DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL PYRAZOLIDINE DIONES CONTANING INDOLE AND BENZIMIDAZOLE MOIETIES
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH
SCIENCES, BANGALORE, KARNATAKA
BY
TANGUTURU RAMKUMAR
I M.PHARM (2009-10)
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 / TANGUTURU RAMKUMARS/O T. PRASAD,
D.NO:-9/13 MAIN BAZAR ,
PAMIDI-515775
DISTRICT:ANATAPUR
STATE :ANDHRA PRADESH
2. / NAME OF INSTITUTION / M.S.RAMAIAH COLLEGE OF PHARMACY, M.S.R.I.T. POST,
M.S.R. NAGAR,
BANGALORE-560054
3. / COURSE OF THE STUDY AND SUBJECT / M.PHARM
PHARMACEUTICAL CHEMISTRY
4. / DATE OF ADMISSION / 29THJUNE 2009
5. / TITLE OF THE TOPIC
DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL PYRAZOLIDINE DIONES CONTANING INDOLE AND BENZIMIDAZOLE MOIETIES.
6. BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
A number of organic compounds obtained by chemical synthesis have useful antimicrobial activity for the treatment of local and systemic infections. Pyrazolidinedione derivatives are an important class of heterocyclic compounds because of their wide spectrum of biological activity and clinical applications. The pyrazolidinedione ring system is very useful intermediate/subunit for the development of molecules of pharmaceutical interest. Pyrazolidinedione derivatives have found application in diverse therapeutic area such anti-microbial, analgesic and anti-inflammatory, anticonvulsant, anti-hypertensive and anti neoplastic activities.1-8
Substituted indole derivatives posses diverse therapeutic activities such as anti-microbial, anti-inflammatory, hypoglycemic, anticancer, antihistaminic and blood platelet anti aggregation activities. They are inhibitors of Pim 1 which is implicated in the developement of a large no of tumors. They are also useful as anti tubercular agents.9-25
Substituted benzimidazole derivatives have been reported to posses antibacterial, anti-inflammatory, anthelmintic, anti-protozoal, antiviral, anti-ulcer and antineoplastic activites.26-40
These findings triggered interest in us to incorporate pyrazolidinediones , indole, and benzimidazole ring systems in one frame work to obtain compounds with better antimicrobial & anti-inflammatory activities.
6.2 REVIEW OF LITERATURE
Ø Synthesis and antimicrobial evaluation of new isoxazoles, pyrazolin-5-ones and pyrazolidine-3,5diones was reported.1
Ø Inhibition of UDP-N-acetylenopyruvyl glucosamine reductase by pyrazolidine -3,5diones and 5-hydroxy-1H-pyrazol-3(2H)-ones was reported.2
Ø Synthesis of new salicylamide derivatives of pyrazolidinediones among others with evaluations of their anti-inflammatory, analgesic and antipyretic activities was reported.3
Ø Anticonvulsant activity of 1-alkyl-4-substituted 3,5-pyrazolidinediones was reported.4
Ø Synthesis and pharmacological evaluation of new pyrazolidine-3,5diones as AT1 and AT2 receptor antagonists was reported.5
Ø Pyrazolidine-3,5-dione angiotensin-II receptor antagonists were reported.6
Ø 3D Structures & AT1 binding properties of pyrazolidine-3,5-diones & Tetrahydropyridazine-3,6-diones were compared with parent antihypertensive drug Irbesartan.7
Ø A pyrazolidine dione derivative was identified as one of the lead molecules in the search for small molecule antagonists of MDM2 oncoprotein as anticancer agents.8
Ø Synthesis and antibacterial activity of some new fluorine containing spiro-3-indolines was reported.9
Ø Synthesis and antimicrobial activity of novel 4-thiazolidinonylindoles was reported.10
Ø Synthesis and antimicrobial activity of some new 2-aminomethyl-5-(4-phenyl-5-mercapto-1,2,4-triazol-3-y1)methoxyindole derivatives was reported.11
Ø Synthesis and fungicidal activity of some 1’-(substituted aryloxyaceto)spiro-[3H-indole-3.2’-thiazolidine]-2,2’-(1H)-diones and 2-aryl-[1,3,4]oxadiazino[5,6-b]indoles was reported.12
Ø Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles as biologically active heterocycles was reported.13
Ø Synthesis and biological evaluation of 1-acetyl-3-(2-acetoxy-3-substituted propyloximino) indol-2(3H)-ones was reported.14
Ø Synthesis and fungitoxicityof1-[N-benzoyl-3(2-substituted-3-sulphonyl-5-methoxyindol-3-yl)-2-pyrazolines and1-(N-phenylsulphonyl)-3-(2-substituted-3‘-sulphonyl)-5-methoxyindol-3-yl]-2-pyrazolines was reported.15
Ø Synthesis of oxadiazolylindole derivatives and their anti-inflammatory activity was reported.16
Ø Synthesis and anti-inflammatory activity of some 3-substituted indolo[2,3] imidazoles was reported.17
Ø Synthesis and anti-inflammatory activity of some new indolyl substituted quinazolin-4-(3H)-ones was reported.18
Ø Synthesis and biological activities of indole-3-propionic acids were reported.19
Ø Synthesis, analgesic and anti-inflammatory activities of bis(indolyl) methanes were reported. 20
Ø Synthesis and pharmacological evaluation of some new 1-(2-aryl-3-indolylmethylene-amino)-3-(aryloxyacetamido)guanidines was reported.21
Ø Design, synthesis, and biological evaluation of pyrrolo [2, 1-c][1,4]benzodiazepine and indole conjugates as anticancer agents was reported.22
Ø Synthesis and antiallergic activites of 10-substituted -4-chloro-12-methyl(or phenyl) -1,2-dihydroqunioxalino[1,2-a]indoles were reported.23
Ø Synthesis of 3-amino-5H-1, 2, 3-triazino [5, 4-b] indol-4-one, and related compounds with blood platelet anti aggregation activity was reported.24
Ø Indolyl-pyrrolone as a new scaffold for Pim 1 inhibitors was reported.25
Ø Synthesis and biological activity of new benzimidazoles was reported.26
Ø Synthesis and antimicrobial activity of 2-imino-4-(benzimidazol-2-yl)-6-aryl-6H-2,3-dihydro-1,3-thia/oxazines was reported.27
Ø Synthesis, antiprotozoal and antibacterial activity of nitro-and halogeno-substituted benzimidazole derivatives was reported.28
Ø Synthesis and biological evaluations of 2-alkyl benzimidazolyl-6-amino-β-d-glucopyranoses was reported.29
Ø Synthesis and antimicrobial activity of di-fluorobenimidazole and 1,2,3- triazole incorporated chromones was reported.30
Ø Synthesis of 3,4-disubstitued -5-mercapto-1,2,4-triazoles and their biological evaluation was reported.31
Ø Synthesis and antimicrobial evaluation of some new chiral substituted benzimidazole derivatives was reported.32
Ø Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA(Methicillin resistant staphylococcus aureus) and anti-VRE(vancomycin resistant enterococcus faecium) agents was reported.33
Ø Synthesis and anti-inflammatory evaluation of some imino-sugars of methylbenzimidazole was reported.34
Ø Synthesis and anthelmintic activity of triheterocycles:[5’-(5’-substituted -3’-phenylindol-2’-yl)-1,3,4-oxadiazol-2-yl-thiomethyl] benzimidazoles was reported.35
Ø Synthesis and antiviral activities of N-substituted -2- substituted –benzimidazole derivatives were reported.36
Ø Synthesis of 2-(thiomethyl-2-benzimidazolyl) benzimidazole and its derivatives of pharmacological interest was reported.37
Ø Studies on synthesis of unsymmetrical 2,2’- bisbenzimidazole sulphides of pharmacological interest were reported.38
Ø Synthesis and antitumor activity of 4 –aryl/alkyl-2-D aldosugar disubstituted bis-benzimidazoles was reported.39
Ø Design, synthesis, SAR studies, and in vivo antitumor activity of N-hydroxy-1,2-disubstituted -1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors were reported.40
Ø Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor were synthesized and subjected to virtual screening, & biological evaluation.41
Ø Formation of 3-pyrazoline-5-thione disulfides from 3,5-pyrazolidinediones. was reported.42
Ø Electrochemical mechanism involving reduction of some pyrazolidine-3, 5-diones in DMSO, relation between their voltammetric behavior and 1H nuclear magnetic resonance spectra were reported.43
Ø Expanding on the purification methodology of polyethylene glycol (PEG) bound molecules, the synthesis of 3, 5-pyrazolidinediones was reported.44
Ø Acylimine mediated N-N bond cleavage of pyrazolidinediones and subsequent conversion to dihydropyrimidinediones and malonamides were reported.45
Ø Synthesis of 4, 4 –bis(2-hydroperxyalkyl) pyrazolidine-3,5-diones using manganese (III)- catalyzed auto oxidation was reported.46
Ø Manganese (III)-based oxidation of 1,2-disubstituted pyrazoldine-3,5-diones in the presence of alkenes was reported.47
Ø A new synthetic method of indoles was reported as a part of study of enamine rearrangement of pyridinum salts.48
Ø An efficient synthesis of 3- substituted indoles by palladium –catalyzed coupling reaction of 3-tributylstannylindoles with organic triflates and halides was reported.49
Ø A new synthesis of indoles by aryl radical cyclisation onto appropriate vinyl bromides was reported.50
Ø A facile synthesis of 4-and 6-chloromethyl-1H-indole-2-carboxylates by replacement of a sulfonic acid functionality with chlorine was reported.51
Ø Novel ring transformation of quinolines to indole derivatives in two steps via 1,4-dihydroquinoline derivatives was reported.52
Ø New synthesis of 3- substituted indoles using lithium trimethylsilyldiazomethane was reported.53
Ø Synthesis of some 2-heteryl substituted indoles was reported.54
Ø A new and efficient one pot synyhesis of indoles from phenylhydrazines and pyruvic acid using microwave irradiation was reported.55
Ø A convenient procedure for the N-alkylation of compounds containing multiple benzimidazole functionalities was reported.56
Ø Solid phase synthesis of 1-Alkyl-2-alkylthio-5-carbamonyl benzimidazoles was reported.57
Ø A Convenient Synthesis of benzimidazole derivatives using 1- Aza-1’,3’-diaza-3,3’-sigmatropic rearrangements- was reported.58
Ø Synthesis of 2-substituted-1-[2’-carboxy-biphenyl-4-yl]methyl benzimidazoles was reported.59
Ø A convenient approach to the synthesis of 2-aryl-4-alkyl-1,3,5-triazino[1,2-a]benzimidazoles was reported.60
Ø A solid phase traceless synthesis of benzimidazoles with three combinatorial steps was reported.61
Ø Two-step solution – phase synthesis of novel benzimidazoles utilizing a UDC (ugi/de-boc/cyclize)strategy was reported.62
Ø Synthesis of substituted benzimidazoles via tosylation of N-aryl amidoxime was reported.63
Ø Robinson’s annulation of benzimidazole chalcones with ethyl aceto acetate under microwave irradiation was reported.64
Ø TiCl4 promoted synthesis of benzimidazole derivatives was reported.65
Ø Synthesis of 2-indolylbenzimidazoles using fischer’s indole method was reported.66
Ø An efficient method to access 2-substituted benzimidazoles under solvent-free conditions was reported.67
Ø A mild, efficient and one-pot synthesis of 2-substituted benzimidazoles by ZrOCl2.8H2O catalyzed ring closure reaction was reported.68
Ø Intramolecular homolytic aromatic substitution of alkyl2-benzimidazolyl sulfones as a means of entry into alkyl radicals for organic synthesis was reported.69
6.3 AIMS AND OBJECTIVES OF STUDY
1) To design and select the title compounds with better physiochemical and ADME characteristics and with less toxicity.
2) To synthesize the selected compounds by both conventional and microwave methods and compare their applicability with respect to the percentage yield and reaction time.
3) To purify the synthesized compounds by recrystallization and chromatographic techniques.
4) To identify and characterize the compounds by qualitative tests, elemental and spectral analysis.
5) To screen the newly synthesized compounds for antimicrobial activity and anti-inflammatory activity.
7. MATERIAL AND METHODS
7.1 SOURCE OF DATA
1. Chemical abstracts.
2. Journals and publications, e.g. Indian Journal of Heterocyclic Chemistry. Indian Journal of Chemistry, Tetrahedron Letters, Indian Drugs, Synthetic communications, Organic communications, Bioorganic and medicinal chemistry etc.
3. Experimental results.
7.2 METHODS OF COLLECTION OF DATA
1) PRE-LABORATORY WORK
Some novel pyrazolidinediones containing indole and benzimidazole moieties will be designed for better physicochemical and ADME characteristics and less toxicity by using Accelrys drug design software modules like DS-proview, Accord for excel, Topkat and TSAR.
The chemicals & reagents required for the synthesis and evaluation of the proposed compounds will be procured from reputed chemical suppliers like Merck, Ranbaxy, Qualigens, Himedia etc.
2) LABORATORY WORK
A) SYNTHESIS
Conventional methods44,54,58 as well as microwave assisted55, 64synthesis will be attempted. The completion of the reaction will be monitored 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 methods70. The purity will be ascertained by TLC.
C) CHARACTERIZATION
The synthesized compounds will be characterized by:
1. Chemical tests for important functional groups.70
2. Study of spectral data.73
D) BIOLOGICAL STUDIES
1. ANTIBACTERIAL ACTIVITY : This will be carried out on both Gram positive and Gram negative organisms like Staphylococcus aureus, Escherichia coli etc using sterile media by disc diffusion method. Zone of inhibition of the compounds synthesized will be compared with that of standard drugs like Amoxicillin, Ciprofloxacin etc. 26,32,71,72
2. ANTIFUNGAL ACTIVITY :This will be carried out on organisms like Candida albicans and Aspergillus niger using media like Sabouraud Dextrose Agar by disc diffusion method. Zone of inhibition of the compounds synthesized will be compared with that of standard drugs like griseofulvin.26,32,71,72
This work will be done using Horizontal Laminar Flow hood.
3. ANTI-INFLAMMATORY ACTIVITY BY CARRAGEENAN INDUCED RAT PAW EDEMA METHOD:
This will be carried out on rat paw by using carragenan as inflammagen, synthesized compounds and standard drug are injected intraperitonially. The percentage inhibition of rat paw edema by the synthesized compounds will be compared with that of standard drug like indomethacin.3,17,20
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?
Yes, Ethical committee clearance has been obtained. Certificate enclosed.
8. LIST OF REFERENCES.
1) Goda FE, Maarouf AR, EL Bendary ER.Synthesis and antimicrobial evaluation of new isoxazole and pyrazole derivatives. Saudi Pharmaceutical Journal, 2003;11(3):111-117.
2) Adam MG, Amedeo F, Jay S, Youjun Y, Anatoly S, Guy S et al. Pyrazolidine -3,5diones and 5-hydroxy-1H-pyrazol-3(2H)-ones, Inhibitors of UDP-N-acetylenolpyruvyl glucosamine reductase . J Med Chem,2006 Apr;49:6027-6036.
3) Fahmy HH, Soliman GA. Synthesis of new salicylamide derivatives with evaluation of their anti-inflammatory, analgesic and antipyretic activities. Arch Pharm Res,2001;24(3):180-189.
4) Kornet MJ, Thorstenson JH, Lubawy WC. Anticonvulsant activity of 1-alkyl-4-substituted 3,5-pyrazolidinediones . J Pharm sci ,1974 July;63(7): 1090-1093.
5) Bertrand LB, Emmanuelle M, Said Y, Jean FG, Raymond H, Jean PH. Synthesis and pharmacological evaluation of new pyrazolidine-3,5diones as AT1 angiotensin II receptor antagonists. J Med Chem,2000;43:2685-2697.
6) Christine C, Bertrand LB, Bernadette N, Jean PH, Francois D. Pyrazolidine-3,5-dione angiotensin-II receptor antagonists. Acta Crystallographica Sec C 2001 ;57:1330-1332.
7) Bertrand LB, Christine C, Emmanuelle M, Said Y, Jean FG, Raymond H, Jean PH. Comparison of 3D Structures and AT1 binding properties of pyrazolidine-3,5-diones and tetrahydropyridazine-3,6-diones with parent antihypertensive drug irbesartan. J Med Chem, 2002;45:4794-4798.
8) John KB, James A, Shantaram K, Shivaputra P , Darius M , Marian O. Small molecule antagonists of the MDM2 oncoprotein as anticancer agents. Current Cancer Drug Targets,2005;5:57-68.
9) Krishna CJ, Anshu D, Sangeeta K. Synthesis and antibacterial activity of some new fluorine containing spiro-3-indolines. Indian J Chem,1990 Dec; 29B:1125-1128.
10) Gadaginamath GS, Shyadligeri AS, Kavali RR. Chemoselectivity of indole-dicarboxylates towards hydrazine hydrate: part III – Synthesis and antimicrobial activity of novel 4-thiazolidinonylindoles.Indian J Chem, 1999 Feb;38B:156-159.
11) Gadaginamath GS, Patil SA. Synthesis and antimicrobial activity of some new 2-aminomethyl-5-(4-phenyl-5-mercapto-1,2,4-triazol-3-y1)methoxyindole derivatives. Indian J Chem,1999 Sep;38B:1070-1074.
12) Ruab A, Bharati M, Nizamuddin. Synthesis and fungicidal activity of some 1’-(substituted aryloxyaceto)spiro-[3H-indole-3.2’-thiazolidine]-2,2’-(1H)-diones and 2-aryl-[1,3,4]oxadiazino[5,6-b]indoles. Indian J Chem,1989 June;28B:526-528.
13) Preeti RK, Niraj SS, Rajeev KD, Parekh HH. Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles as biologically active heterocycles. Indian J Chem, 1999 May;38B:572-576.
14) Padhy AK, Sahu SK, Panda PK, Kar DM, Misro PK. Synthesis and biological evaluation of 1-acetyl-3-(2-acetoxy-3-substituted propyloximino) indol-2(3H)-ones. Indian J Chem,2004 May;43B:971-975.
15) Singh RP, Mishra HC, Singh D. Synthesis and fungitoxicity of 1-[N-benzoyl-3(2-substituted-3-sulphonyl-5-methoxyindol-3-yl)-2-pyrazolines and 1-(N-phenylsulphonyl)-3-(2-substituted-3‘-sulphonyl)-5-methoxyindol-3-yl]-2-pyrazolines. Indian J Hetero Chem, 2007 Jan-Mar;16:213-216.
16) Sonar VN, Shaik KY, Sreenivasulu N. Synthesis of oxadiazolylindole derivatives and their anti-inflammatory activity. Indian J Hetero Chem., 2001 Apr-Jun;10:299-302.s
17) Sushma D, Nitin K, Siddeswaran M. Synthesis and anti-inflammatory activity of some 3-substituted indolo[2,3] imidazoles. Indian J Hetero Chem, 2005 July-Sep;15:91-92.
18) Pankaj K, Chatrasal SR, Sudhir KB, Paurl R, Jai S, Ashok K. Synthesis and anti-inflammatory activity of some new indolyl substituted quinazolin-4-(3H)-ones. Asian J Chem,2008;20(3):1827-1832.
19) Girisha M, Jaishree B, Purohit MG, Thippeswamy BS, Patil BM. Synthesis and biological activites of indole-3-propionic acids. Indian J Chem, 2008 Jan-Mar;17:275-276.
20) Kuppusamy S, Paramasivan TP, Doraisamy M , Rajendran M. Synthesis, analgesic and anti-inflammatory activities of bis(indloyl)methanes. Indian J Chem,2009 Feb;48B:267-272.
21) Hussain MI, Jamali MR. Synthesis and pharmacological evaluation of some new 1-(2-aryl-3-indolylmethylene-amino)-3-(aryloxyacetamido)guanidines.Indian J Chem,1989 June;28B:532-534
22) Jeh JW, Shen KY, Wan PH, Ming CH, Fu-lung L, Ming KH et al. Design, synthesis, and biological evaluation of pyrrolo [2,1-c][1,4]benzodiazepine and indole conjugates as anticancer agents. J Med Chem,2006;49:1442-1449.