SYNTHESIS OF NOVEL PYRAZOLE DERIVATIVES & EVALUATION OF THEIR BIOLOGICAL ACTIVITIES
M.Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Mr. SHAHIN MUHAMMED.T.K, B.Pharm.
Under the Guidance of
Dr. C. SREEDHAR, M.Pharm, Ph.D.
Professor HOD,
Department of Pharmaceutical Chemistry.
2009-2011
Department of Pharmaceutical Chemistry,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli, Bangalore -560090
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS
FOR DISSERTATION
1 /Name of the candidate and address
/Mr. SHAHIN MUHAMMED.T.K
Shakthi Hostel, Soldevanahalli, Chikkabanavara Post, Hesaraghatta Main Road,Bangalore - 560090
2 / Name of the institution / ACHARYA & B.M. REDDY COLLEGE OF PHARMACY.
89/90, Soldevanahalli, Chikkabanavara post, Hesaraghatta main road,
Bangalore - 560090
3 / Course of study and subject /
MASTER OF PHARMACY
(PHARMACEUTICAL CHEMISTRY)4 / Date of the admission / 20th June 2009
5 /
Title of the topic:
SYNTHESIS OF NOVEL PYRAZOLE DERIVATIVES & EVALUATION OF THEIR BIOLOGICAL ACTIVITIES6.0 / BRIEF RESUME OF THE INTENDED WORK:
6.1:- NEED FOR PRESENT STUDY:
Pyrazole refers to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions. Being so composed and having pharmacological effects on humans, they are classified as alkaloids, although they are rare in nature.
The pyrazole derivatives are well known for various activities like PGE2 inhibitory,26 Antidepressant,4,28 Anticonvulsant,2 Antiviral,17,30 Leishmanicidal,11 Analgesic,14,20 Anti-inflammatory,22 Antiobesity,18 Anticancer,19 hypoglycemic21 and Anti hypertensive activities.3
The inflammatory response is accompanied by the clinical signs of erythema, edema and pain (algesia). Inflammation may lead to osteoarthritis and rheumatoid arthritis.
The existing non-steroidal anti-inflammatory drugs have side effects like gastric or intestinal ulceration and bleeding that sometimes can be accompanied by anemia from the resultant blood loss. Other side effects of these drugs that result from blockade of the synthesis of endogenous prostaglandins and thromboxane-A2 include disturbances in platelet functions and changes in renal function. Search for newer drugs with fewer side effects will help to overcome these problems.
Epilepsy is a very common disorder with prevalence of 5-10 persons per 1000. The characteristic event in epilepsy is the seizure. About 50 million people worldwide have epilepsy, with almost 90% of these people being in developing countries. 30% of people with epilepsy do not have seizure control even with the best available medications.
Thus, this atrocious disease is a big blow to humanity and continual search for newer therapeutic agents are the only way to fortify against this awful threat.
6.2:- REVIEW OF LITERATURE:
1. Aziz MA et al28 synthesized a series of pyrazolone derivatives and were evaluated each for antidepressant and anticonvulsant activity.
The structures of the compounds have been established on the basis of their elemental analysis and spectral (IR, 1H NMR, and MS) data.
2. Frigola J et al1 synthesized 3-Amino-l-aryl pyrazole derivatives. The inhibitory activities on cyclooxygenase, lipoxygenase, thromboxane synthetase and platelet aggregation were assayed.
The identity of the compounds was confirmed by 1H NMR, and IR spectral data.
3. Cottineau B et al12 has developed a simple and efficient method for the synthesis of 3-methoxy-4-aryl methylene pyrazole derivatives.
The structures of the compounds have been established on the basis of their elemental analysis and spectral (IR, 1H NMR, and MS) data.
4. Ju Y et al9 has been developed Microwave-assisted syntheses of pyrazole derivatives by cyclocondensation of hydrazine derivatives with alkyl dihalides.
The identity of the compounds was confirmed by 1H NMR, and Mass spectral data.
5. Cheng H et al10 synthesized heteroaryl–phenyl-substituted pyrazole derivatives as canine selective COX-2inhibitors. They carried out Structure–activity relationship (SAR) studies of this class of compounds.
The structures of the compounds have been established on the basis of their elemental analysis, IR, 1H NMR, and MS spectral data.
6. Palaska E et al4 synthesized 3,5-diphenyl-2-pyrazoline derivatives. The antidepressant activities of these compounds were evaluated.
The chemical structures of the compounds were proved by means of their UV, IR, 1H-NMR spectroscopic data and elementary analysis.
7. Gioiello A et al34 developed a facile one-pot procedure for the synthesis of pyrazole-5-carboxylates.
The chemical structures of the compounds were proved by means of their IR, 1H-NMR spectroscopic data and microanalysis.
8. Bekhit AA et al5 synthesized novel series of structurally related 1H-pyrazolyl derivatives. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity.
The identity of the compounds was confirmed by 1H NMR and IR spectral data. The elemental analysis was also performed.
9. Sauzem PD et al20 synthesized novel 3-or4-substituted 5-trifluoro methyl-5-hydroxy-4,5-dihydro-1H-1-carboxyamide pyrazoles. The analgesic and anti-inflammatory properties of the synthesized compounds are assessed.
The chemical structures of the compounds were proved by means of their 1H-NMR and mass spectroscopic data and elementary analysis.
10. Singh SK et al8 carried out synthesis and SAR/3D-QSAR studies on the COX-2 inhibitory activity of 1, 5-diaryl pyrazoles.
The structures of the compounds have been established on the basis of their elemental analysis, HPLC, IR, 1H NMR, and MS spectral data.
11. Bandgar BP et al22 synthesized novel series of pyrazole chalcones. The synthesized compounds are evaluated for their anti-inflammatory, antioxidant and antimicrobial activity.
The compounds structure was confirmed by spectral data (IR, 1HNMR and MS).
12. Kelecki NG et al14 synthesized a series of 1-thiocarbamoyl-3-substituted phenyl-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole derivatives. They evaluated MAO-B inhibitory, anti-inflammatory and analgesics activity.
The structures of the compounds have been established on the basis of their elemental analysis and spectral (IR, 1H NMR, and MS) data.
13. Navidpour L et al13 designed and synthesized a new type of 1-aryl-5-(4 methyl sulfonyl phenyl) imidazoles. The compounds are evaluated for selective cyclooxygenase-2(COX-2) inhibitory activity with in vivo anti-inflammatory activity.
The structures of the compounds have been established on the basis of their elemental analysis and spectral (IR, 1H NMR, and MS) data.
14. Michon V et al2 synthesized 3- and 5-amino pyrazole N-benzoyl derivatives. Then they evaluated their anticonvulsant activity.
1H- and 13C-NMR study is carried out for the confirmation of the prepared compound.
15. Mogilaiah K et al31 Synthesized 3-aryl- 4-formyl-1-[3-(3-chlorophenyl) - 1,8-naphthyridin-2-yl] pyrazoles and evaluated their antibacterial activity. The compounds are confirmed by IR, 1HNMR, MS spectral data.
16. Pattan SR et al33 synthesized a series 3-Methyl-pyrazol-5(4H)-one derivatives. The synthesized compounds are evaluated for antitubercular activity.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
17. Prakash O et al32 synthesized novel 1, 3-diaryl-4-cyanopyrazoles and evaluated antibacterial activity.
The structural assignments of the new compounds were based on their elemental analysis and spectral data (IR, 1H NMR and MS).
18. Das N et al21 synthesized some new aryl pyrazol-3-one derivatives. The biological evaluation is carried out for potential hypoglycemic activity.
The physicochemical characterization like elemental analysis, melting point and yield were determined for all the synthesized compounds and characterized by UV, IR and NMR spectroscopy.
19. Bernardino AMR et al11 synthesized a series 1-(4-X-phenyl)-1H-pyrazole-4-carbohydrazides. The synthesized compounds are evaluated for leishmanicidal activity.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
20. Fan CD et al19 Synthesized a series of novel 1-(2'-hydroxy-3'-aroxy propyl)-3-aryl-1H-pyrazole-5-carbohydrazide derivatives. They investigated the effects of the compounds on A549 cell growth.
The structural assignments of the new compounds were based on their elemental analysis and spectral data (IR, 1H NMR and MS).
21. Zitouni GT et al3 synthesized some thiazolyl-pyrazoline derivatives. The biological evaluation is carried out for their hypotensive activity.
All the synthesized compounds were characterized by UV, IR and NMR spectroscopy.
22. Ahmed OM et al29 reported the synthesis and anti-tumor activities of some new pyrazolo pyrimidines. Cyclocondensation of 3-aminopyrazoles with sodium salt of 3-hydroxy-1-(2-naphthyl) prop-2-en-1-one gives pyrazolo pyrimidine derivatives. These derivatives showed potent anti-tumor cytotoxic activity in vitro using different human cancer cell lines.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
23. Castagnolo D et al23 reported the synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis.
The structural assignments of the new compounds were based on their elemental analysis and spectral data (IR, 1H NMR and MS).
24. Ouyang G et al17 synthesized 1-substituted-5-substituted phenyl thio-4-pyrazol aldoxime ester derivatives. The biological evaluation is carried out for their hypotensive activity. The synthesized compounds were characterized by physical constants, and the structures of the title compounds were further confirmed by IR,1H
NMR, 13CNMR and elemental analysis.
25. Schmidt D et al24 reported the synthesis of pyrazole acids as niacin receptor agonists for the treatment of dyslipidemia.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
26. Rashad AE et al27 reported the synthesis of some pyrazoles and fused pyrazolo pyrimidines. And they evaluated for anti-HSV-1 activity.
The structural assignments of the new compounds were based on their elemental analysis and spectral data (IR, 1H NMR and MS).
27. Barcelo M et al15 reported the synthesis and binding affinity of new pyrazole and isoxazole derivatives as potential atypical antipsychotics. The synthesized compounds were characterized by physical constants, and the structures of the title compounds were further confirmed by IR,1HNMR, 13CNMR and elemental analysis.
28. Akbas E et al7 reported the synthesis of new pyrazolo[3,4]pyridazine derivatives. And they studied the antibacterial and antifungal activities of the synthesized compounds.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
29. Fadda AA et al25 reported the synthesis and molluscicidal activity of some new thiophene, thiadiazole and pyrazole derivatives.
The structural assignments of the new compounds were based on their elemental analysis and spectral data (IR, 1H NMR and MS).
30. Park HJ et al6 synthesized a series of new pyrazole and isoxazole derivatives and studied the antipsychotics activity of the newly synthesized compounds.
The synthesized compounds were characterized by physical constants, and the structures of the title compounds were further confirmed by IR,1HNMR, 13CNMR and elemental analysis.
31. Sabbagh O et al30 reported Synthesis and antiviral activity of new pyrazole and thiazole derivatives.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
32. Barsoum FF et al26 reported the Facile synthesis of bis (4,5-dihydro-1H-pyrazole-1-carboxamides) and evaluated for their anti-inflammatory properties.
The structural assignments of the new compounds were based on their elemental analysis and spectral data (IR, 1H NMR and MS).
33. Alvarado M et al18 reported the synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents.
The synthesized compounds were characterized by physical constants, and the structures of the title compounds were further confirmed by IR,1HNMR, 13CNMR and elemental analysis.
34. Larsen SD et al16 reported the re-design pyrazole inhibitors of HMG-CoA reductase.
All the structures of the newly synthesized compounds have been supported by IR,
1H NMR, MS and CHN analysis.
6.3:- OBJECTIVES OF THE STUDY:
Ø To synthesize the novel pyrazole derivatives through an amide linkage.
Ø To characterize the synthesized molecules by different analytical techniques such as FTIR, NMR and Mass spectral data.
Ø To screen the above synthesized compounds for in vivo anti-inflammatory and anti convulsant activities.
Ø To publish the research in peer reviewed journals.
7.0 / MATERIALS AND METHODS:
7.1:- SOURCE OF DATA:
The data will be obtained from Chemical abstracts and various Journals like Indian Journal of Chemistry, Journal of Heterocyclic Chemistry, Bioorganic and Medicinal Chemistry Letters, and Europian Journal of Medicinal Chemistry. Data will also be collected from Indian Institute of Science, Bangalore, through Helinet of RGUHS and various libraries.
7.2:- METHOD OF COLLECTION OF DATA:
A) SYNTHESIS OF THE COMPOUNDS:
Chemicals and other reagents required for synthesis will be procured from standard company sources.
Compounds will be synthesized by using standard techniques and also if required by the use of microwave irradiation. TLC will be used to monitor the reaction at various stages and purification of the compound will be done by standard recrystallization procedure.
B) CHARACTERIZATION OF THE COMPOUNDS:
The synthesized compounds will be characterized by preliminary laboratory techniques such as melting point, boiling point etc. Compounds synthesized will be confirmed by FTIR, Mass Spectroscopy and NMR spectral data. The Mass and NMR spectral data of the synthesized compound will be collected by sending compounds to other research centers like IISc, Bangalore, IICT, Hyderabad, IIT, Chennai, etc.
C) 1) Screening of anti-inflammatory activity35:
In vivo anti-inflammatory activity study:
Method Used: Carrageenan-induced paw edema model.
Animals Used: Albino Wistar rats.
Number of animals used: 72 numbers
Carrageenan-induced paw edema model:
A 1% w/v suspension of carrageenan will be prepared freshly in normal saline and injected into subplantar region of left hind paw (usually 0.1mL in rats and 0.025-0.05 mL in mice). In control group animals, only vehicle will be injected. Test drug is usually administered orally or intraperitoneally, according to body weight immediately or half an hour or one hour before (depending on the expected peak effect) carrageenan challenge. A mark will be made on the ankle joint of each rodent. Paw volume up to the ankle joint will be measured in drug treated and untreated groups before and 3 h after carrageenan challenge using a plethysmograph filled with mercury.
2) Screening of anticonvulsant activity35
In vivo anticonvulsant activity study:
Method Used: Maximal Electroshock Seizure pattern test
Animals Used: Albino Wistar rats.
Number of animals used: 72 numbers
Maximal Electroshock Seizure pattern test:
The mices will be treated with the different doses of test drugs or reference, phenytoin sodium 30 mg/kg p.o. After 1 h they will be subjected to the shock of 25 mA by convulsiometer through ear electrodes for 0.25 s. Abolition of the hind limb tonic extensor component of the seizure is defined as protection, and results will be expressed as number of animals protected/number of animals tested.
7.4:- DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON THE PATIENTS OR OTHER HUMAN/ANIMALS? IF SO, PLEASE DESCRIBE BRIEFLY.