“SYNTHESES AND CHARACTERIZATION OF SOME NEW
IMIDAZOLES AND THIOPHENES FOR THEIR IN-VITRO
ANTICANCER AND ANTIMICROBIAL SCREENING”
SYNOPSIS FOR
M.PHARM. DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
Mr. ALAKESH DEBNATH
I M.PHARM
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
PES COLLEGE OF PHARMACY
BANGALORE-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 PHARMACY
HANUMANTHANAGAR
BANGALORE-560 050
PERMANENT ADDRESS:
NETAJEE ROAD
P.O. ALIPURDUAR
DIST. JALPAIGURI
PIN: 736121
STATE: WEST BENGAL
PES COLLEGE OF PHARMACY
HANUMANTHANAGAR
B.S.K.1st STAGE
BANGALORE:-560 050
MASTER OF PHARMACY
(PHARMACEUTICAL CHEMISTRY)
2. Name of the institution
3. Course of the study
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
O
N
CH
O
H
NHCH2
N
O
NH
N
R
S
NH
R
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 toxicitythe 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-[3,4,5trimethoxy(1,1';4',1'') terphenyl] -1H-benzo [d] imidazole for its anticancer activity as tubulin polymerization
inhibitor. [2012]
H3CO
H
N
H3CO
N
CH3
H3CO
H
(1)
2. Karlo Wittine et al. (2) reported the synthesis and anticancer activity of 1-[2-(3,4-Bis-benzyloxy-5oxo-5H-furan-2-ylidene)-ethyl]-1H-imidazole-4,5-dicarboxylic acid dimethyl ester derivative. [2012]
O
O
O
O
O
N
O
O
N
O
(2)
3. Soroor Soraya and Seyed (3) Sina Soraya reported the
chlorobenzylideneamino)-4-phenyl-1H-imidazol-2-amine. [2012]
N
anticancer activity of
N
N
Cl
NH2
(3)
1-(4-
4. Subhas S. Karki et al. (4) synthesized and studied the vitro anticancer activity of 2-Benzyl-5-formyl6-(4'-fluorophenyl)-imidazo[2,1-b][1,3,4]thiadiazole as potent anticancer agent. [2011]
F
N
S
N
N
O
(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)-1Hbenzo[d]imidazole-5-carboxylate [2011].
NH
N
N
Cl
O
N
O
(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].
Br
N
N
Cl
S
N
(6)
7. Jianjun Chen et al.(7) reported the Synthesis and anticancer activity of novel 2-aryl-4- benzoylimidazole derivatives targeting tubulin polymerization like Methyl-2-(p-tolyl)-1H-imidazol-4-yl(3,4,5
trimethoxyphenyl)methanone. [2011].
O
O
O
N
HN
O
(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]
F
O
N
HN
O
(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]
N
N
N
(9)
NH2
For Antimicrobial Activity:
10. Xian-Yu Sun et al.(12) reported the antibacterial activity of of 7-alkyloxy-4,5-dihydro imidazo[1,2a]quinoline derivatives like 7-Heptyloxy-4,5-dihydro-imidazo[1,2 a]quinoline.[2012]
N
N
O
(10)
11. Jawaharmala et al.(10) reported the antimicrobial activity of some imidazole derivatives like 2-(2chlorophenyl)-1-phenyl-1H-phenanthro[9,10-d] imidazole. [2012]
N
Cl
N
(11)
12. Shailesh P. Zala et al.(11) synthesized some imidazoles like 2-(p-toluidino)-1-(2,4-diphenyl-1Himidazol-1-yl)ethanone to prove its antimicrobial activity.[2012]
N
N
O
NH
H3C
Ghhh11
(12)
13. Christina Ruby Stella.P et al.(13) reported the anti-microbial evaluation
of newly synthesized imidazole derivatives like 2-amino-5-(4,5-dihydro -1H-imidazol2-ylthio) benzoicacid.[2012]
HO
O
NH2
NH
N
S
H
(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]
N
O
N
N
H
(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(3thienyl)methanol.[2012]
OH
S
S
(15)
16. N.Sivasubramanian et al.(16) reported the Synthesis, Characterization, Anti-Microbial and AntiCancer Activity of Novel Heterocyclic System .[2012]
CH3
N
O
N
S
N
S
(16)
17. Synthesis of Annulated Thiophene Derivatives like 3-benzoyl-2-phenylhydrazono-4-imino-4,5,6,7tetrahydrobenzo[b] thieno[2,3-d]pyrimidine and Their Antitumor Evaluations was reported by Karam
Ahmed El-Sharkawy1 et al.(17) [2012]
O
HN
HN
N
S
N
N
H
(17)
18. Hassan A. El-Sayed et al. (18) reported the anticancer activity of 4-(4-chlorophenyl)-2-(2',3',4',6'-tetraO-acetyl-b-D-galactopyranosyloxy)-6-(thien-2-yl)nicotinonitrile.[2011]
O
S
O
N
O
O
O
O
O
O
O
Cl
N
O
(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 ]
O
N
N
S
N
S
S
N
O
S
O
O
O
O
(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]
N
CH
S
N
N
(20)
Cl
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)-4,5dimethylthiophene-3-carboxamide.[2012]
O
O
CH2
N
H
N
S
CH
(21)
OCH3
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-dihydro1H-pyrazol-4-ylamino)thiophene-3-carboxylate of antipyrine as potential antimicrobial
agents. (2011)
O
Ph
COOC2H5
N
HN
N
NH2
S
(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)
H2N
C
O
N
N
NH
S
CN
C
N
O
N
HN
Ph
NH2
(23)
6.3
SCHEMES
6.3.1 SCHEME I
Synthesis of new imidazole derivatives
NH2
HN
H2N
NH
NH
+
O
CHO
HC
HN
N
furan-2-carbaldehyde
H 2N
O
. H2CO3
OR
+
Furfuraldehyde
Aminoguanidine bicarbonate
Br
O
OR
2-bromo-1-phenylethanone
N
2-Bromoacetophenone
CH
O
H
N
NH2
N
6.3.2
SCHEME II
Synthesis of new Thiophene derivatives
CNCH2COOC2H5
+
H2NH2C
ethyl 2cyanoacetate
O
furan-2-ylmethanamine
O
H
+
O
H
HN
4-methylpentan-2-one
O
S, (Et)2NH,
C2H5OH
NCH2C
2-cyano-N-(furan-2-ylmethyl)
acetamide
O
NHCH2
O
S
NH2
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, BANGALORE
PESCP LIBRARY, BANGALORE
RGUHS 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?
-NO7.6 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, antiHCV 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[2,1b][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 1,2,5trisubstituted 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-4benzoyl-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 2,4,5triphenyl-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-4,5,6,7tetrahydrobenzo[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 AprilJune ;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 4,5,6,7tetrahydrobenzothiophene moiety. Eur J Med Chem.2010;45: 1338–1345.
9
Signature of the candidate :
(ALAKESH DEBNATH)
10. Remarks of the guide:
11. Name and designation of:
11.1 GUIDE
FORWARDED WITH REQUEST
FOR APPROVAL
Dr. J. SARAVANAN
Prof. and HOD
Department of Pharm Chemistry,
PES College of Pharmacy
Bangalore- 560 050
11.2 SIGNATURE
11.3 CO-GUIDE
NOT APPLICABLE
11.4 SIGNATURE
11.5 HEAD OF THE DEPARTMENT
Dr. J. Saravanan
Prof. and HOD
Department of Pharm Chemistry,
PES College of Pharmacy
Bangalore- 560 050
11.6 SIGNATURE
12. 12.1 REMARKS OF THE PRINCIPAL:
12.2 SIGNATURE:
Prof. Dr. S. Mohan
Principal & Director,
PES College of Pharmacy,
Bangalore-560 050