“SYNTHESES AND CHARACTERIZATION OF SOME NEW IMIDAZOLES AND THIOPHENES FOR THEIR IN-VITRO

ANTICANCER AND ANTIMICROBIAL SCREENING”

SYNOPSIS FORM.PHARM. DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCESKARNATAKA

BYMr. ALAKESH DEBNATH

I M.PHARMDEPARTMENT OF PHARMACEUTICAL CHEMISTRY

PES COLLEGE OF PHARMACYBANGALORE-560 050

(2012-2014)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. Name of the candidate and address

Mr. ALAKESH DEBNATH Ι. M. PHARM(PHARMACEUTICAL CHEMISTRY)PES COLLEGE OF PHARMACYHANUMANTHANAGARBANGALORE-560 050

PERMANENT ADDRESS:NETAJEE ROADP.O. ALIPURDUARDIST. JALPAIGURIPIN: 736121STATE: WEST BENGAL

2. Name of the institution PES COLLEGE OF PHARMACYHANUMANTHANAGARB.S.K.1st STAGEBANGALORE:-560 050

3. Course of the study MASTER OF PHARMACY (PHARMACEUTICAL CHEMISTRY)

4. Date of Admission 22 JUNE, 2012

5. Title of the topic:

“SYNTHESES AND CHARACTERIZATION OF SOME NEW IMIDAZOLES AND THIOPHENES FOR THEIR IN-VITRO ANTICANCER AND

ANTIMICROBIAL SCREENING”

1 2

6. BRIEF RESUME OF THE INTENDED WORK:

6.1 Need for the study:

ANTICANCER ACTIVITY OF IMIDAZOLE & THIOPHENES:

Cancer is a major worldwide health problem which is the second leading cause of mortality in developed countries and most frightening disease in humans. Improvements in treatment and prevention have led to a decrease in cancer deaths, but the number of new diagnoses continues to rise. Treatment of cancer cells with agents that interfere with microtubule assembly causes mitotic arrest and eventually cell death.

Development of anticancer drugs with fewer or no side effects is important for the treatment of cancer. The search for such potential anticancer drugs have led to the discovery of synthetic small molecules with anti-carcinogenic activity and limited harmful side effects particularly with respect to the immune system.

The tubulin binding agents interact with the tubulins on the binding sites and cause aberrations in the tubulin assembly kinetics and thus altered stabilities of the microtubule structure. A number of microtubule-targeted tubulin binding agents are clinically effective drugs in cancer treatment. Imidazole a five membered heterocycle having three carbon atoms, two nitrogen atoms and two double bonds having efficient anticancer, antimicrobial , anti-inflammatory, , mutagenic and antimalarial activity.

The imidazole ring is a constituent of several important natural products, including purine, histamine, histidine and nucleic acid. Being a polar and ionisable aromatic compound, it improves pharmacokinetic characteristics of lead molecules and thus used as a remedy to optimize solubility and bioavailability parameters of proposed poorly soluble lead molecules. Imidazole derivatives have occupied a unique place in the field of medicinal chemistry. The incorporation of the imidazole nucleus is an important synthetic strategy in drug discovery. The high therapeutic properties of the imidazole related drugs have encouraged the medicinal chemists to synthesize a large number of novel chemotherapeutic agents.

Thiophene belongs to a class of heterocyclic compounds containing a five membered ring made up of one sulphur as heteroatom with the formula C4H4S. Thiophene and its derivatives exist in petroleum or coal.Various substituted and condensed Thiophenes have been reported to possess an array of pharmacological & biological properties including anticancer, anticonvulsant,

antioxidant, anti-inflammatory, analgesic, antibacterial, antifungal and so on.

ANTIMICROBIAL ACTIVITY OF IMIDAZOLE & THIOPHENES:

Microbes are causative agents for various types of disease like pneumonia, amoebiasis,

typhoid, malaria, common cough and cold various infections and some severe diseases like

tuberculosis, influenza, syphilis, and AIDS as well.

Antimicrobial drugs are effective in the treatment of infections because of their selective toxicity-

the ability to kill an invading microorganism without harming the cells of the host. In most

instances, the selective toxicity is relative, rather than absolute, requiring that the concentration of

the drug be carefully controlled to attack the microorganism while still being tolerated by the

host. During the past decade, imidazole derivatives have occupied a unique place in the field of

medicinal chemistry. They have wide range of biological activities. They are well known

antibacterial, antiparasitic, anthelmintic ,analgesics, anti-inflammatory, , platelet aggregation

inhibitors and antiepileptic agents.

Various approaches were made to check the role of thiophene moiety as antimicrobial agent from

the discovery of molecule to the present scenario. Many therapeutic agents having thiophene

moiety have been developed possessing antimicrobial activity. In view of the above mentioned

findings and as continuation of our effort  and  to identify new candidates that may be value

designing new, potent, selective and less toxic antimicrobial agents.

6.2 REVIEW OF THE LITERATURE :

6.2.1 References pertaining to Imidazole :

For Anticancer Activity:

1. Ahmed Kamal et al. (1) reported the synthesis and evaluation of some clubbed imidazoles like 5-Methyl-2-[3,4,5-trimethoxy(1,1';4',1'') terphenyl] -1H-benzo [d] imidazole for its anticancer activity as tubulin polymerization inhibitor. [2012]

(1)

2. Karlo Wittine et al. (2) reported the synthesis and anticancer activity of 1-[2-(3,4-Bis-benzyloxy-5-oxo-5H-furan-2-ylidene)-ethyl]-1H-imidazole-4,5-dicarboxylic acid dimethyl ester derivative. [2012]

(2)

3. Soroor Soraya and Seyed (3) Sina Soraya reported the anticancer activity of 1-(4-chlorobenzylideneamino)-4-phenyl-1H-imidazol-2-amine. [2012]

(3)

4. Subhas S. Karki et al. (4) synthesized and studied the vitro anticancer activity of 2-Benzyl-5-

formyl-6-(4'-fluorophenyl)-imidazo[2,1-b][1,3,4]thiadiazole as potent anticancer agent. [2011]

(4)

5. Rodrigo Abonia et al.(5) synthesized some novel 1,2,5-trisubstituted benzimidazoles as potential antitumor agents like Methyl 1-(5-tert-butyl-1H-pyrazol-3-yl)-2-(4-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate [2011].

(5)

6. Potent anticancer activity of 5-Bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b] [1,3,4] thiadiazole was reported by Malleshappa N. Noolvi et al. (6) [2011].

(6)

7. Jianjun Chen et al.(7) reported the Synthesis and anticancer activity of novel 2-aryl-4- benzoyl-imidazole derivatives targeting tubulin polymerization like Methyl-2-(p-tolyl)-1H-imidazol-4-yl(3,4,5 trimethoxyphenyl)methanone. [2011].

(7)

8. Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents like (4-Fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone. By Jianjun Chen et al. (8) [2011]

(8)

9. 1-(Benzylideneamino)-4-phenyl-1H-imidazol-2-amine was reported by Wen-Tai Li,et al.(9) as Orally Active Anticancer Agent. [2010]

(9)

For Antimicrobial Activity:

10. Xian-Yu Sun et al.(12) reported the antibacterial activity of of 7-alkyloxy-4,5-dihydro imidazo[1,2-a]quinoline derivatives like 7-Heptyloxy-4,5-dihydro-imidazo[1,2 a]quinoline.[2012]

(10)11. Jawaharmala et al.(10) reported the antimicrobial activity of some imidazole derivatives like 2-(2-chlorophenyl)-1-phenyl-1H-phenanthro[9,10-d] imidazole. [2012]

(11)

12. Shailesh P. Zala et al.(11) synthesized some imidazoles like 2-(p-toluidino)-1-(2,4-diphenyl-1H-imidazol-1-yl)ethanone to prove its antimicrobial activity.[2012]

Ghhh11 (12)

13. Christina Ruby Stella.P et al.(13) reported the anti-microbial evaluationof newly synthesized imidazole derivatives like 2-amino-5-(4,5-dihydro -1H-imidazol-2-ylthio) benzoicacid.[2012]

(13)

14. Namita Gupta and D.P.Pathak(14) reported the antimicrobial activity of N-substituted imidazole like N- cyclohexyl-2-(1H-imidazol-1yl) acetamide.[2011]

(14)

6.2.2 References pertaining to Thiophenes:

For Anticancer Activity:

15. Nagendra Kumar Kaushik et al.(15) reported the Synthesis and Anticancer Activity of Di(3-thienyl)methanol.[2012]

(15)

16. N.Sivasubramanian et al.(16) reported the Synthesis, Characterization, Anti-Microbial and Anti-Cancer Activity of Novel Heterocyclic System .[2012]

(16)

17. Synthesis of Annulated Thiophene Derivatives like 3-benzoyl-2-phenylhydrazono-4-imino-4,5,6,7-

tetrahydrobenzo[b] thieno[2,3-d]pyrimidine and Their Antitumor Evaluations was reported by Karam Ahmed El-Sharkawy1 et al.(17) [2012]

(17)

18. Hassan A. El-Sayed et al. (18) reported the anticancer activity of 4-(4-chlorophenyl)-2-(2',3',4',6'-tetra-O-acetyl-b-D-galactopyranosyloxy)-6-(thien-2-yl)nicotinonitrile.[2011]

(18)

For Antimicrobial Activity:

19. Synthesis and Antimicrobial Studies of Some Novel Bis-[1,3,4]thiadiazole and Bis-thiazole Pendant to Thieno[2,3-b]thiophene Moiety like 3,3′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(3-oxo-2-(4-(2-oxo-2H-chromen-3-yl)-3- phenylthiazol-2(3H)-ylidene)propanenitrile) was reported by Nabila Abdelshafy Kheder et al. (19) [ 2012 ]

(19)

20. Yerra Rajeshwar et al. (20) reported the antimicrobial activity of Thieno[2,3-d] pyrimidine like (E)-N-(4-chlorobenzylidene)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine. [2012]

(20)

21. Mohammad asif iqbal et al. (21) reported the antimicrobial screening of some novel substituted Thiophenes like (E)-2-(4-methoxybenzylideneamino)-N-(furan-2-ylmethyl)-4,5-dimethylthiophene-3-carboxamide.[2012]

(21)

22. Hala M. Aly et al.(22) reported the design and synthesis of some new thiophene,

thienopyrimidine derivatives like ethyl 2-amino-4-(2-methyl-5-oxo-1-phenyl-2,5-dihydro-

1H-pyrazol-4-ylamino)thiophene-3-carboxylate of antipyrine as potential antimicrobial

agents. (2011)

(22)

23. M.A. Gouda et al. (23) reported the synthesis and antimicrobial activities of some new thiazole

and pyrazole derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety. (2010)

(23)

6.3 SCHEMES

6.3.1 SCHEME I

Synthesis of new imidazole derivatives

6.3.2 SCHEME II

Synthesis of new Thiophene derivatives

6.4 OBJECTIVES OF THE STUDY:

1. To achieve the syntheses of some new Substituted Thiophenes and Imidazoles adopting standard protocols.

2. The purity and progress of the reactions will be monitored by TLC. 3. The purification of the compounds will be carried out by recrystallization using suitable solvents.

4. To characterize the structures of newly synthesized compounds by UV, IR, NMR, CHN

analysis and MASS spectra.5. To evaluate the antimicrobial and anticancer activity of the title compounds by standard

protocols to study the structure-activity relationships and to optimize the structure.6. To publish the research work in peer reviewed journals.

7.1 MATERIALS AND METHODS:

Chemicals and other reagents will be purchased from standard companies. The progress of the reactions will be monitored by micro thin layer chromatography. The standard protocols will be followed for purification of the products. Structures of the synthesized molecules will be confirmed by the analytical and spectral data. The biological screening results will be used to study structure-activity relationships.

7.2 Sources of data:

IISC LIBRARY, BANGALOREPESCP LIBRARY, BANGALORERGUHS DIGITAL LIBRARY (Helinet)CENTRAL COLLEGE LIBRARY, BANGALORE

7.3 Method of collection of data:Chemical Abstracts, Journals like Indian Journal of Chemistry, Journal of Medicinal Chemistry, Indian Journal of Heterocyclic Chemistry, Journal of American Chemical Society, Indian Journal of Pharmaceutical Sciences, International journal of Bioscience, Asian Journal of Medicinal Chemistry, Journal of Organic chemistry, European Journal of Medicinal Chemistry, Tetrahedron, Bioorganic & Medicinal Chemistry and Helinet.

7.4 PHARMACOLOGICAL EVALUATION:

Antimicrobial activity will be evaluated by using Cup-Plate Method. Anticancer activity will be evaluated by using MTT assay on different cell lines.

7.5 Does the study require any investigation or interventions to be conducted on patients or other humans or animals? -NO-

7.6 Has ethical clearance been obtained from your institution in case of 7.4?

-NOT APPLICABLE-

8. LIST OF REFERENCES:

1. Kamal A, Reddy MK, Shaik TB, Rajender, Srikanth YV, Reddy VS, et al. Synthesis of terphenyl benzimidazoles as tubulin polymerization inhibitors. Eur J Med Chem. 2012 Apr;50:9-17.

2. Wittine K, Stipkovic Babic M, Makuc D, Plavec J, Kraljevic Pavelic S, Sedic M, et al. Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-

HCV and antitumor activity evaluations. Bioorg Med Chem. 2012 Jun 1;20(11):3675-85.

3. Soraya S and Soraya S.S. Computational Studies on Effects of 1-(4-Chlorobenzylideneamino)- 4-Phenyl-1HImidazol-2-Amine as an Anticancer Drug on DNA.International Journal of Bioscience, Biochemistry and Bioinformatics.2012; Vol. 2, No. 2:126-130.

4. Karki SS, Panjamurthy K, Kumar S, Nambiar M, Ramareddy SA, Chiruvella KK, et al. Synthesis and biological evaluation of novel 2-aralkyl-5-substituted-6-(4'-fluorophenyl)-imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent anticancer agents. Eur J Med Chem. 2011 Jun;46(6):2109-16.

5. Abonia R, Cortes E, Insuasty B, Quiroga J, Nogueras M, Cobo J. Synthesis of novel 1,2,5-trisubstituted benzimidazoles as potential antitumor agents. Eur J Med Chem. 2011 Sep;46(9):4062-70.

6. Noolvi MN, Patel HM, Singh N, Gadad AK, Cameotra SS, Badiger A. Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives. Eur J Med Chem. 2011 Sep;46(9):4411-8.

7. Chen J, Li CM, Wang J, Ahn S, Wang Z, Lu Y, et al. Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl-imidazole derivatives targeting tubulin polymerization. Bioorg Med Chem. 2011 Aug 15;19(16):4782-95.

8. Chen J, Wang Z, Li CM, Lu Y, Vaddady PK, Meibohm B, et al. Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents. J Med Chem. 2010 Oct 28;53(20):7414-27.

9. Li WT, Hwang DR, Song JS, Chen CP, Chuu JJ, Hu CB, et al. Synthesis and biological activities of 2-amino-1-arylidenamino imidazoles as orally active anticancer agents. J Med Chem. 2010 Mar 25;53(6):2409-17.

10. Sun X.Y, ,Wu R, Wen X, Guo L, Zhou C.P, Li J, et al. Synthesis and evaluation of antibacterial activity of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline

derivatives.European Journal of Medicinal Chemistry. (2013) ; 60 :451-455

11. Jawaharmal, Lamba H.S., Narwal S, Singh G, Saini D.R, Kaur A , et al. Synthesis of Novel Imidazole Compounds and Evaluation of Their Antimicrobial Activity. Indo Global Journal of

Pharmaceutical Sciences. 2012; 2(2): 147-156.

12. . Zala S.P, Badmanaban R., Sen D.J and Patel C.N. Synthesis and biological evaluation of 2,4,5-triphenyl-1H-imidazole-1-yl Derivatives. Journal of Applied Pharmaceutical Science. 2012 June ;02 (07): 202-208.

13. Christina Ruby Stella.P, Rajam S, Venkatraman.B.R. Characterization and anti-microbial evaluation of newly synthesized imidazole derivatives. International Journal of ChemTech Research. 2012;Vol.4, No.4: pp 1447-1450.

14. Gupta N, Pathak DP. Synthesis and Evaluation of N-substituted Imidazole Derivatives for Antimicrobial Activity. Indian J Pharm Sci. 2011 Nov;73(6):674-8.

15. Kaushik NK, Kim HS, Chae YJ, Lee YN, Kwon GC, Choi EH, et al. Synthesis and anticancer activity of di(3-thienyl)methanol and di(3-thienyl)methane. Molecules. 2012;17(10):11456-68.

16. Sivasubramanian N, Reddy M.V, Aravinda M,,.Sravanthi R And .Sirisha S. Synthesis, Characterization, Anti-Microbial And Anti-Cancer activity of novel heterocyclic system containing bridgehead nitrogen atom. Chemical Science Transactions.2012;1(2):401-409.

17. El-Sharkawy K.A, El-Sehrawi H.M, Ibrahim R.A. The Reaction of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophenes with Benzoyl-Isothiocyanate: Synthesis of Annulated Thiophene Derivatives and Their Antitumor Evaluations. International Journal of Organic Chemistry.2012;2.126-134.

18. El-Sayed HA, Moustafa AH, Haikal Ael F, Abu-El-Halawa R, El Ashry el SH. Synthesis, antitumor and antimicrobial activities of 4-(4-chlorophenyl)-3-cyano-2-(beta-O-glycosyloxy)-6-(thien-2-yl)-nicotinonitrile. Eur J Med Chem. 2011 Jul;46(7):2948-54.

19. Kheder NA, Mabkhot YN. Synthesis and Antimicrobial Studies of Some Novel Bis-[,,]thiadiazole and Bis-thiazole Pendant to Thieno[2,3-b]thiophene Moiety. Int J Mol Sci. 2012;13(3):3661-70.

20. Rajeshwar Y, Naresh.K, Jayaveera K.N.Synthesis and Antimicrobial Studies of Some Novel

Thieno[2,3-d]pyrimidine derivatives.International Journal of PharmTech Research. 2012 April-June ;Vol.4, No.2:pp 648-654.

21. Iqbal M.A, Satyendra D , Apurba T , Patel M, Monika K, Girish K et al . Synthesis and Antimicrobial screening of some Novel Substituted Thiophenes. Hygeia journal for drugs & medicines.2012;vol4(1):112-118.

22. Aly HM, Saleh NM, Elhady HA. The design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents . Eur J Med Chem. 2011;46:4566-4572.

23. Gouda MA, Berghot MA, Abd El-Ghani GE, Khalil AM .The synthesis and antimicrobial activities of some new thiazole and pyrazole derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety. Eur J Med Chem.2010;45: 1338–1345.

9 Signature of the candidate :

(ALAKESH DEBNATH)

10. Remarks of the guide: FORWARDED WITH REQUEST FOR APPROVAL

11. Name and designation of: 11.1 GUIDE

11.2 SIGNATURE

Dr. J. SARAVANAN

Prof. and HODDepartment of Pharm Chemistry,

PES College of PharmacyBangalore- 560 050

11.3 CO-GUIDE

11.4 SIGNATURE

NOT APPLICABLE

11.5 HEAD OF THE DEPARTMENT

11.6 SIGNATURE

Dr. J. SaravananProf. and HOD

Department of Pharm Chemistry,PES College of Pharmacy

Bangalore- 560 050

12. 12.1 REMARKS OF THE PRINCIPAL:

12.2 SIGNATURE: Prof. Dr. S. Mohan Principal & Director, PES College of Pharmacy, Bangalore-560 050