Synthesis and pharmacological evaluation of

benzothiazole derivatives

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore - 560 041

By

Mr. KIRAN. B. DHAMAK B.Pharm

Under the Guidance of

Dr. Vinod Mathew Ph.D

Asst. Professor & HOD

Department of Pharmaceutical Chemistry,

Acharya & B.M.Reddy College of Pharmacy,

Soldevanahalli, Chikkabannavara (Post)

Hesaraghatta Main Road, Bangalore - 560 090

2007-08

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 /

Name of the candidate and address

/

KIRAN. B. DHAMAK

142,3rd CROSS,
BEHIND WIDIA SCHOOL BUS STOP,
NAGASANDRA POST,
HESARAGHATTA MAIN ROAD,
BANGALORE - 560 073.
2 / Name of the institution /

ACHARYA & B.M. REDDY COLLEGE OF PHARMACY

SOLDEVANAHALLI,
CHIKKABANNAVARA (Post), HESARAGHATTA MAIN ROAD,
BANGALORE - 560 090.
3 / Course of study and subject /

MASTER OF PHARMACY

(PHARMACEUTICAL CHEMISTRY)
4 / Date of the admission / JUNE 2007
5 /

Title of the topic

Synthesis and pharmacological evaluation of benzothiazole derivatives.
6 /

Brief resume of the intended work

6.1 Need for the study
Research program for the discovery of new antimicrobial drug for improving the evaluation criteria are under way of many laboratories. Small and simple heterocyclic structures often have surprising complex biological properties. Benzothiazole plays a vital role in the field of medicinal chemistry. The literature study reveals that benzothiazole moiety is an important pharmacophore and exhibits outstanding biological activities.
Benzothiazole derivatives have been shown to possess a variety of pharmacological properties viz; antimicrobial, antibacterial, antifungal, anti-inflammatory, analgesic, CNS depressant, anticonvulsant and antitubercular activities. Being a heterocyclic compound, benzothiazole finds use in the research as a starting material for the synthesis of larger, usually bioactive structures. Its aromaticity makes it relatively stable, although as a heterocyclic, it has reactive sites which allow for funtionalization.
Many dyes such as Primuline, Thioflavin (for histology staining) and pharmaceutical drug such as Riluzole (to treat amyotrophic lateral sclerosis), Ethoxzolamide (in the treatment of glaucoma, duodenal ulcer and as a diuretic) have benzothiazole as a structural moiety.
The imidazole nucleus and its related structures are known to play a crucial role in the structure and functioning of a number of biologically important molecules. Among them, benzimidazole is one of the most important heterocyclic rings which showed different biological activities, for example antibacterial, antifungal, antiparasitic and antiviral.
Imidazole derivatives have been extensively studied since the discovery of the broad spectrum antimycotic activity of bifonazoie, clotrimazole, econazole, isoconazole, ketoconazole, miconazole and tioconazole, which are at present very important chemotherapeutic agents.
Thiazoles and their derivatives have attracted continuing interest over the years because of their varied biological activities, recently found application in drug development for the treatment of allergies, hypertension, inflammation, schizophrenia, bacterial, HIV infections, hypnotics and more recently for the treatment of pain, as fibrinogen receptor antagonists with antithrombotic activityand as new inhibitors of bacterial DNA gyrase.
Triazoles are basic aromatic heterocyclic agents which are stable and the most recent addition to the list of antifungal drugs.Various 1,2,4-triazoles have been reported to possess varied pharmacological activities like antidepressant, antibacterial, antifungal, antitubercular, anticonvulsant, antioxidant, antitumor, anti-inflammatory, antiviral, insecticidal and sedative properties. Certain 1,2,4-triazoles also find applications in the preparation of photographic plates, polymers and as analytical reagents for the estimation of metals such as silver, copper and lead. Armed with such findings, 1,2,4-triazole nucleus would be incorporated into benzothiazole nucleus to transform them into better drugs.
In view of the above mentioned findings and our effortto identify new candidates that may be value in designing new, potent, selective and less toxic antimicrobial, anti-inflammatory and analgesic agents, we report in the present work the synthesis of some new benzothiazole derivatives possessing various biologically active heterocyclic rings like imidazole, benzimidazole, thiazole, triazole etc.
Following are the structures of some medicinal compounds having benzothiazole nucleus.


6.2 Review of literature
  1. K.G.Baheti, S.V. Kuberkar have synthesized 4H-pyrimido [2,1-b] benzothiazole-8
substituted-2-thiomethyl-3-cyano-4-ones by the reaction of 2-amino-6-substituted benzothiazole with ethyl-2-cyno-3,3-bismethylthio acrylate in the presence of dimethylformamide and anhydride potassium carbonate. The synthesized compounds were evalutated for their analgesic, CNS depressant and antimicrobial activity.
  1. Ms. S.B. Kapratwar, K.G. Baheti, S.V. Kuberkar have synthesized 3-substituted 1,2,4-triazolo(3,4-b) benzothiazoles and newly synthesized compounds were characterized on the basis of elemental analysis and spectral data.
  2. Sadique Akhtar Javed, Nadeem Siddiqui, Sushma Drabu studied the synthesis of some 2-[(4’-halophenyl) thioureido]-6-substituted benzothiazoles by refluxing equimolar quantity of 2-amino-6-substituted benzothiazole and 4-substituted phenylisothiocyanates. The compounds were evaluated for their antibacterial activity and some of these compounds showed moderate activity.
  3. Mahfuz Alam, Nadeem Siddiqui reported the synthesis of new benzothiazole incorporated sulphonamides by treating 2-(4-aminophenylsulphonamido)-6-halo/alkyl benzothiazoles with alkylisothiocyanates. The synthesized compounds were confirmed on the basis of their spectral data and were further evaluated for anticonvulsant activity.
  4. Wei Huang, Guang FuYang reported the synthesis of polyflurinated 2- benzylthiobenzothiazole under solvent free condition. The compounds were studied for antifungal activity and some of these synthesized compounds showed moderate activity.
  5. B. Shivkumar, K.Sojan Paul, R. Nagendra Rao, E. Jayachandran have synthesized some 6-fluoro-7-substituted- 1,2,3,4-tetrazolo(5,1-b) benzothiazole. The compounds were studied for their antibacterial and antifungal activities.
  6. B.M. Gurupadayya, M. Gopal, Basavaraja Padmashali, V.P. Vaidya reported the synthesis and antimicrobial, anti-inflammatory, analgesic activity of fluoro benzothiazoles.
  7. Sandhya Bawa, Harish Kumar have synthesized 6-fluoro-2-[4-formyl-3-(substituted phenyl) pyrazol-1-yl] benzothiazole by using Vilsmeier Haack reaction. The structures of the synthesized compounds have been established on the basis of elemental analysis and spectral data. All the compounds have been screened for their antibacterial activity.
  1. Benzothiazole: A new profile of biological activities has been studied by Rana Arpana, N Siddiqui, S A Khan. The synthesized benzothiazole showed interesting biological activities such as antitumor, antimicrobial, anthelmintic, antileishmanial, anticonvulsant and antiinflammatory.
  2. A new series of 2-amino [5’-(4-sulphonyl benzylidene)-2,4-thiazolidinedione]-6-fluoro benzothiazoles were synthesized by R. Shashikant Pattan, Amol Khade, P.D. Pawar, A.D. Taranalli, B.S. Kittur, S.D. Borkar. The structures of the compounds were confirmed by IR, NMR, mass spectra and elemental analysis. The title compounds were screened for their anti-inflammatory activity and some of these compounds have shown promising anti-inflammatory activity.
These observations prompted us to carry out the synthesis of some new substituted benzothiazole derivatives for their pharmacological activity.
6.3 Objectives of the study
1. To synthesize some novel benzothiazole derivatives.
2. The purity and progress of the reactions will be monitored by micro TLC.
3. Purification of the compounds will be carried by methods like recrystallization and column chromatography (if needed) by using suitable solvents.
  1. The newly synthesized compounds will be characterized by IR, NMR, mass spectra and elemental analysis.
  2. The newly synthesized compounds will be evaluated for their pharmacological activities and structure activity relationship will be studied.
  3. Publish the research work in peer reviewed journal.

7 / Materials and methods:
7.1 Sources of data
Chemical Abstracts
Indian Journal of Chemistry section B
Indian Journal of Heterocyclic Chemistry
Journal of Medicinal Chemistry
Journal of Heterocyclic Chemistry
Indian Journal of Pharmaceutical Sciences
European journal of medicinal chemistry
Bioorganic and Medicinal Chemistry Letters
Word wide web
J-Gate@ Helinet etc.
7.2 Method of collection of data
All the chemicals would be purchased from Merck Specialties 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
8 /

References:

  1. K.G. Baheti and S.V. Kuberkar; Synthesis and biological activity of 4H-pyrimido [2,1-b]benzothiazole-8-substituted-2-thiomethyl-3-cyano-4-ones. Indian J. of Heterocycl Chem 2003. 12:343-346.
  2. Ms. S.B. Kapratwar, K.G. Baheti and S.V. Kuberkar; Synthesis of 3-substituted 1, 2, 4-triazolo(3,4-b) benzothiazoles. Indian J. of Heterocycl Chem. 2004 13:241-244.
  3. Sadique Akhtar Javed, Nadeem Siddiqui and Sushma Drabu; Synthesis and antibacterial activity of some 2-[(4’-halophenyl) thioureido]-6-substituted benzothiazoles. Indian J. of Heterocycl Chem. 2004 13:287-288.
  4. Mahfuz Alam and Nadeem Siddiqui; Synthesis of new benzothiazole incorporated sulphonamides as potential anticonvulsants. Indian J. of Heterocycl Chem. 2004 13:361-364.
  5. Wei Huang, Guang FuYang; Microwave assisted, one pot synthesis and fungicidal activity of polyflurinated 2-benzylthiobenzothiazole. Bioorg.Medi.Chem.Lett. 2005 14:8280-8285.
  6. B. Shivkumar, Sojan K. Paul, R. Nagendra Rao and E. Jayachandran; Synthesis and microbiological evaluation of 6-fluoro-7-substituted-1,2,3,4-tetrazolo(5,1-b) benzothiazoles. Indian J. of Heterocycl Chem. 2005 15:71-72.
  7. B.M. Gurupadayya, M. Gopal, Basavaraja Padmashali & V.P. Vaidya; Synthesis and biological activities of fluoro benzothiazoles. Indian J. of Heterocycl Chem. 2005 15:169-172.
  8. Sandhya Bawa and Harish Kumar; Synthesis 6-fluoro-2-[4-formyl-3-(substituted phenyl) pyrazol-1-yl] benzothiazole as potential antimicrobial activity. Indian J. of Heterocycl Chem. 2005 14:249
  9. Rana Arpana, N Siddiqui, S A Khan ; Benzothiazoles: A new profile of biological activities. Indian J. Pharm. Sci. 2007 69:10-17.
  1. R. Shashikant Pattan, Amol Khade, P.D. Pawar, A.D. Taranalli, B.S. Kittur and S.D. Borkar; Synthesis of 2-amino [5’-(4-sulphonyl benzylidene)-2,4-thiazolidinedione]-6-fluoro benzothiazoles as anti inflammatory agents. Indian J. of Heterocycl Chem. 2007 16:299-300.

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  1. Wei Huang, Guang FuYang; Microwave assisted, one pot synthesis and fungicidal activity of polyflurinated 2-benzylthiobenzothiazole. Bioorg.Medi.Chem.Lett.2005 14:8280-8285.
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Signature of the candidate:

Remarks of the guide: Recommended

Name and Designation of:
11.1 Guide Dr. VINOD MATHEW
Asst. Professor & HOD
Department of Pharmaceutical Chemistry,
Acharya & B.M. Reddy College of Pharmacy
Bangalore-90.
11.2 Signature

11.3 Co-Guide
NIL
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

12.1 Remarks of the Principal: Recommended

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