“Synthesis and Biological Evaluation of
Pyrazoline Derivatives”
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Mrs. Rajpati Kumari,
Under the Guidance of
Mr. D. Giles,
Sr. Lecturer
Department of Pharmaceutical Chemistry,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara Post,
Bangalore -90
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 /Name of the candidate and address
/Mrs. Rajpati Kumari
w/o Sri Sudhir Kumar,Post- M.I.T.(Brahmpura),
Juran Chhapra,
Dist-Muzaffar Pur,
Bihar-842 003
2 / Name of the institution / Acharya & B.M. Reddy College of Pharmacy
89/90, Soldevanahalli,
Chikkabanavara post,
Bangalore - 560090
3 / Course of study and subject /
MASTER OF PHARMACY
(PHARMACEUTICAL CHEMISTRY)4 / Date of the admission / 30th May 2008
5 / Title of the Topic
“Synthesis and Biological Evaluation of
Pyrazoline Derivatives”
6.0 /
Brief resume of the intended work
6.1 Need for studyAnalgesia is defined as an unpleasant sensation, usually evoked by an external or internal noxious stimulus. Analgesia (pain) is a warning signal and primarily protective in nature but causes discomfort. Excessive pain may be unbearable and cause other effect sinking sensation, sweating, nausea, palpitation, and rise or fall in blood pressure. Analgesic is a drug that selectively relieves pain by acting in the CNS or a peripheral pain mechanism without significantly altering consciousness and without affecting its cause. The commonly used analgesics are aspirin, paracetamol and morphine. But they are not free of side effects. Morphine generally produces side effects such as respiratory depression nausea and vomiting. It also produces sleep and comma at higher doses, where as gastric pain, mucosal erosion/ulceration and blood loss are concerned with aspirin and hepatotoxicity with paracetamol is reported.1
Pyrazoline derivatives exhibiting variety of pharmacological properties like analgesic,2,3 anti-inflammatory,3,4 lipooxygenase inhibiting,5 antimicrobial,6-10 herbicidal,12 antidepressant,11 molluscicidal,13 cholinesterase inhibiting,15 antiamoebic12,15 antimycobacterial,16,17 anticonvulsant,18 antitubercular,19 and ulcerogenic activities20.
Following are the some structures containing pyrazoline derivative possessing analgesic activity.
a) 1(H)-3-aryl-5-[5-(2-nitro-4-methoxyphenyl)-2furyl]-2-pyrazoline.2
b) 4-([5′-substituted aryl-4,′ 5′-dihydropyrazol-3′-yl) amino phenol.3
c) 3-(4-biphenyl)-5-substituted-(4′-methyl phenyl)-2 pyrazoline.4
d) 5-(3-indolyl)-1-(4-sulfamylphenyl-3-trifluromethyl pyrazoline.5
a
b
c
d
Hence, we plan to synthesize newer potent pyrazoline derivatives & subsequently study for their analgesic activity.
6.2 Review of Literature:
Ø Some arylfuryl ∆2-pyrazolines derivatives were synthesized and evaluated by Holla BS et al for their antimicrobial, analgesic and anthelmintic activities.2
Ø Some novel pyrazoline derivatives were synthesized by Sahu SK et al and evaluated for their analgesic, anti-inflammatory and antimicrobial activities.3
Ø A series of 3-(4-biphenyl)-5-substituted phenyl-2-Pyrazolines and 1-benzoyl-3-(4-biphenyl)-5-substituted phenyl-2-pyrazolines derivatives were synthesized by condensation of chalcones with hydrazine hydrate in solvent ethanol and DMF by Amir M et al and the newly synthesized compounds were screened for their anti-inflammatory and analgesic activities.4
Ø 1-(4-sulfamylphenyl)-3-trifluromethyl-5-indolyl pyrazolines were synthesized by Reddy MVR et al and evaluated for their cyclooxygenase-2(COX-2) and lipo-xygenase (LOX) inhibitors activities.5
Ø Some pyrazolines derivatives were synthesized by Bharmal F et al by treatment with 2-chloro-8-methyl-3quinolinecarbaldehyde with aromatic acetophenones yielded 1-aryl-3-(2'-chloro-8'-methylquinoline-3'-yl)-2-propene-1-ones which on cyclization with hydrazine hydrate furnished the corresponding 3-(2'-chloro-8'-methylquinoline-3'-yl)-5-aryl-1-H/acetyl pyrazolines and investigated for their antimicrobial activity against various strains of bacteria and fungi.6
Ø 1-substituted 3-aryl-5-(3′-bromophenyl)-pyrazolines derivatives were synthesized by Nimavat KS et al and screened for their anticancer, anti-tubercular and antimicrobial activities.7
Ø 1-isonicotinoyl/carboxamido-2-pyrazolines derivatives were synthesized by
Jamode VS et al and evaluated for antimicrobial activity against Staphylococcus aureas, Escherichia coli, Proteus mirabilis and Pseudomonas aeruginosa.8
Ø Dobaria AV et al synthesized a series of Pyrazoline and isoxazoles derivatives by the action of hydrazine hydrate and hydroxylamine hydrochloride respectively on 1-aryl-3-(2′-chloro-7′-methylquinolin-3′-yl)-2-propen-1-ones-2. All the compounds were screened for their invivo antifungal and antibacterial activities.9
Ø 3,5-diaryl-1-phenyl/ isonicotinoyl-2-pyrazolines and 3,5-diaryl-6-carbethoxy cyclohexenone derivatives were synthesized by Vijayvergiya D et al and investigated for antibacterial and herbicidal activities.10
Ø 1,3,5-triphenyl-2-pyrazolines and 3-(2″-hydroxynaphthalene-1″-yl)-1,5
-diphenyl-2 pyrazoline derivatives were synthesized by Prasad YR et al and investigated for their antidepressant activity.11
Ø 1-(thiazolo[4,5-b]quinoxaline-2-yl)-3-phenyl-2-subsituted pyrazoline derivatives were synthesized by Abid M et al and investigated for their anti-amoebic activitiy.12
Ø Novel bis(1-acyl-2-pyrazolines) derivatives were synthesized by Barsoum FF et al and investigated for their anti-inflammatory and molluscicidal activities.13
Ø 1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines were synthesized by Ucar G et al and carried out cholinesterase and selective monoamine oxidase B inhibiting activity for treatment of Parkinson’s and Alzheimer’s disease.14
Ø Bhat AR et al carried out cyclization of chalcone with N-4 substituted thiosemicarbazides under basic condition led to the formation of new compounds, thiocarbamoyl bis-pyrazoline derivatives and their anti-amoebic activity was evaluated by micro dilution method against HMI:IMS strain of Entamoeba histolytica.15
Ø N1-Nicotinoyl-3-(4′-hydroxy-3′-methylphenyl)-5-[(substituted)phenyl]-2-Pyrazolines were synthesized by Shaharyar M et al and evaluated for their antimycobacterial activity against M. tuberculosis. 16
Ø Yar MS et al synthesized phenoxy acetic acid derivatives of pyrazolines and the synthesized derivatives were evaluated for their antimycobacterial activities.17
Ø 1-phenyl, 1- thiocarbamoyl and I-N substituted thiocarbomoyl -3-(2-furyl)-5-phenyl/(2-furyl)-2 pyrazoline derivatives were synthesized by Ozdemir Z et al and evaluated for their antidepressant and anticonvulsant activities.18
Ø Ali MA et al synthesized a series of N-substituted pyrazolines derivatives by the reaction of 5-(-4-(substituted) Phenyl)-3-(4-hydroxy-3-methylphenl)-4,5-dihydro-1H-1-pyrazolyl-2-toluidino methane thione and 5-(substituted) phenyl-3-(4-hydroxy-3-methylphenyl)-4,5-dihydro-1H-1-pyrazolyl-2-methylanilino methane thione followed by the reaction between hydrazine hydrate and chalcones by condensation with appropriate aryl isothiocyanate. The synthesized compounds were evaluated for their invitro anti-tubercular activity against Mycobacterium tuberculosis.19
6.3 Objectives of the study:
1) To synthesize some newer derivatives of pyrazoline.
2) To characterize the synthesized compounds by different analytical techniques such as IR, NMR and Mass spectral data.
3) To screen the synthesized compounds for their analgesic activities.
7.0 / Materials and methods:
7.1 Sources of data
Databases like Indian Journal of Heterocyclic Chemistry, Indian Journal of Medicinal Chemistry, European Journal of Medicinal Chemistry, Bioorganic and Medicinal Chemistry Letters, Tropical Journal of Pharmaceutical Research, European Journal of Pharmacology,
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. The reactions will be monitored by TLC. Purification of the compound will be done by standard procedures like recrystallization.
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 the compounds to research centers like IISc, Bangalore.
C) Screening of analgesic activity:
In vitro analgesic activity study:
Method Used: Acetic acid Writhing method.
Animals Used: Swiss albino mice.
No. of animals used: 72 nos.
Acetic-acid induced writhing in mice:20
The animals are weighed, numbered, and divided into two groups (five animals each). Appropriate volume of acetic acid solution is administered to the first group (which serves as control), and placed individually under glass jar for observation. The onset of wriths is noted.
The number of abdominal contractions, trunk twist response and extension of hind limbs as well as the number of animals showing such response during a period of 10min is recorded. The test compound is injected to the second group of animals. Fifteen minutes later, acetic acid solution is administered to these animals. The onset and severity of writhing response is noted. The mean writhing scores in control and compound treated groups are calculated & inhibition of pain response by compound is noted.
7.3 Does the study require any investigation or interventions to be conducted on patients or other humans or animals?
YES
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
CLEARED
8.0 / REFERENCES:
1. Tripathi KD. Essentials of Medicinal and Pharmaceutical Chemistry. 5th ed. New Delhi: Jaypee Brothers Medical Publishers; 2004;172,182,479.
2. Holla BS, Veerendra B, Shivananda MK, Latha KP, Vaidya VP. Antimicrobial, analgesic and anthelmintic activity of some arylfuryl ∆2-pyrazolines. Indian J Heterocycl Chem 2003;12:385-6.
3. Sahu SK, Banerjee M, Samantray A, Behera C, Azam MA. Synthesis, analgesic, anti-inflammatory and antimicrobial activities of some novel pyrazoline derivatives. Trop J Pharm Res 2008;7(2):961-8.
4. Amir M, Kumar H, Khan SA. Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents. Bioorg Med Chem Lett 2008;18:918-22.
5. Reddy MVR, Billa VK, Pallela VR, Mallireddigari MR, Boominathan R, Gabriel JL et al. Design, Synthesis and biological evaluation of 1-(4-sulfamylphenyl)-3- trifluoromethyl-5- indolyl pyrazolines as cyclooxygenase -2(COX-2) and lipooxygenase (LOX) inhibitors. Bioorg Med Chem Lett 2008; 16:3907-16.
6. Bharmal F, Kaneriya D, Parekh H. Synthesis and biological activity of some pyrazolines. Indian J Hetrocycl Chem 2002;12:21-4.
7. Nimvat KS, Popat KH, Joshi HS. Synthesis, anticancer, antitubercular and antimicrobial activity of 1-substituted 3-aryl-5-(3′-bromophenyl)-pyrazolines. Indian J Hetrocycl Chem 2003;12:225-8.
8. Jamode VS, Chandak HS, Bhagat PR, Tambekar DH. Synthesis and antimicrobial evaluation of some 1-isonicotinoyl/carboxamido-2-Pyrazolines. Indian J Hetrocycl Chem 2003;12:323-6.
9. Dobaria AV, Patel JR, Parekh HH. Synthesis of pyrazoline and isoxazole derivatives bearing chloroquinoline nucleus as potential antimicrobial agents. Indian J Chem 2006;42B:2019-22.
10. Vijayvergiya D, Kothari S, Verma BL. Synthesis and biological activity of some new 3,5-diaryl-1-phenyl/isonicotinoyl-2-pyrazolines and 3,5-diaryl-6-carbethoxy cyclohexenone derivatives. Indian J Hetrocycl Chem 2003;13:105-10.
11. Prasad YR, Rao AL, Prasoona L, Murali K, Kumar PR. Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2″-hydroxy naphthalen-1″-yl)-1,5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 2005;15:5030-4.
12. Abid M, Azam A. Synthesis, characterization and antiamoebic activity of 1-(thiazolo[4,5-b]quinoxaline-2-yl)-3-phenyl-2- pyrazoline derivatives. Bioorg Med Chem Lett 2006;16:2812-6.
13. Barsoum FF, Hosni HM, Girgis AS. Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties. Bioorg Med Chem Lett 2006;14:3929-37.
14. Ucar G, Gokhan N, Yesilada A, Bilgin AA.1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazoline: A novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson’s and Alzheimer’s diseases. Neurosci Lett 2005;382: 327- 31.
15. Bhat AR, Athar F, Azam A. Bis-pyrazolines: Synthesis, characterization and antiamoebic activity as inhibitors of growth of Entamoeba histolytica. Eur J Med Chem 2007;20:1- 6.
16. Shaharyar M, Siddiqui AA, Ali MA, Sriram D, Yogeeswari P. Synthesis and in vitro antimycobacterial activity of N1-nicotinoyl-3-(4’-hydroxy-3’-methyl phenyl)-5-[(sub)phenyl]-2-pyrazolines. Bioorg Med Chem Lett 2006; 16:3947-9.
17. Shaharyar M, Siddiqui AA, Ali MA. Synthesis and evaluation of phenoxy acetic acid derivatives as an anti-mycobacterial agents. Bioorg Med Chem Lett 2006; 16:4571-4.
18. Ozdemir Z, Kandile HB, Gumige B, Calis U, Bilgin AA. Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med Chem 2007;42:373-9.
19. Ali MA, Shaharyar M, Siddiqui AA. Synthesis, structural activity relationship and anti-tubercular activity of novel pyrazoline derivatives. Eur J Med Chem 2007;42: 268-75.
20. Kulkarni SK. Handbook of experimental pharmacology 3rd ed. Delhi 1999;127-30.
9.0 /
Signature of the Candidate
10.0 / Remarks of the Guide11.0 / 11.1 Name and Designation of
Guide / Mr. D. GILES.
Sr. Lecturer,
Department of Pharmaceutical Chemistry,
Acharya & B.M. Reddy College of Pharmacy,
Bangalore-90
11.2 Signature
11.3 Co-Guide
/ NIL11.4 Signature
11.5 Head of the Department
( Incharge)/ Mr. A. CENDIL KUMAR.
Asst. Professor,
Department of Pharmaceutical Chemistry,
Acharya & B.M. Reddy College of Pharmacy, Bangalore-90
11.6 Signature
12.0 /12.1 Remarks of Principal
12.2 Name of the Principal / Dr. DIVAKAR GOLI.Principal,
Acharya & B.M. Reddy College of Pharmacy, Bangalore-90
12.3Signature
10