SYNTHESIS OF NOVEL PYRAZOLIDINE-3,5-DIONE
DERIVATIVES AND THEIR BIOLOGICAL ACTIVITY
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH
SCIENCES, BANGALORE, KARNATAKA
BY
VILAS SHELAR. M
I M.PHARM (2007-08)
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
M.S. RAMAIAH COLLEGE OF PHARMACY
BANGALORE-560054
RAJIV GANDHI UNIVERSITY OF HEALTH
SCIENCES, BANGALORE, KARNATAKA
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT
FOR DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS /VILAS SHELAR. M
POST; HATTARGI. TQ; HUKKERI. DIST; BELGAUM.PIN-591243 (KARNATAKA)
2. / NAME OF INSTITUTION / M.S.RAMAIAH COLLEGE OF PHARMACY, M.S.R.I.T. POST BANGALORE-560054
3. / COURSE OF THE STUDY AND SUBJECT / M.PHARM
(PHARMACEUTICAL CHEMISTRY)
4. / DATE OF ADMISSION / 1st JUNE 2007
5. /
TITLE OF THE TOPIC
SYNTHESIS OF NOVEL PYRAZOLIDINE-3,5-DIONEDERIVATIVES AND THEIR BIOLOGICAL ACTIVITY
6. BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
In recent years there has been considerable progress in the search for ideal non steroidal anti-inflammatory agents. As a result, some pyrazolidine-3,5-dione derivatives emerged in the pain killer market which inhibit prostaglandin formation by inhibiting the cyclo-oxygenase activity of prostaglandin-H-synthase (PHS).1,2,3,4,
Pyrazolidine-3,5-diones were also shown to be the novel inhibitors of UDP-N-Acetylenol pyruvyl glucosamine (MurB) with activity against gram-positive bacteria. 5,6,7
Apart from anti-inflammatory and antibacterial activities, derivatives of pyrazolidine-3,5-dione were reported to possess herbicidal,8-12 acaricidal11,12 and fungicidal13,14 activities. They also find use as colouring agents, photographic, light sensitive and thermal printing materials.15,16 Recently, some new Pyrazolidine-3,5-diones were evaluated as AT1 angiotensin II receptor antagonists.17
Therefore, it is considered worthwhile to synthesize some novel pyrazolidine-3,5-dione derivatives which might possess enhanced biological activity and carry out preliminary investigation of antimicrobial activity18 as well as in vitro anti-inflammatory activity.19
6.2 REVIEW OF LITERATURE
Ø Different Non Steroidal Anti-Inflammatory Agents including some pyrazolidine-3,5-dione derivatives were discussed.1
Ø Pyrazolone and pyrazolidinedione derivatives, their uses and adverse effects were discussed.2
Ø Preparation and evaluation of electrophillic derivatives of phenylbutazone as inhibitors of prostaglandin-H-synthase was reported.3
Ø Relationship of Prostaglandin Hydroperoxidase dependent oxidation of Phenylbutazone to inhibition of Prostaglandin Cyclooxygenase was reported.4
Ø Pyrazolidine-3,5-diones & 5-Hydroxy-1H- pyrazol-3(2H)-ones as inhibitors of UDP-N-acetylenol pyruvyl glucosamine reductase were reported.5
Ø 4-Alkyl and 4,4’-dialkyl-1,2-bis(4-chlorophenyl) pyrazolidine-3,5-dione derivatives as new inhibitors of bacterial cell wall were reported.6 .
Ø 3,5-Dioxopyrazolidines as novel inhibitors of UDP-N-acetylenol pyruvyl glucosamine reductase (MurB) with activity against Gram-positive bacteria were reported.7
Ø Preparation of herbicidal pyrazolidinedione derivatives was reported.8
Ø Preparation of 1-(heteroaryl) pyrazolidine-3,5-dione herbicides was reported.9
Ø Preparation of herbicidal 1,4-di-heteroaryl pyrazolidin-3,5-diones was reported.10
Ø Herbicidally, acaricidally and insecticidally active pyrazolidine-3,5-dione derivatives and their preparation was reported.11
Ø Synthesis of 4-aryl-4-substituted pyrazolidine-3,5-dione derivatives was reported.12
Ø Synthesis and application of some-1-(8-hydroxy-5-quinolinyl) alkylidene-substituted heterocycles as bactericide, fungicide and bioregulators was reported.13
Ø Synthesis of some biologically active derivatives of 1-phenyl-3,5-pyrazolidinedione was reported.14
Ø Arylidene pyrazolidinediones as dye-donar elements for thermal transfer was reported.15
Ø 3,5-pyrazolidinedione derivatives were studied as new magenta dye forming compounds.16
Ø Synthesis and pharmacological evaluation of new pyrazolidine-3,5-diones as AT1 angiotensin II receptor antagonists was carried out.17
Ø Cup plate method for antimicrobial activity was discussed.18
Ø Anti-inflammatory activity of Dehydrozingerone and its analogs by inhibition of Albumin denaturation method was reported.19
Ø Preparation of 4-substituted 1,2-diphenyl-3,5-pyrazolidinediones as antiarthritics was reported.20
Ø The synthesis of 4-[(2-hydroxy-4quinolyl)methyl]-3,5-pyrazolidinediones and related products was reported.21
Ø Reactions of 3,5-pyrazolidinedione and its derivatives were studied.22
Ø Synthesis of N-Alkenyl-3,5-pyrazolidinediones from ketone hydrazones, PCl3 and malonic acid was reported.23
Ø Solvent free accelerated synthesis of 2-hydrazinobenzothiazole derivatives using microwave was reported.24
Ø Manganese(III)-catalysed facile direct hydroperoxidation of some heterocyclic 1,3-dicarbonyl compounds was reported.25
Ø Reaction of 4-acylaminomethylpyridine N-oxides with Phenylbutazone in the presence of acetic anhydride was reported.26
Ø Synthesis of 4,4-bis(2-hydroperoxyalkyl)pyrazolidine-3,5-diones using manganese (III)-catalysed autoxidation was reported.27
Ø Comparison of 3D structures and AT1 binding properties of pyrazolidine-3,5-dione and tetrahydropyrazine-3,6-diones with parent antihypertensive drug Irbesartan was reported.28
Ø Various purification methods like fractional crystallization, recrystalization, distillation and chromatographic methods were discussed.29
6.3 OBJECTIVES OF STUDY
1) To synthesize the proposed derivatives with optimum yield.
2) To purify the synthesized compounds.
3) To characterize the synthesized compounds by Spectral interpretation and by means of chemical tests.
4) To evaluate the biological activity of the synthesized compounds.
7. MATERIAL AND METHODS
7.1 SOURCE OF DATA
1) Chemical abstracts, MEDLINE, websites.
2) Journals and publications.
3) Lab based studies.
7.2 METHODS OF COLLECTION OF DATA
Pre-laboratory And Laboratory Work
1) Pre-laboratory Work
The chemicals & reagents required for the synthesis & evaluation of the proposed compounds will be procured from reputed chemical suppliers like Merck, Ranbaxy, Qualigens, Himedia etc
2) Laboratory Work
a) Synthesis
Conventional methods of synthesis8-14,20,21 as well as microwave assisted synthesis24 will be attempted. The completion of the reaction will be determined by TLC. Advantages and feasibility of the methods will be analyzed.
b) purification
The synthesized compounds will be purified by different methods like fractional
crystallization, recrystallization, distillation and chromatographic methods.29 The purity will be ascertained by TLC.
c) Characterisation
The synthesized compounds will be characterized by:
1. Chemical tests for important functional groups.
2. Study of spectral data.
d) Biological studies
Antimicrobial activity will be performed by using cup plate method18 and in vitro anti
inflammatory activity by inhibition of albumin denaturation method.19
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS ?
" No"
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTION IN CASE OF 7.3?
" NOT APPLICABLE"
8. LIST OF REFERENCES
1) David A Williams, Thomas L Lemke. Foye’s Principles of Medicinal Chemistry. 5th ed. New Delhi (India). A Wolters Kluwer Company. Lippincott Williams & Wilkins, BI Publications Pvt Ltd 2005; 751-790.
2) Jaime N Delgado, William A Remers. Wilson & Giswold’s Text book of Organic Medicinal and Pharmaceutical Chemistry. 9thed. J B Lippincott company(NY) 1991; 668-670.
3) Vennerstrom Jonathan L, Holmes Thomas J Jr. Preparation and evaluation of electrophillic derivatives of phenylbutazone as inhibitors of prostaglandin-H- synthase. J Med chem 1987; 30(3): 563-567. chem Abstr 1987; 106: 84474a.
4) Michael F Hughes, Ronald P Mason, Thomas E Eling. Prostaglandin Hydroperoxidase-Dependent Oxidation of Phenylbutazone: Relationship to inhibition of Prostaglandin Cyclooxygenase. Mol Pharmacol 1988; 34: 186-193.
5) Adam M Gilbert, Amedeo Failli, Jay Shumsky, Youjun Yang, Antatoly Severin, Guy Singh, et al. Pyrazolidine-3,5-diones & 5-Hydroxy-1H-pyrazol-3(2H)-ones, Inhibitors of UDP-N-acetylenol pyruvyl Glucosamine reductase. J Med Chem 2006 Sept; 49: 6027-6036.
6) Kristina M K, Kutterer Jamie M Davis, Guy Singh, Youjun Yang, William Hu, Anatoly Severin, et al. 4-Alkyl and 4,4’-dialkyl 1,2-bis(4-chlorophenyl) pyrazolidine-3,5-dione derivatives as new inhibitors of bacterial cell wall. Bioorg Med chem lett 2005 May; 15(10): 2527-2531.
7) Younju Yang, Antony Severin, Rajiv Chopra, Girija Krishnamurti, Guy Singh, William Hu, et al. 3,5-Dioxopyrazolidines, Novel inhibitors of UDP-N-Acetylenol pyruvyl glucosamine reductase (MurB) with activity against Gram-Positive bacteria. Antimicrob Agents Chemother 2006 Feb; 50: 556-564.
8) Newton, Trevor William. Preparation of herbicidal pyrazolidinedione derivatives Eur Pat Appl Ep 616772, chem Abstr 1994; 121: 274461b.
9) Newton, Trevor William. Preparation of 1-(heteroaryl)pyrazolidine-3,5-dione herbicides. PCT Int Appl WO 94 22,853, Chem Abstr 1995; 122: 160667 p.
10) Scheiblich, Stefan. Preparation of herbicidal 1,4-di-heteroaryl pyrazolidin-3,5-diones. PCT Int Appl WO 94 22,854, Chem Abstr 1995; 122: 81389w.
11) Cederbaum Frederik, Brunner Hans George, Boeger Manfred. Herbicidally, acaricidally and insecticidally active pyrazolidine-3,5-dione derivatives and there preparation. PCT Int Appl WO 92 16,510. Chem Abstr 1993; 118: 38935b.
12) Takahashi Nobuyoshi, Nakagawa Hirofumi, Endo Yoshinori. 4-aryl-4-substituted pyrazolidine-3,5-dionederivatives. WWW.freepatentsonline.com/6180568.html.
13) Khalil Zarif Haleem, Yanni Amal sabet, Khalaf Ali Ali, Foaad Abdo, Raafat. Synthesis and application of some 1-(8-hydroxy-5-quinolinyl) alkylidene substituted heterocycles as bactericide, fungicide and bioregulators. Bull Chem Soc Jpn 1988; 61(4): 1345-1349 (Eng). Chem Abstr 1989; 110: 38850e.
14) Abou El Ela Ahmed, Donia Shafie G. Synthesis of some biologically active derivatives of 1-phenyl-3,5-pyrazolidinedione. Pol J Chem 1988; 62(4-6): 465-467(Eng). Chem Abstr 1990; 112: 77879g.
15) Evans Steven, Weber Helmet, Diehl Donald R. Arylidene pyrazolidinediones as dye-donar elements for thermal transfer. U. S. US 4,853,366. Chem Abstr 1990; 112: 58468f.
16) Kaneko Yutaka, Sugino Motoaki, Tomotake Atsushi. Study on new magenta dye forming compounds. 3,5-pyrazolidinedione derivatives. Nippon Shashin Gakkaishi 1994; 57(5): 298-303. Chem Abstr 1995; 123: 97636f.
17) Bertrand Le Bourdonnec, Emmanuelle Meulon, Said Yous, Jean-Francois Goossens, Raymond Houssin, Jean-Pierre Henichart. Synthesis and pharmacological evaluation of new pyrazolidine-3,5-dione as AT1 angiotensin II receptor antagonist. J Med Chem 2000; 43: 2685-2697.
18) W B Hugo, A D Russel. Pharmaceutical microbiology. 6th ed. Blackwell Science Ltd 2003; 229-255.
19) G Elias, M N A Rao. Inhibition of Albumin Denaturation and Anti inflammatory Activity of Dehydrozingerone and Its Analogs. Indian J Exp Biol 1988 July; 26: 540-542.
20) Indruch Miroslav, Gabriel Jiri, Mayer Jiri. Preparation of 4-substituted 1,2-diphenyl-3,5-pyrazolidinediones as antiarthritics. Czech CS 229,793. Chem Abstr 1988; 108: 131806p.
21) Ayalp, Abidin. The synthesis of 4-[(2-hydroxy-4-quinolyl)methyl]-3,5-pyrazolidinediones and related products. Pak J Pharm Sci 1989; 2(2): 29-32 (Eng). Chem Abstr 1991; 114: 247233c.
22) Salem Mounir A I, Madkour Hasan M F, Al-Nuaimi I S, Al-qaradawi S Y. Study on 3,5-pyrazolidinedione and its derivatives. J Serb Chem Soc 1993; 58(2): 89-100(Eng). Chem Abstr 1993; 119: 8731k.
23) Graziano Baccolini, Michele Gianelli. N-Alkenyl-3,5-pyrazolidinediones from ketone hydrazones, PCl3 and malonic acid. Tetrahedron 1995; 51(34): 9487-9492.
24) M B Deshmukh, S S Jagtap, S A Deshmukh. Solvent free accelerated synthesis of 2-hydrazinobenzothiazole derivatives using microwave. J Indian Chem Soc 2006 Oct; 83: 1055-1057.
25) Md. Taifur Rahman, Hiroshi nishino. Manganese(III)-catalysed facile direct hydroperoxidation of some heterocyclic 1,3-dicarbonyl compounds. Organic Letters 2003; 5(16): 2887-2890.
26) M F Brana, J M Castellano, M C Redondo. Reaction of 4-acyl amino methyl pyridine N-oxides with Phenylbutazone in the presence of acetic anhydride. J Heterocycl Chem 1987; 24: 741-743.
27) Md Taifur Rahman, Hiroshi nishino, Chang-Yi Qian. Synthesis of 4,4-bis(2-hydroperoxyalkyl) pyrazolidine-3,5-diones using manganese(III)-catalysed autoxidation. Tetrahedron Lett 2003; 44: 5225-5228.
28) Bertrand LE Bourdonnec, Christine Cauvin, Emmanuelle Meulon, Said Yous, Jean-Francois Goossens, Francois Durant, Raymond Houssin, et al. Comparison of 3D structures and AT1 binding properties of Pyrazolidine-3,5-dione and Tetrahydropyrazine-3,6-diones with parent antihypertensive drug Irbesartan. J Med Chem 2002; 45: 4794-4798.
29) Brian S Furniss, Antony J Hannaford, Peter W G Smith, Austin R Tatchell. Vogel’s Practical Organic Chemistry. 5th ed, Longman group UK Ltd 1991; 131-250.
9. / Signature of Candidate10. / Remarks of the guide
11. / Name and Designation of
11.1 / Guide / PROF. C. H. S. Venkataramana
Department of Pharmaceutical chemistry
M.S. Ramaiah college of pharmacy Bangalore-560054.
11.2 / Signature
11.3 / Co-Guide / Not Applicable
11.4 / Signature / Not Applicable
11.5 / Head of the Department
(in charge) / PROF. C. H. S. Venkataramana
Department of Pharmaceutical chemistry
M.S. Ramaiah college of pharmacy Bangalore-560054.
11.6 / Signature
12 / Remarks of the
Principal
12.1 / Signature
2