SYNTHESIS AND ANTITUMOR ACTIVITY OF OXAZOLE AND ISOXAZOLEDERIVATIVES

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560 041

By

Mr. AMIT GHOSH ,B.Pharm

Under the Guidance of

Mr. GURUBASAVARAJA SWAMY P.M

Professor

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. Amit Ghosh

#609, 7th cross, AGB Layout,
Hesaraghatta Main Road, Chikkabanawara Post,
Bangalore-560 090
2 / Name of the institution / ACHARYA & B.M. REDDY COLLEGE OF PHARMACY.
89/90, Soldevanahalli, Chikkabanavara post, Hesaraghatta main road,
Bangalore – 560090.
Office: 080-65650815.
3 / Course of study and subject /

MASTER OF PHARMACY

(PHARMACEUTICAL CHEMISTRY)
4 / Date of the admission / 1st December 2010
5 /

Title of the topic:

SYNTHESIS AND ANTITUMOR ACTIVITY OF OXAZOLE AND ISOXAZOLEDERIVATIVES.
6.0 / Brief resume of the intended work
6.1 : Need for study:
The field of medicinal chemistry is devoted to the discovery and development of new molecules for treating of many diseases. The process of establishing a new molecule is exceedingly complex and involves the talents of people from a variety of disciplines including from the field of synthetic chemistry especially from the field of heterocyclic chemistry.
The biological and pharmacological properties shown by the many heterocyclic molecules made them one of the prime interest of the many pharmaceutical industry and as a result of this, the synthesis of heterocyclic compounds bearing hetero atoms like nitrogen and oxygen emerged as powerful technique for generating lead molecules. Keeping in view the importance of heterocyclic molecule we plan to develop oxazoles and isoxazoles for their biological activity.
The biological significance of nitrogen containing heterocycles has received a considerable attention during recent years. In search of newer potential drugs the coupling of nitrogen containing heterocycles like oxazoles and isoxazoles with other bioactive molecules have been the most common approach in many medicinal chemist laboratory.
Oxazole26is the parent compound for a vast class ofheterocyclicaromaticorganic compounds. These areazoleswith an oxygen and a nitrogen separated by one carbon.

Isozazole1,23 is an azole with an oxygen atom next to nitrogen.

Both these nucleus are found in natural products like ibotenic acid 1 and they also exhibit potential therapeutic and many pharmacological activities.

A large number of natural products in particularly from marine2 environment containing oxazoline and isoxazoline heterocycles. For example Neopeltolide 2

which was isolated from deep water sponge of the family Neopeltidae2which is a potent
inhibitor of in-vitro proliferation of A-549 human lung carcinoma and they also inhibit the growth of the fungal pathogen Candida albicans .
Ariakemicins2, a polypeptide antibiotic which was discovered from marine bacteria of
Rapidithrix2species which inhibits the growth of Gram positive bacteria.

Natural aromatic nitrogen heterocycles with oxygen as in isoxazoles, oxazoles, 1,3,4-oxadiazoles, and 1,2,4-oxadiazoles obtained from curcumin22 (Curcuma longa) are of great importance since they have a variety of bioactivities. Following areexamples on oxazoles and isoxazoles that exhibit antibacterial activities :


Acivicin23 [(S)-Amino-((S)-3-Chlor-4,5-dihydro-5-isoxazol; AT-125; NSC-163501] is a fermentation product of Streptomyces sviceus which is active in a variety of mouse tumor models including leukemias, ovarian carcinoma, and the human breast tumor xenograft.
The drug is being introduced into clinical phase I studies under the sponsorship of the National Cancer Institute.

Acivicin
Marketed drugs containing oxazoles :24,25,26
Famoxadone is useful in agricultural applications as a soil disinfectant, fungicide and plant growth stimulator , supplied by Pharmachem ( Wuhan ) International Co. LTD .

Marketed drugs containing isoxazole24,25,26 :-
Leflunomide is used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. Marketed by Winthrop Pharmaceuticals UK Ltd.

Sulfafurazole and Zonisamide are used as sulfonamide antibacterial and antiepileptic respectively.

Keeping in view of biological importance of oxazoles and isoxazole derivatives and inspired from scope of research in this field, we have planned to carry out the research work on the synthesis of oxazoles and isoxazole derivatives from chalcone intermediate to explore their biological profile.
7.0 / 6.3 : Objectives of the study
  1. To synthesize some newer derivatives of oxazoles and isoxazoles. In the present research work a bio active chalcones were synthesized by treating different substituted aldehydes with a molecule bearing reactive acetyl group.
  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 in vivo anti-cancer activity.
  4. To publish the research works in peer reviewed journals.
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, Bio-organic and Medicinal Chemistry Letters, Acta crystallographica, through Helinet of RUGHS etc.
7.2 : Method of collection of Data :
A) Synthesis of the compounds:
Chemicals and other reagents required for the synthesis will be procured from standard company sources. Compounds will be synthesized by using standard procedures. The reactions will be monitored by TLC and purification of the compounds will be carried out by recrystallization method using suitable solvent.
Scheme 1

*TsNHOH – N-hydroxyl-4-toluene-sulphonamide
Scheme 2

R’



R /
R’-CHO / Different aldehydes

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