Synthesis and Pharmacological Evaluation of
Indane-1,3-dione Derivatives
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560 041
By
Mr. ANDHALE GANESH SAKHARAM
Under the Guidance of
Mr. D. GILES
Senior Lecturer
Department of Pharmaceutical Chemistry,
Acharya B.M. Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara Post,
Bangalore -560090
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 /Name of the candidate and address
/Mr. ANDHALE GANESH SAKHARAM
3rd Floor, Number422, 29th cross, Bagalgunthe, Nagasandra Post,Bangalore-560073
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 May 2008
5 /
Title of the topic:
Synthesis and Pharmacological Evaluation ofIndane-1,3-dione Derivatives
6.0 /
Brief resume of the intended work
6.1 Need for studyThe inflammatory response is accompanied by the clinical signs of erythema, edema, hyperalgia and pain (algesia). Inflammation may lead to osteoarthritis and rheumatoid arthritis.
The existing nonsteroidal 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.1
Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of number of autoimmune and inflammatory diseases. It has been demonstrated that TNF-α production in proinflammatory cells become attenuated by an elevation of intracellular cyclic adenosine 3ʹ, 5′-monophosphate. This is regulated by phosphodiesterase family of enzymes. Inhibition of one such enzyme, the calcium-independent and cAMP-specific PDE4, represents an attractive approach toward immunoinflammatory disease therapy.2
The indane-1,3-dione derivatives have shown potential anticoagulant, analgesic, anti-inflammatory and antimicrobial activities.
Indane-1,3-dione3 constitute a unique group of compounds due to its 1,3-dicarbonyl nature, which offer wide scope for studies in problems of theoretical organic chemistry particularly on the basis of tautomerism and dual reactivity.
Indane-1,3-dione
2-substituted derivatives of indane-1,3-diones have shown promising activity as anticoagulant, anticancer, analgesic, anti-inflammatory, fungicidal and bactericidal agents.4-7
Some 5 and 6 membered heterocyclic rings, having potential analgesic, anti-inflammatory and antimicrobial activities which when fused with Indane -1,3-dione, gives synergistic effect.
Hence, we plan to synthesize novel indane-1,3-dione derivatives and subsequently study for their anti-inflammatory and antimicrobial activity.
6.2 Review of literature
v Wei He et al synthesized a novel series of 2,2-disubstituted indane-1,3-dione based PDE4 inhibitors and its structure-activity relationship studies led to the identification of inhibitors with nanomolar potency and oral activity in a murine endotoxemia model for TNF-α inhibition.3
v Giles D et al synthesized 2-substituted thiophenyl derivatives of indane-1,3-dione and were investigated for their anticoagulant, analgesic, anti-inflammatory, antifungal, antibacterial and anticancer activities.4
v Robert-Piessard S et al synthesized derivatives of 2-polyaza-arylindane-1,3-diones which were diversely substituted on the heterocycle and the homocycle in order to study for their anti-inflammatory activity.5
v 3-(2-/4-pyridinyl) indane-1,3-diones and structurally related compounds resulting from the replacement of pyridine by quinoline and benzimidazole were synthesized by Robert-Piessard S et al and evaluated for their anti-inflammatory and antineoplastic activity.6
v Meena S et al synthesized 2-(aryl-methylene)-(1H)-indane-1,3-(2H)-diones and evaluated for their potential antifungal and antimicrobial activities.7
v 2-arylidene-4-cyclopentene-1,3-diones and 2-arylideneindan-1,3-diones were synthesized by Inayama S et al and examined for their antitumor activity against ascites sarcoma-180. All the 2-arylidene-4-cyclopentene-1,3-diones and one arylideneindan-1,3-dione exhibited a high degree of activity.8
v Sulfur derivatives of indane-1,3-dione were synthesized and evaluated for their pharmacological activity by Mitka K et al.9
v Salama MA et al synthesized some newly substituted phenylhydrazono ideno-thiazolo[3,2-b]pyrimidin-3-ones and evaluated for antimicrobial activity which was determined using cup plate method.10
v 2-(3-aminopropionyl)-1,3-indanediones containing a basic side chain in 2nd position have been synthesized by Hamama WM et al. Because of their anticoagulant and psychopharmacological properties, 2-acetyl-1,3-indane dione was subjected to Mannich reaction with dimethylamine, morpholine or piperazine and para-formaldehyde to afford the Mannich bases. 11
v Hammouda M carried out reaction of indane-1,3-dione with indole, 2-phenylindole, antipyrine, 4-aminoantipyrine and 3-amino-1-phenylpyrazol-2-in-5-one which afford 3-(Indole-3′-yl) inden-1-one, 3-(2′-phenyl-indol-3′-yl)inden-1-one and 3-(2′,3′-dimethyl-5′-oxo-1′-phenyl-3′-pyrazolin-4′-yl)inden-1-one respectively. Treatment of these with hydrazoic acid under Schmidt reaction conditions gave the respective 4-substituted carbostyriles.12
v Bicyclo-3,4-dihydropyrimidinediones were synthesized by Shanmugam P et al from cyclic 1,3-diketones such as 5,5-dimethyl-1,3-cyclohexanedione (dimedone) and 1,3-indanedione.13
v Kozlov NG et al synthesized 2-Methoxy-4-(12-oxo-12H-benzo[f]indeno [1,2-b]quinolin-13-yl) phenyl esters of carboxylic acid by three component condensation of indane-1,3-dione, 2-naphthylamine, and O-acylvanillin. 2-arylidenindan-1,3-diones formed during the reaction were isolated. 14
v Rajendra S et al synthesized a series of thiosemicarbazones derived from indanedione-1,3 & reported for antiviral and antibacterial screening by using plastic panel and agar diffusion techniques respectively.15
v Bryce MR et al studied on a series of mono, bis, tris(1,3-dithiol-2-ylidene)
derivatives of 1,3-indanedione and investigated for X-ray crystal structure of the complex.16
v Geita LS et al synthesized spiro [(indane-1,3-dione)-2,3′(2′-substituted 1′-azirines)] by intra molecular cyclization of 2-acylindane-1,3-dione oximes. Their structures and properties were investigated and it was established that the C-N and C-C single bonds are cleaved during opening of three-membered ring.17
v Aliev ZG et al studied an X-ray diffraction structural analysis on the dimer 2,2′-bis-[2-(p-dimethylaminophenyl)indane-1,3-dione] which displayed mechanochromic properties due to decomposition to free radicals.18
v Thiadiazoline derivatives were synthesized by Elwan NM et al and they treated indane-1,3-dione-2-thiocarboxanilides with hydrazonoyl halides.19
v Moustafa AH et al synthesized substituted 4-azafluorenes by ammonium acetate base catalyzed cyclocondensation of 2-arylmethylene indan-1-ones and 2-arylmethylene indan-1,3-diones with ethylcyanoacetate, diethylmalonate, ethylacetoacetate, indane-1-one and α-tetralone.20
v Thirumamagal BTS et al synthesized 2-aryl-1,3-indanedione by the condensation of the sulfone with aryl aldehyde and have considerable interest due to their anticoagulant, parasiticidal and a range of biological activities.21
v Bahera RK et al synthesized several 4,5-dihydroindeno [1,2-c] [1,2] diazepin-
6(1H)-ones by condensing 2-substituted ethyl 1,3-indanedione with hydrazine.22
6.3 Objectives of the study
1. To synthesize some newer derivatives of indane-1,3-dione.
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, anti-inflammatory and antimicrobial activities.
4. To publish the research work in peer reveiwed journals.
7.0 / Materials and methods:
7.1 Sources of data
Databases like Chemical abstracts, Biological abstracts, Medline, and Journal of Chemistry section B, Indian Journal of Heterocyclic Chemistry, European Journal of Medicinal Chemistry, Bioorganic and Medicinal Chemistry Letters, Acta crystallographica, Helinet of RUGHS etc.
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 and purification of the compound will be done by recrystallization method.
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 center at IISc, Bangalore.
C) 1) Screening of anti-inflammatory activity:23
Invitro 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 is prepared freshly in normal saline and injected into subplantar region of left hind paw (usually 0.1mL in rats and 0.025-0.05mL in mice). In control group animals, only vehicle is 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 is made on the ankle joint of each rodent. Paw volume up to the ankle joint is measured in drug treated and untreated groups before and 3 hours after carrageenan challenge using a plethysmograph filled with mercury.
2) Screening of antimicrobial activity:24,25
SCREENING OF ANTIBACTERIAL ACTIVITY BY DISC DIFFUSION
METHOD:
Antimicrobial studies will be carried out on both Gram positive and Gram negative organisms like Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Bacillus subtilis etc using sterile media like Mueller-Hinton Agar etc by Disc Diffusion Method. Zone of inhibition of the compounds synthesized will be noted and compared with that of standard drugs like Amoxicillin, Ciprofloxacin etc. The entire work will be done using horizontal Laminar Flow hood.
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. Jackson RL, Jason DM. Goodman and Gilman′s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill Medical publication division; 2001.
2. Wei H, Fu-chih H, Hanney B, Souness J. Novel cyclic compounds as potent phosphodiesterase 4 inhibitors. J Med Chem 1998;41:4216-23.
3. Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR. Vogel′s, text book of practical organic chemistry. 5th ed. India: Saurabh Printers Pvt. Ltd; 2004
4. Giles D, Prakash MS, Ramaseshu KV. Synthesis and biological evaluation of substituted thiophenyl derivatives of indane-1,3-dione. E-J chem 2007;4(3):428-33.
5. Robert-Piessard S, Leblois D, Kumar P, Robert JM, Baut GL, Sparfel L et al. Synthesis and anti-inflammatory activity of 2-polyaza-arylindane-1,3-diones and their N- or O-substituted derivatives. J Med Chem 1990;35:737-47.
6. Robert-Piessard, Leblois D, Courant J, Baut GL, Petit JY. Synthesis and pharmacological activity of 3-(2- and 4-pyridinyl) indane-1,3-diones and structural analogues with potential anti-inflammatory and antineoplastic activity. Ann Pharm Fr 1998;56(4):160-8.
7. Meena S, Shankar D, Ramaseshu KV, Giles D, Prakash MS, Venkataraman S. Synthesis of 2-(aryl methylene)-(1H)-indane-1,3-(2H)-diones as potential fungicidal and bactericidal agents. Indian J Chem 2006;45(B):1572-5.
8. Inayama S, Mamoto K, Shibata T, Hirose T. Structure and antitumor activity relationship of 2-arylidene-4-cyclopentene-1,3-diones and 2-arylideneindan-1,3-diones. J Med Chem 1976;19(3):433-6.
9. Mitka K, Kowalski P, Sulko J, Wozniak M, Kloc J, Chodkowska A et al. Synthesis and pharmacological properties of sulfur derivatives of indane-1,3-dione. Acta Pol 2002;59(5):387-93.
10. Salama MA, ElEssa SA. Synthesis and reactions of new substituted phenylhydrazono ideno-thiazolo (3,2) pyrimidin-3-ones of possible antimicrobial activity. Indian J Chem 2001;40(B):678-81.
11. Hamama WM, Kandeel EM, Hammouda M. Synthesis and some reactions of 2-(3-aminopropionyl)-1,3-indanediones. Pharmazie 1988;43:529-32.
12. Hammouda M. Reaction of indane-1,3-dione with indole, indole derivatives and other heterocycles. Indian J Chem 1993;32(B):1181-4.
13. Shanmugam P, Sabastein C, Perumal PT. Synthesis of fused dihydropyrimidinones from cyclic-1,3-dicarbonyl compounds: modified biginelli synthesis of 1,2,3,4,5,6,7,8-octahydroquinazolinediones and 3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-diones. Indian J Chem 2004;43(B):135-40.
14. Kozlov NG and Basalaeva LI. Vanillin esters in reactions with indan-1,3-dione. Chem Heterocycl Compd 2006;42(9):1223-7.
15. Rajendra S, Varma and Lewis NW. Thiosemicarbazones derived from indanedione-1,3. J Pharm Sci 1967;56(6):775-6.
16. Bryce MR, Malcolm AC, Adrian JM, Andrei SB and Judith AKH. 1,3-Dithiol-2-ylidene derivatives of 1,3-indanedione. Tetrahedron 1999;55:9915-22.
17. Geita LS, Dalberga LE, Grinvalde AK and Yankovska IS. Synthesis and study of Spiro [(indane-1,3-dione)-2,3′-azir-1′-ines] and their cleavage products. Khim Geterosikl 1976;1:65-9.
18. Aliev ZG, Chekhlov AN, Atovmyan LO. Crystal and molecular structure of 2,2′-bis[2-(p-dimethylaminophenyl)indane-1,3-dione] displaying mechanochromic properties. Zh Strukt Khim 1990;31:103-7.
19. Elwan NM, Huwaida MH and Hamdi MH. Synthesis and reaction of indane-1,3-dione-2-thiocarboxanilides with hydrazonoyl halides and active chloromethylene compounds. Heteroat Chem 2002;13(7):585-91.
20. Moustafa AH, Kaddah AM, Gado SH, El-Abbady SA. Cyclocondensation of cyanoacetamide and N-substituted cyanoacetamides with 2-arylmethylene indan-1-one and indan-1,3-diones. J f prakt Chemie 1982;324(6):1045-51.
21. Thirumamagal BTS, Sureshbabu N. Formation of 2-arylindane-1,3-diones and 3-alkylphthalides from methyl o-[α-phenylsulfonyl]toluate. Tetrahedron Lett 2008; 49:512-5.
22. Bahera RK and Nayak A. Reaction of Indane-1,3-diones with hydrazine and thiourea. Indian J Chem 1976;14(B):223-4
23. Kulkarni SK, Handbook of experimental pharmacology. 3rd ed. Delhi: Vallabh
Prakashan;1999
24.Edwin H L, Alberbalows, William J H, Jean S H. Manual of Clinical Microbiology. 4th ed. Washington: American Society for Microbiology; 1985
25.Hugo W B, Russel A D. Pharmaceutical Microbiology 6th ed. London: Blackwell Science Ltd., 1998
9.0 /
Signature of the Candidate
10.0 / Remarks of the Guide11.0 / Name and Designation of
11.1Guide
11.2 Signature
/ Mr. D. GilesSenior Lecturer,
Acharya B.M. Reddy College of Pharmacy,
Bangalore-90
11.3 Co-Guide
11.4 Signature
/ NIL11.5 Head of the Department
( Incharge)11.6 Signature
/ Mr. A. Cendil KumarAsst. Professor,
Department of Pharmaceutical Chemistry,
Acharya B.M. Reddy College of Pharmacy, Bangalore-90
12.0 /
12.1Remarks of Principal
12.2 Name of the Principal12.3 Signature / Dr. Divakar Goli
Principal,
Acharya and B.M. Reddy College of Pharmacy, Bangalore-90
13