Studies on Synthesis andPharmacological activity of substituted indole derivatives

M. Pharm Dissertation Protocol Submitted to

RajivGandhiUniversity of Health Sciences, Karnataka

Bangalore - 560 041

By

Mrs. PUTHA LOHITHA B.Pharm

Under the Guidance of

Dr. VINOD MATHEWM.Pharm, Ph.D

Head,Department of Pharmaceutical Chemistry

Department of Pharmaceutical Chemistry,

Acharya &B. M .Reddy College of Pharmacy,

Soladevanahalli,Hessaragatta Main Road,

Bangalore-90

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the candidate and address / Mrs.PUTHA LOHITHA
ACHARYA& B.M. REDDY COLLEGE OF PHARMACY,
SOLADEVANAHALLI,
HESSARAGATTA MAIN ROAD,
BANGALORE- 560090.
Permanent Address
C/O P.VIJAYA BHASKAR REDDY,
2705- 2 E-BLOCK, SAHAKARA NAGAR,
BANGALORE - 560 093.
2. / Name of the institution / ACHARYA& B.M. REDDY COLLEGE OF PHARMACY,
SOLADEVANAHALLI,
HESSARAGATTA MAIN ROAD,
BANGALORE - 560090.
3. / Course of the study / MASTER OF PHARMACY
(PHARMACEUTICAL CHEMISTRY)
4. / Date of Admission / 1stJune 2007
5. / Title of the topics:
Studies on Synthesis and Pharmacological activity of substituted indole derivatives
6. / Brief resume of the intended work
6.1 Need for the study
Indole is an aromaticheterocyclicorganic compound, having a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogencontaining pyrrole ring. The indole structure can be found in many organic compounds like the amino acidtryptophan and in tryptophan-containing protein, in alkaloids, and in pigments.
Indole along with their several derivatives finds a prominent place in synthetic organic chemistry, as they found to be potent pharmacophores. Indole derivatives have displayed versatile pharmacological properties such as anti-inflammatory, anticancer, antidiabetic, antimalarial, antibacterial, antifungal, anticonvulsant and cardiovascular activities. Indole along with its derivatives has been associated as a common denominator of psychotropism and several review articles have appeared on the medicinal uses of some well known indole derivatives. The discovery of many indole alkaloids with varied biological properties has attracted the organic chemistry to evolve new routes for the synthesis of functionalized indoles.
Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitterserotonin, melatonin, the hallucinogenspsilocybin, DMT, 5-MeO-DMT, or the ergolines like LSD. Other indolic compounds include the plant hormone Auxin, the anti-inflammatory drug indomethacin, and the betablockerpindolol.
Mannich bases were found to possess potent activities such as antibacterial, antifungal, antiviral, antimalarial and CNS depressant, antitubercular, antimalarial, vasorelaxing, anticancer, and analgesic drugs. They are also used in polymer industry as paints and surface active agents.
1, 3, 4-Oxadiazoles are an important class of heterocyclic compounds with broad spectrum of biological activities. Substituted 1, 3, 4-oxadiazoles have revealed antibacterial, antifungal, anti-inflammatory, analgesic, anticonvulsant, antihypoglycemic, and insecticidal properties. Compounds possessing oxadiazole moiety showed anticancer and tyrosinase inhibitory activity. Oxadiazoles find use as fluorescent whiteners and also act as muscle relaxants.
Thiazolidine ring is associated with the penicillin molecule forming part of the β-lactam structure. 4-Thiazolidinone derivatives have been demonstrated to possess antibacterial, antifungal, anticonvulsant, anticancer and antituberculosis activities.
Keeping these observations in view and our interest in search of pharmacologically active heterocycles, it was contemplated to synthesize indole derivatives containing heterocycles of biological importance and to pursue in vitro antibacterial, antifungal, anti-inflammatory and analgesic screening.
Following are the structures of medical compounds containing indole rings

6.2Review of literature:
  • P.K. Dubey and Balaji Babu reported the synthesis and characterization of some 2-hetero aryl substituted indoles. These substituted indoles were confirmed on the basis of elemental analysis and IR, NMR and mass spectral data.1
  • Kakul Husain, et al reported the synthesis, characterization and antiamoebic activity of new indole-3-carboxaldehyde thiosemicarbazones. The new series of indole-3-carboxaldehyde thiosemicarbazones were prepared by condensing indole-3-carboxaldehyde with cycloalkylaminothiocarbonyl hydrazines.The chemical structures of all the compounds were established by elemental analyses, electronic, IR, 1H NMR and 13C NMR spectral data.2
  • C. Gilles Bignan et al studied 3-(4-Piperidinyl)indoles and 3-(4-piperidinyl)pyrrolo-[2,3-b]pyridines as ligands for the ORL-1 receptor.3
  • Yuichi Sugimoto et alreported the design, synthesis, and biological evaluation of indolederivatives as novel nociceptin/orphanin FQ (N/OFQ) receptor antagonists.4
  • G.P. Kalaskar et al studied the synthesis and evaluation of in vivo anti-inflammatory activity of indole-3-aceetic acids.The structures of the synthesized compounds wereestablished on the basis of IR, NMR, mass spectral data and elemental analysis. The entire compounds were further evaluated for their anti-inflammatory and most of the compound showed promising anti-inflammatory activity.5
  • Deepa Sinha et al reported the synthesis, characterization and biological activity of Schiff base analogues of indole-3-carboxaldehyde.The synthesized analogues were characterized on the basis of IR, NMR, mass spectral data and elemental analysis. 6
  • G. Manjunath Bhovi and S. Guru Gadaginamath studied the synthesis and characterization of some new 1-[2-phenylthioethyl] 1-[2-phenoxyethyl]-3-ethoxycarbonyl-5-methoxy-2-methylindoles/benz[g] indoles.These synthesized indole derivatives were screened for their antimicrobial activity.7
  • G.S. Gadaginamath, et al reported the synthesis and antimicrobial activity of some new 3-acetyl-5-(3-methyl-5-hydroxypyrazol-4-yl) oxy-2-methylindoles.8
  • R.S. Gani, S.R. Pujar and G.S. Gadaginamath reported the synthesis and antimicrobial activity of some new oxadiazolyl methoxyindole derivatives.The compounds synthesized were screened for their antibacterial and antifungal activities.9
  • S. Dundappa Donawade, A V Raghu and S. Guru Gadaginamath studied the synthesis and antimicrobial activity of novel linearly fused 5-substituted-7-acetyl-2,6-dimethyloxazolo[4,5-f]indoles.They were characterized on the basis of their spectral and analytical data. The compounds were further screened for antibacterial and antifungal activites.10
  • N. Vijai Pathak et al reported the mass spectral studies and anti-inflammatory activity of some bis (2,2’-diaryl-3,3’-alkylidene/arylidene/heteroarylidene) indoles.Some representative compounds were screened for their anti-inflammatory activity. Some of the tested compounds were found to possess significant activity while other compounds showed weak to moderate activity.11
Thus, in continuation of our ongoing program of research on the synthesis of some biologically active compounds, it was thought to be interesting to synthesize compounds containing the features namely, having indole moiety incorporated with various heterocyclic rings and evaluated their antimicrobial and anti-inflammatory activities.
6.3 Objectives of the study
  1. To achieve the synthesis of some novel indole derivatives.
  2. The purity and progress of the reactions will be monitored by micro TLC.
  3. The purification of the compounds will be carried by purification methods like recrystallization and column chromatography (if needed) by using suitable solvents.
  4. To characterize the structures of newly synthesized compounds by IR, NMR, mass spectra and elemental analysis.
  5. To evaluate the biological activities of the newly synthesized compoundsand structure activity relationship will be studied.
  6. To publish the research work in peer reviewed journals.

7. / Materials and methods:
7.1 Sources of data
Chemical Abstracts
Indian Journal of Chemistry
Indian Journal of Heterocyclic Chemistry
Journal of Heterocyclic Chemistry
Bioorganic & Medicinal Chemistry
European Journal of Medicinal Chemistry
Helinet etc.
7.2 Method of collection of data
All the chemicals would be purchased from Merck Specialities Pvt. Limited, Mumbai, Himedia Laboratories Pvt. Limited Mumbai and Alfa Aesar-A Johnson Matthey Company, Chennai. Analytical TLC would be performed on Silica Gel F254 plates (Merck) with visualization by UV light. Melting point would be determined in open capillaries on a Thermonik melting point apparatus, Mumbai, India. The IR spectra (KBr, Max, cm-1) would be recorded on Brucker FTIR spectrophotometer. 1H-NMR ( ppm, CDCl3/ DMSO- d6) spectra would be recorded using Brucker WM-400 spectrometer with TMS as internal standard. Mass spectra would be recorded on Micromass Q-TOF and Shimadzu LCMS 2010A Mass spectrometer. Microbial strains would be procured from Institute of Microbial Technology, Chandigarh.
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
References:
  1. P.K. Dubey and Balaji Babu; Synthesis of 2-Heteryl substituted indoles. Indian J. Heterocl Chem 2007 16: 357-360.
  2. Kakul Husain, Mohammad Abid and Amir Azam; Synthesis, characterization and antiamoebic activity of new indole-3-carboxaldehyde thiosemicarbazones and their Pd (II) complexes. Eur. J. Med. Chem.200742: 1300-1308.
  3. C. Gilles Bignan, Kathleen Battista, J. Peter Connolly, J. Michael Orsini, Jingchun Liu, A. Steven Middleton and B. Allen Reitz; 3-(4-Piperidinyl)indoles and 3-(4-piperidinyl)pyrrolo-[2,3-b]pyridines as ligands for the ORL-1 receptor.Bioorg. Med. Chem. Lett 2006 16: 3524-3528.
  4. Yuichi Sugimoto, Atsushi Shimizu, Tetsuya Kato, Atsushi Satoh, Satoshi Ozaki, Hisashi Ohta and Osamu Okamoto; Design, synthesis, and biological evaluation of indole derivatives as novel nociceptin/orphanin FQ (N/OFQ) receptor antagonists.Bioorg. Med. Chem. Lett 2006 16: 3569-3573.
  5. G.P. Kalaskar, M. Girisha, M.G. Purohit, B.S. Thippeswamy and B.M. Patil;Synthesis and evaluation of in vivo anti-inflammatory activity of indole-3-aceetic acids.Indian J. Heterocl Chem 2007 16: 325-328.
  6. Deepa Sinha, Anjani K. Tiwari, Sweta Singh, Gauri Shukla, Pushpa Mishra, Harish Chandra and Anil K. Mishra: Synthesis, characterization and biological activity of Schiff base analogues of indole-3-carboxaldehyde. Eur J Med Chem, Article in Press.
  7. G.Manjunath Bhovi and S. Guru Gadaginamath; Synthesis and antimicrobial activity of some new 1-[2-phenylthioethyl] 1-[2-phenoxyethyl]-3-ethoxycarbonyl-5-methoxy-2-methylindoles/benz [g] indoles.Indian J. Heterocl Chem 2004 13: 293-296.
  8. G.S. Gadaginamath, S.R. Pujar, M.G. Bhovi and C.M. Kamanavalli ;Synthesis and antimicrobial activity of some new 3-acetyl-5-(3-methyl-5-hydroxypyrazol-4-yl) oxy-2-methylindoles. Indian J. Heterocl Chem 2004 13: 209-212.
  9. R.S. Gani, S.R. Pujar and G.S. Gadaginamath; Chemoselective reaction of indole dicarboxylate towards hydrazine hydrate: Synthesis and antimicrobial activity of some new oxadiazolyl methoxyindole derivatives Indian J. Heterocl Chem 2002 12: 25-28.
  10. S.Dundappa Danawade, A V Raghu and S .Guru Gadaginamath; Synthesis and antimicrobial activity of novel linearly fused 5-substituted- 7-acetyl-2,6-dimethyloxazolo[4,5-f]indoles.Indian J. Heterocl Chem 2007 46B: 690-693.
  11. N. Vijai Pathak, Ragini Guptha, Meenu Garg and Ashok Kumar; Mass spectral studies and anti-inflammatory activity of some bis (92,2’=diaryl-3,3’-alkylidene/arylidene/heteroarylidene) indoles Indian J. Heterocl Chem 2003 13: 159-162.


9. Signature of the candidate:

10. Remarks of the guide: Recommended
11. Name and Designation of:
11.1 Guide Dr. VINOD MATHEW
Asst. Professor
Department of Pharmaceutical Chemistry
Acharya & B.M. Reddy College of Pharmacy
Bangalore-90.
11.2 Signature

11.3 Co-Guide Mr. ZARANAPPA
11.4 Signature

11.5 Head of the department Dr. VINOD MATHEW
Asst. Professor
Department of Pharmaceutical Chemistry
Acharya & B.M. Reddy College of Pharmacy
Bangalore-90.
11.6 Signature

12 Remarks of the Principal:

12.1 Name of the principal: Dr. Divakar Goli
Acharya & B.M. Reddy College of Pharmacy
Bangalore-90.
12.2 Signature