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Synthesis and Evaluation of Novel 2-bromo- 4-nitro-1,
5-diphenyl substituted -1-H-imidazole Derivatives
as Anticancer Agent
R. D. Bendgude*1, M. S. Kondawar2, R. V. Hirave3andS. B. Patil4
1SVERI’S College of Pharmacy,
Pandharpur, Dist-Solapur, Maharashtra-413 304, INDIA.
2Appasaheb Birnale College of Pharmacy,
South Shivaji Nagar, Sangli, Maharashtra-416416, INDIA.
3Sahyadri College of Pharmacy Methwade,
Sangola Dist-Solapur, Maharashtra-413317, INDIA.
4Adarsh College of Pharmacy, Vita, Dist-Sangli, Maharashtra-415 311, INDIA.
email: ravibendagude@rediffmail.com
(Received on: April 14, 2018)
ABSTRACT
In present study a series of novel 2–bromo4nitro1, 5dihenyl substituted -1H-imidazole derivatives were screened for anticancer activity. The derivatives were screened for anticancer activity by using HeLa (Human cervical carcinoma) cell lines. In present study imidazole plays important role in the development of new drug for the treatment of cancer. Now a days a large no of novel drugs were discovered for treatment of cancer. The identification of novel anticancer agents that can potently target cancer cells. The new series of synthesized compounds IVd, IVh and A-IVj showed highly potent cytotoxic activity. The results indicating that newly synthesized compounds containing diphenyl substitution with 3-NO2, 4-NO2, 2-Cl and 4-OH were evaluated for their in vitro anticancer activity against HeLa cells. The synthesized imidazole derivatives gave significant cytotoxic activity against HeLa (human cervical carcinoma) cell lines when compared with 5-flurorouracil.
Keywords: Imidazole, schiffs base, TOSMIC, HeLa, and anticancer activity.
INTRODUCTION
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leading causes were lung cancer, stomach cancer, colo-rectal cancer, liver cancer and brest cancer2. The development of new anticancer therapeutic agents is one of the fundamental goals
in medicinal chemistry. In recent years there has been concerned search for the discovery and development of potent and selective anticancer agents. Imidazolesare probably the most well known heterocyclic which is common and important feature for variety of natural and medicinal agents. It has been reported that heterocyclic compounds containing nitrogen posses’ potent anticancer activity, Imidazole derivatives have occupied a unique place in field of medicinal chemistry. Imidazole or its derivatives have received significant attention owing to their diverse range of biological properties such as analgesics3, antiinflammatory4-7, antiparasitic8,
platelet aggregation inhibitors9, tuberculostatic10, anticancer11 and anticonvalsant.12-14 . Chemistry
Imidazoles are heterocyclic compounds containing five membered planar rings.Imidazole containing basically 3 C and 2 N atom present in 1st and 3rd position15. It is
soluble in water and other polar solvents. They are amphoteric and therefore can function as both acid and base. It also possesses weakly acidic property16. Imidazole derivatives are
reported to possess wide spectrum of activities. Imidazole forms the main structure of some well known components of human organism like amino acid histidine, purine histamine vit.B12 and biotin.
EXPERIMENTAL Material and Methods
All the reagents, chemicals and solvents were purched from S.D fine, sigma Aldrich and spectrochem Mumbai. All the anticancer cell lines were obtained from NCCS, Pune, India.
Table 1: Structures of synthesized compounds A-Iva- A-IVj
Code no. Structures Code no. Structures
A-IVa
N N O2N
F Br N C H3 C H3 A-IVf N N O2N
NO2 NO2 Br O H A-IVb N N O2N
NO2 NO2 Br O H A-IVg N N O2N
NO2 NO2 Br O2N
A-IVc
N N O2N
O2N
Br Cl NO2 A-IVh N N O2N
Br O H NO2 A-IVd N N O2N
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In vitro anticancer activity (MTT assay) 17
Cancer cell cultures
HeLa (human cervical carcinoma) cell lines were purchased from NCCS, Pune, India. All cell lines were grown and maintained in suitable (RPMI-1640) media and were grown and subcultured in medium supplemented with 10% fetal bovine serum,1% L-Glutamine.1% p penicillin streptomycin –streptomycin-amphotericine-B antibiotic solution. Cells were seeded in 25 cm2 tissue culture flasks at densities of 250000cell/flask .All cells were trypsinated using
trypsin-EDTA solution and seeded in 96 well plates.
The HeLa cell line was maintained in MEM medium supplemented with 10% fetal bovine serum. The cells were plated at a density of 2 × 105 cells per well in a 96-well
plate, and cultured for 24 h at 37 °C. The cells were subsequently exposed to various concentrations of desired sample (10-50 µg/ml). The plates were incubated for 24 h, and cell proliferation was measured by adding 10 µL of MTT (thiazolyl blue tetrazolium bromide) dye (5 mg/ml in phosphate-buffered saline) per well. The plates were incubated for a further 4 h at 37 °C in a humidified chamber containing 5% CO2. Formazan
crystals formed due to reduction of dye by viable cells in each well were dissolved in 200 µl DMSO, and read the plate on Elisa plate reader at 550 nm.
A-IVc
N N O2N
O2N Br Cl
NO2
A-IVh
N N O2N
Br O
H
NO2
A-IVd
N N O2N
NO2 Br N
C H3
C H3
A-IVi
N N
Br N
NO2
NO2 C
H3
C H3
A-IVe
N N O2N
Br O
H
A-IVj
N N O2N
F Br
O2N
In vitro anticancer activity (MTT assay) 17
RESULT
Table 3: Anticancer activity of tested compounds (A-IVa to A-IVj) against HeLa cell lines Compound IC50 (μg/mL)
A-IVa 44.25
A-IVb 50.33
A-IVc 54.32
A-IVd 35.05
A-IVe < 50
A-IVf 48.88
A-IVg 44.13
A-IVh 25.15
A-IVi 33.58
A-IVj 32.52
DISCUSSION
All the synthesized derivatives were screened for anticancer activity by using HeLa (Human cervical carcinoma) cell lines. The new series of synthesized compounds IVd, A-IVh and A-IVj showed highly potent cytotoxic activity. The compounds A-IVa, and A-IVc showed moderate anticancer activity .All the compounds have showed mild to moderate anticancer activity against HeLa Cancer cell.
CONCLUSION
A novel series of 2–bromo-4-nitro-1, 5-dihenyl substituted -1H-imidazole derivatives were synthesized.The synthesized compounds were active against HeLa cancer cell. Among all synthesized derivatives, compound A-IVd ,A-IVh and A-IVj were found to be most potent anticancer agents when compared with 5-flurorouracil as standard drug. The results indicated that p-dimethylamino, 2-fluoro, 4-OH and 2-nitro substitution enhances the potency of 1, 5 Diphenyl 2-nitro – 4 bromo substituted 1-H-imidazole moiety. From the above study it could be concluded that the synthesized derivatives could provide a search light for further development of novel potent anticancer agents and could used for the design and development of new anticancer agents. Structural activity relationship was reduced from biological results and will be used in future design and development of new active compounds. The possible improvements in the biological activity can be further achieved by slight modification in the substituent on the basic imidazole ring.
ACKNOWLEDGMENT
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