects.
Of late, selective COX II inhibitors were developed and marketed successfully for the first few years. However, post marketing surveillance has led to the withdrawal of many of these drugs due to detection of nephrotoxicity.
Nitrogen heterocyclic compoundssuch as pyrazole, pyrazolone, pyrazolines, pyrazolidines, pyrazolidinediones and others are of special interest because they constitute an important class of natural and synthetic products, many of which exhibit useful biological activities.
Pyrazolerefers to the class of simple aromatic ring organic compounds of the heterocyclic diazole series characterized by a five membered ring structure. The term pyrazole was first given to this class of compounds by “Ludwig Knorr” in the year 1883. In 1959, the first natural pyrazole; 1-pyrazolyl alanine was isolated from seeds of watermelons.
Pyrazole with an additional keto group led to the development of pyrazolone, a five membered ring lactam. When pyrazolone were discovered, they were only known for anti-inflammatory effects. But later they were reported for many other pharmacological actions.
These compounds are strong inhibitors of cyclooxygenase isoenzymes, platelet thromboxane synthesis, and prostanoid synthesis.
The biological activity of these drugs has also been attributed to its scavenging effect against reactive oxygen and nitrogen species as well as to the inhibition of neutrophils oxidative burst. This reduces the risk for chronic conditions including cardiovascular diseases and neoplasm.
Therefore, in spite of availability of wide variety of NSAIDs, there still exists a need for a suitable candidate with minimal adverse effects, especially for patients requiring long term use.
6.2: REVIEW OF LITERATURE:
Novel pyrazole and pyrazoline derivatives of 4(3H)-quinazoline were evaluated for anti-inflammatory activity by Farghaly and co-workers1.
Menozzi and co-workers have worked extensively on pyrazoles as anti-inflammatory agents. A series of papers have been published highlighting the importance of pyrazole in molecules for exhibiting anti-inflammatory activity and antiplatelet activity. Comparison was done with aspirin and other salicylic acid derivatives. Among the classes of pyrazole derivatives that were screened include 1-aryl-1H-pyrazole-5-acetic acids, 4H-thieno(3,4-c) pyrazole, n-substituted-4-carboxy-1-phenyl-1H-pyrazole-5-propanamides2,3,4.
Aldo Balasmo and co-workers studied different heterocycles as substituents in pyrazole for evaluating selectivity on COX inhibition assay. He has reported one of the pyrazole compounds with a modest inhibitory activity towards both types of isoenzymes5.
Meena Patel et al have reported the synthesis of pyrazolo-oxazines, pyrazolo-benzoxazines and pyrazolo-oxazoles. All the molecules were evaluated for anti-inflammatory activity and as potential COX-2 inhibitors6.
Flora Barsoum and colleagues have reported the synthesis of a variety of bis [3-aryl-4, 5-dihydro-1H-pyrazol-1-carboxaldehydes] via reaction of bis [1-aryl-2-propen-1-ones] with hydrazine hydrate and formic acid. Many of the tested compounds were demonstrated to have remarkable anti-inflammatory properties without an ulcerogenic liability7.

Structure–activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl (thio) ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivativeson canine COX enzymes is described by Subhas Sakya and co-workers. The authors suggest that the 4-cyano-5-alkyl ethers to have excellent potency and selectivity, whereas their 5-thioethers analogues to be less potent and selective in canine whole blood (CWB) COX-2 assay8.

Heteroaryl phenyl substituted pyrazoleswere synthesized by Hengmiao et al. These were demonstrated to be highly selective and potent inhibitors of canine COX2 enzymes. One of the test compounds reported had an IC50 value of 12 nM and selectivity of COX1/COX2 greater than 4000. In addition to anti-inflammatory effect, analgesic effect was also evaluated9.

Nesrin-Gokhan Kelikei et al have studied novel pyrazole derivatives as dual MAO B inhibitors and anti-inflammatory agents. 1- Thiocarbamoyl -1,3-substitutedphenyl-5-(2-pyridyl)-4,5-dihydro-(1H)pyrazole derivatives were found to be promising MAO-B inhibitors. In vivo studies by carrageenan induced rat paw oedema and acetic acid induced capillary permeability studies have shown that the molecules were promising anti-inflammatory agents. Experiments demonstrated no symptoms of ulcers in test models. The authors have ascribed the usefulness of MAO B inhibition activity to treatment of dementia and Alzheimer’s disease10.
Babasaheb Bandgar et alhave reported synthesis of a series of pyrazoles by Claisen–Schmidt condensation reaction. All the compounds were evaluated for their anti-inflammatory (TNF-α and IL-6 inhibitory assays), anti-oxidant (DPPH free radical scavenging assay) and anti-microbial activities (agar diffusion method) against some pathogenic bacteria and fungi. Of the ten compounds screened, threewere found promising in all the in vitro screens. SAR was also summarized11.

Babasaheb Bandgar et alhave proposed a combinatorial library of 3,5-diaryl pyrazole derivatives. All the synthesized compounds were evaluated for their anti-cancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-α and IL-6. Out of fifteen screened, four derivatives were demonstrated to have potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. Cytotoxicity studies on CCK-8 cell lines are also reported12.
Chandanam, Sreedhar, A.C.Bajji and B.M. Vrushabendra Swamy, have reported the synthesis of 2-(p-Acetamidophenoxy)-1-aryl-3-phenyl-3-oxo-prop-1ene(substituted)pyrazoles. The compounds have evaluated for antibacterial activity using B. substilis, S. aureus, P. vulgareus and E. coli. All compounds exhibited moderate antibacterial activity13.
S.A.Swelam and Nagwa M.Fawzy developed the synthesis of some pyrozole-1-carboximide derivatives under dry media microwave. Effects of microwaves in dry media organic reactions have shown synthetic utility for the preparation of chalcones14.
R. Venkat Raghavan, V. Vijaykumar, N.Sucheta Kumari, described synthesis of some novel bioactive 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones via efficient cross-Claisen condensation and screened for anti-bacterial, anti-fungal activities. They treated aryl oxy/thio acetic acid ethyl esters with acid chlorides, then by the addition of hydrazine results in formation of 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones15.
Mohy El-Din et al have studied theanti-inflammatory and analgesic activities as well as some of the expected side effects of some pyrazole derivatives as potential COX-2 inhibitors. Twelve compounds were screened for their anti-inflammatory activity using carrageenan-induced paw oedema and cotton pellet granuloma tests. Only one compound was found to be a less potent inhibitor of COX-2than Celecoxib. This study recommends a more in-depth investigation into the therapeutic effects and toxicity profile of this compound including its cardiovascular toxicity16.
Aamal A. Al-Mutairi, Fatma E.M. El-Baih, Hassan M. Al-Hazimi, prepared different pyrazolone derivatives by microwave versus ultrasound assisted methods beside the traditional methods. They established that yields by microwave synthesis were better or equivalent to conventional method17.
G. Mariappan et al described analgesic, anti-inflammatory, anti-pyretic and toxicological evaluation of some newer 3-methyl pyrazolone derivatives. Evaluation was for analgesic activity by tail flick and acetic acid induced writhing method, anti-inflammatory activity by carrageenan-induced rat paw edema and Freund’s adjuvant-induced polyarthritis model. From the work they conclude that these molecules are comparably more effective to the standard drug indomethacin18.
6.3 MAIN OBJECTIVE OF THE STUDY :
The main aim of present work is an attempt to,
Design and Synthesis of novel pyrozole derivatives for their anti-inflammatory activity

Characterization of all the synthesized compounds using physical constant, TLC, Elemental analysis and Spectroscopic methods (IR, 1HNMR and Mass spectrum)
To increase the yield of required product.
Evaluation of the synthesized compounds for their anti-inflammatory activity by using carrageenan induced paw edema method.
7. / MATERIALS & METHODS
7.1 SOURCE OF THE DATA:
The Preliminary data required for the experimental study was obtained from
Library, Govt. College of Pharmacy. Bengaluru.
Library and information centre, Rajiv Gandhi University of Health Science, Bengaluru.
 direct.
JRD TATA memorial Library IISc. Bengaluru.
Journals and e-journals.
7.2 METHODS OF COLLECTION OF DATA:
To check the progress and completion of reaction
To confirm the formation of products by various physical and analytical techniques
The above experimental data will be obtained in the research lab of Department of Pharmaceutical Chemistry and Department of pharmacology, Government College of Pharmacy, Bengaluru - 27
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR INTERVENTIONS TO BE CONDUCTED ON ANIMALS? IF SO, PLEASE DESCRIBE IN BRIEF.
Yes, the study needs the experiment on animals.
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTE IN CASE 7.3?
Applied for CPCSEA approval and ethical clearance of Government College of Pharmacy.
8. / LIST OF REFERENCES:
  1. Farghaly AM,Chaaban I,Khalil MA, Behkit A. Synthesis of novel pyrazole, pyrazoline derivatives of 4(3H)-quinazoline. Arch Pharm (Weinheim).1990;323(5):311-5.
  2. Menozzi G,Mosti L,Schenone P,Amico MD,Filippelli A, Rossi F. 4H-thieno [3, 4-c] pyrazole derivatives with anti-inflammatory, analgesic, anti-pyretic, platelet anti-aggregating activities.II Farmaco.1992;47(12):1495-511.
  3. Menozzi G,Mosti L,Schenone P,Amico MD,Falzarano C,Rossi F. N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides with anti-inflammatory, analgesic, anti-pyretic, platelet anti-aggregating activities. II Farmaco.1993;48(4):539-549.
  4. Menozzi G,Mosti L,Schenone P,Amico MD,Falciani M, Filippelli W. 1-Aryl-1H-pyrazole-5-acetic acids with anti-inflammatory, analgesic, other activities. II Farmaco.1994;49(2):115-9.
  5. Aldo Balsamo, Isabella Coletta, Angelo Guglielmotti, Carla Landolfi, Francesca Mancini, Adriano Martinelli,et al.,Synthesis of heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)-(arylmethyloxy) amine COX-2 inhibitors. Eur J Med Chem. 2003;38(2):157-168.
  6. Meena PV, Randy B,Sandra M, Rodger H. Synthesis of 4, 5-diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors. J Org Chem.2004;69(21):7058-65.
  7. Flora FB, Hanaa MH, Adel SG. Novel bis (1-acyl-2-pyrazolines) of potential anti-inflammatory, molluscicidal properties.Bioorg Med Chem.2006;14(11):3929-3937.
  8. Subas MS, Kristin MD, Martha L, Bryson R, Andrei S, Robert JR, et al.,5-Heteroatom substituted pyrazoles as canine COX-2 inhibitors.BioorgMed Chem Lett.2006;16(2):288-292.
  9. Hengmiao C, Kristin MD, Jin L, Subas MS, Kazuo A, Tomoki K,et al.,Synthesis, SAR of heteroaryl-phenyl-substituted pyrazole derivatives as highly selective, potent canine COX-2 inhibitors. Bioorg Med Chem Lett.2006;16(8):2076-2080.
  10. Nesrin G, Samiye Y, Esra K, Umut S, Ozen O, Gulberk U, et al., Some novel pyrazole derivatives as dual MAO-B inhibitors, anti-inflammatory analgesics. Bioorg Med Chem.2007;15(17):5775-5786.
  11. Babasaheb PB, Shrikant SG,Ragini GB,Nalini MG, Chandrahasya NK. Synthesis and biological evaluation of a novel series of pyrazole chalcones as anti-inflammatory, anti-oxidant, anti-microbial agents.Bioorg Med Chem Lett. 2007;17(24):8168-8173.
  12. Babasaheb PB, Jalinder VT,Shrikant SG,KhobragadeCN,Suchita CW, Prasad DK. Synthesis of novel 35-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer, anti-inflammatory agents.Bioorg Med Chem Lett.2008;18(16):6149-6155.
  13. Chandanam, Sreedhar, Bajji AC, Vrushabendra S. Synthesis of2-(p-Acetamidophenoxy)-1-aryl-3-phenyl-3-oxo-propene (substituted) pyrazoles. Asian J Chem.2008;20(3):2302-2310.
  14. Swelam SA and Nagwa MF. Microwave assisted synthesis of some pyrozole-1-carboximide derivatives. Asian J Chem. 2008;20(3):1707-1710.
  15. Venkat R, Vijaykumar V, Sucheta KN. Synthesis of some novel bioactive 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones via efficient cross-Claisen condensation. Eur J Med Chem. 2009;44:3852-3857.
  16. Mohy El-Din,Mahmoud MS, Amira M andBistawroos A. A novel COX-2 inhibitor pyrazole derivative proven effective as an anti-inflammatory, analgesic drug.Basic & Clinical Pharmacology & Toxicology.2010;107:919-990.
  17. Aamal A, Fatma EM, Hassan M. Microwave versus ultrasound assisted synthesis of some new heterocycles based on pyrazolone moiety. J Saudi Chem Soc.2010;14:287-299.
  18. Mariappan G, Saha BP, Sutharson L, Ankit S, Garg S, Pandey L, et al., Analgesic, anti-inflammatory, anti-pyretic, toxicological evaluation of some newer 3-methyl pyrazolone derivatives. Saudi Pharm J.2011;19:115-122.