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Synthesis of some new chalcone derivatives and evaluation of their Anticancer activity

Afzaye Rasool, Rakesh Panda and Dr. Monica Kachroo*

Department of Pharmaceutical Chemistry, Al-Ameen college of Pharmacy, Bangalore, 560027

Corresponding Author:
Dr. Monica Kachroo
Department of Pharmaceutical Chemistry
Al-Ameen college of Pharmacy, Bangalore, 560027
E-mail: [email protected]

Received Date: 01-06-2013; Accepted Date: 29-06-2013

Citation: Afzaye Rasool, Rakesh Panda, Dr. Monica Kachroo. “Synthesis of some new chalcone derivatives and evaluation of their Anticancer activity” Int. J. Drug Dev. & Res., July-September 2013, 5 (3): 309-315

Copyright: © 2013 Dr. MonicaKachroo et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

 

Abstract

Chalcones which are also known as α,β-unsaturated ketones is an important class of organic compounds and reported to possess a wide spectrum of biological activities such as antibacterial, antifungal, anticancer, anti-inflammatory etc. The biological activity of chalcone is mainly because of an enone pharmacophore in their structures, the importance of which is well documented in the literature. Although a number of drugs are available in the market, the thirst for discovering a new drug with better pharmacokinetic profile, lesser toxicity has become imperative for obvious reasons and also due to the fast development of microbial resistance towards existing molecules. Therefore in the present study some novel chalcones have been synthesized for biological activities like anti-cancer , antibacterial and antioxidant activity. Cyclic ketones having α-hydrogens was treated with various aromatic aldehydes in alcohol, in the presence of potassium hydroxide to form corresponding α,β-unsaturated compounds. The structures of these compounds are supported by their UV, IR, NMR and Mass spectral data. The compounds have been evaluated for their anti-cancer, antibacterial and antioxidant activities.

Keywords

Chalcones, anticancer, antibacterial, antioxidant.

Introduction

The chalcones are α, β-Unsaturated ketones containing the reactive keto ethylene group -COCH= CH-, the presence of α,β-Unsaturated carbonyl system in chalcone makes it biologically active. Some substituted chalcones and their derivatives have been reported to exhibit a wide variety of biological properties such as anthelmintic [1], anti-microbial [2], antimycobacterial [4], antifungal [5], anticancer [6-9], anti-oxidant [10], and antiinflammatory [11] activity etc.

In the present work attention has been focused on the synthesis of chalcones from various aldehyde moieties and its derivatives. The structure of various synthesized compound was assigned on the basis of UV, IR, 1H-NMR, 13C-NMR, and Mass spectral data. The synthesized compounds were further screened for anticancer, antibacterial and antioxidant activity.

Material and Method

➢ Melting points of the synthesized compound was determined using Thiele’s melting point apparatus and was found uncorrected.

➢ Purity of the compounds was checked by thin layer chromatography using silicagelG in solvent system n-hexane-ethyl acetate (3:1) and the sport were located under iodine vapour and UV light.

➢ The UV spectra of the synthesized compounds were recorded on UV–Visible spectrophotometer (model Shimadzu 8700) using alcohol and the values of wave length (λ max) were reported in nm.

➢ IR spectra of all compounds were recorded on FTIR spectrometer (model Shimadzu 8700) in the range of 400 -4000 using KBr.

1H NMR spectra were recorded on Amx - 400 MHz NMR spectrometer using CDCl3 and chemical shifts (δ) are reported in parts per million downfield using Tetramethylsilane (TMS).

13C NMR (400 MHz) spectra were recorded in deuterated CDCl3 in Amx-400 liquid state NMR spectrometer .Chemical shifts (δ) are reported in parts per million.

➢ Mass spectra were recorded on Mass spectrophotometer (model Shimadzu) by MS

image

Procedure for the preparation of 1-(4-Acetylphenyl)- pyrrolidine-2, 5-dione

4-Aminoacetophenone (0.01M), succinic anhydride (0.01M) and acetic acid (40 ml) was added in round bottom flask, refluxed for 2 hr and kept overnight, filtered and recrystalized from ethanol. The elution was done with nhexane: ethyl acetate (4: 1) crystallized from ethanol as white colour, yield 52 %, m.p 129- 131°C, Rf- 0.6 (structure-3)

Procedure for the preparation of 1-(4(3- Substituted phenyl) acryloyl)phenyl} pyrrolidine- 2, 5-dione

A mixture of 1-(4-acetyl-phenyl)-pyrrolidine-2, 5- dione (0.01M) and aryl aldehyde (0.01M) was stirred in ethanol (40 ml) and an aqueous solution of KOH (40%, 15 ml) was added to it. The stirring was continued for 6 hr and the mixture was kept overnight at room temperature and it was then poured into crushed ice and acidified with HCl. The solid separated was filtered and recrystallized from ethanol. (Table-1)

Procedure for the preparation of 1-{4[5- substitutedphenyl)-1H-pyrazol-3yl] phenyl} Pyrrolidine-2, 5 Dione.

A mixture of chalcone (0.01M), hydrazine hydrates (0.01M) and ethanol 25ml was refluxed for 12 hr .The mixture was concentrated by distilling out of the solvent under reduced pressure and poured into ice water. The precipitate obtained was filtered, washed and recrystalized with ethanol.

image

Compound Code R1 R2 R3 R4 Molecular formula Molecular weight M.P°C % of yield
1a OCH3   OCH3   C21H19NO5 365 147-148 62
1b   OCH3 OCH3 OCH3 C22H21NO6 395 161-163 91.4
1c   NO2     C19H14N2O5 350 158-160 78.2
1d Cl       C19H14O3NCl 339 137-138 95
1e OH     OCH3 C20H17NO5 351 142-144 92
1f     NO2   C19H14N2O5 350 132-134 92
1g     OH   C19H15NO4 321 162-164 91
1h     OC2H5   C21H19NO4 349 132-134 85
1i NO2       C19H14N2O5 350 96-98 75
1j Cl   Cl   C19H13O3NCl2 350 118-120 85
1k N(C2H5)2       C19H16N2O3 320 95-98 79

Table 1: Physiochemical parameters of 1-(4(3-Substituted phenyl) acryloyl)phenyl} pyrrolidine-2, 5 dione

image

Compound Code R1 R2 R3 R4 Molecular formula Molecular weight M.P°C % of yield
2a OCH3   OCH3   C21H19NO4 377 110-112 77.7
2b   OCH3 OCH3 OCH3 C22H21N3O5 407 110-112 21.1
2c   NO2     C19H14N4O4 362 110-112 81.2
2d Cl       C19H14N3O2Cl 361 115-120 32.3
2e OH     OCH3 C20H17N3O4 363 118-120 33.3
2f     OC2H5   C21H19N3O3 361 45-48 27

Table 2: Physiochemical parameters of Procedure of 1-{4[5-substitutedphenyl)-1H-pyrazol-3yl] phenyl} Pyrrolidine-2, 5 Dione.

Compound code λmax
(nm)
Mass m/e IR (KBr)
Vmax cm-1
1H NMR δ ppm 13C NMR
1a 365   3002( Ar C-H)
2927(Ali C-H)
1602(C=C)
1307(OCH3)
δ 7.5-8.13 4H, (m, 2H of ArH + 2H of CH=CH) ;
δ 6.40-6.7 3H (m, ArH of
dimethoxy benzene) ; δ 3.84-3.88 6H
(s,2xOCH3) ; δ 1.8 4H (s,
2xCH2 of succinimide)
 
1b 329   3100 (Ar C-H)
2935(Ali C-H)
1589(C=C)
1280 (OCH3 )
1178 (C-N)
δ 7.94 1H (s, CH=CH) ; δ
7.95 1H  (s, CO CH=CH)
;δ 7.2-7.82 4H (m ,ArH) ;δ 6.60-6.85 2H (m, ArH of
trimethoxy benzene) ;δ 3.8-3.9 9H (s, 3xOCH3); δ
1.8 4H (s, 2xCH2 of succinimide)
 
1d 317 395(M+2) 3059 (Ar C-H)
2923 (AliC-H)
1649 (C=O)
1608 (C=C)
1178 (C-N)
δ 8.17 1H (s, CH=CH); δ
8.09  1H  (s, CO CH=CH); δ 6.62-7.95 8H  (m,  ArH); δ 1.21-1.90  4H  (s, 2xCH2 of succinimide).
188.36          (C=Oenone),         151.56
(C=O,succinimide),       139.36     (Ci),
135.66,   131.61,   134.15,125.36 [(Ca),
(Cc) and (Ce), (Cd), (Cb) and (Cf) respectively of C6H4- succinimide].128.      13(Ch),      131.6,
131.07,  130.6,  128.74,  127.35  [(Ca’),
(Cb’),   (Cc’),   (Cd’   and   Ce’)   Cf’
respectively of o-Chloro C6H3]

Table 3: Spectral characteristics of 1-(4(3-Substituted phenyl) acryloyl)phenyl} pyrrolidine-2,5-dione.

Compound code λmax (nm) IR (KBr) Vmax cm-1
2a 314 3358(N-H)
1596(C=N)
2b 327 3361(N-H)
1600(C=N)
2c 327 3357(N-H)
1591(C=N)
2d 382 3342(N-H)
1612(C=N)
2e 522 3213(N-H)
1599(C=N)

Table 4: Spectral characteristics of 1-{4[5-substitutedphenyl)-1H- pyrazol3yl] phenyl} Pyrrolidine-2, 5-Dione.

Biological activity

1. Anticancer studies [6-9]:

➢ Method: Trypan blue exclusion method(Dalton lymphoma ascities)

➢ Animal used: Tumor bearing mice

➢ Chemical used: Phosphate buffered saline

Method

➢ Cells were aspirated from the peritoneal cavity of tumor bearing mice.

➢ The cells were washed three times using PBS.

➢ The viability of the cells were checked using trypan blue (cell viability should be above 98%)

➢ The number of cells were counted using haemocytometer and after approximate dilution cell number adjusted to 1×10-7 cell/ml

➢ The experiment was setup by incubating different concentration of the drug with 1×106 cells

➢ Final volume of the assay mixture was made upto 1ml using PBS and incubated at 37°C for about 3 hours.

➢ 0.1ml of trypan blue was added after incubation and number of dead cell was counted using haemocytometer.

The number of stained and unstained cells was counted separately and percentage cell death was calculated using the formula:

image

Drug conc Percent cell Death (DLA)
µg/ml 1a 1b 1d 1h 2a 2b 2e
200 µg 57% 9% 15% 2% 27% 21% 84%
100 µg 39% 6% 10% 42% 14% 14% 75%
50 µg 25% 2% 7% 34% 8% 5% 60%
20 µg 15% 0 5% 20% 5% 2% 48%
10 µg 5% 0 0 8% 2% 0 33%

Table 5: Anticancer activity of chalcone by using DLA method

Compound code Zone of inhibition (in mm)
Staphylococcus aureus Bacillus subtilis Streptococcus pneumonia Salmonella typhi
Ampicillin 39 40 38 40
1a 29 32 28 38
1b 33 36 31 34
1c 32 34 30 33
1d 36 38 32 36
1h - 18 13 -
2a - 15 13 -
2b 31 30 32 30
2c 25 19 17 13

Table 6: in-vitro antibacterial activity of chalcones determined by agar diffusion method

image

2. Antibacterial activity [2]:

The synthesised compound were screened for their antibacterial activity against two gram positive bacterial strains B.subtilis( NCIM 2697), S.aureus( NCIM 2079) and two gram negative bacterial strains S.pneumonia( NCIM 5082), S.typhi(NCIM 2263) by using cup plate method.The zone of inhibition was measured in mm, under similar condition the controlled experiment was carried out using antibiotics( Ampicillin) as a standard drug for comparison.

3. Antioxidant activity [10]:

All the synthesized compounds were evaluated for their in-vitro free radical scavenging activity by DPPH (2, 2-diphenyl-1-picryl hydrazyl) reduction method using ascorbic acid as the standard.

Result and Discussion

➢ Structures of synthesized compounds was confirmed and characterized with the help of analytical data such as FTIR, mass spectroscopy, 1H NMR and C13 NMR.

➢ The synthesized compound 1a, 1h and 2d have shown good anti-cancer activity at concentration 100 μg/ml and 200 μg/ml. The compound 2a has shown moderate activity at concentration 200 μg/ml. The compound 1b, 1d and 2b did not exhibit prominent activity.

➢ Compound 1a, 1b, 1c, 1d and 2d exhibited good antibacterial activity at 100 μg/ ml. 1e, and 2c shows moderate activity while 1f, 1g, and 1i, exhibhited less antibacterial activity.

➢ 1a, 1b, 1c, 1d, 1e, 2a and 2d exhibited significant antioxidant activity with maximum inhibition at 40 μg/ml. 1g, 1j, 2b and 2c exhibited moderate antioxidant activity whereas 1h exhibited very low activity at 40 μg/ ml.

Acknowledgement

Authors are thankful to Prof. B.G. Shivananda, Principal, Al-Ameen College of Pharmacy, for providing all the facilities and timely help during the conduct of project in the college.

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