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synthesis of some new chalcone derivatives and their biological activity by Afzaye Rasul

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Synthesis of some new chalcone derivatives and their biological activity:

Synthesis of some new chalcone derivatives and their biological activity BY Afzaye Rasul Under the guidance of Dr. Monica Kachroo Professor Department of pharmaceutical chemistry Al- ameen college of pharmacy Bangalore 560030 1 5/28/2012

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Contents: Introduction Objectives Review of literature Methodology Spectral study Biological activity Result Discussion Conclusion References 2 5/28/2012

Introduction: :

Introduction: Chalcone is an aromatic ketone and an enone that forms the central core for a variety of important biological compounds, which are known collectively as chalcones or chalconoids. Benzylideneacetophenone is the parent member of the chalcone series. 3 5/28/2012

Objectives::

Objectives: Synthesis of some new chalcone and its derivatives Characterization of newly synthesized compounds through UV, IR , 1 HNMR , 13 C-NM Rand Mass spectral analysis. Evaluation of new chalcones for their biological properties such as anti-cancer, anti-oxidant and antibacterial activities. 4 5/28/2012

Review of literature :

Review of literature Prasad YR, Kumar PP, Kumar PR, Rao AS described about synthesis and antimicrobial activity of some new chalcones of 2-acetyl pyridine. Tiwari B, Pratapwar AS, Tapas AR, Butle SR, Vatkar BS described about synthesis and antimicrobial activity of some chalcone derivatives Ahmed MR, Sastry VG,Bano N, Ravichandra S, Raghavendra M. synthesis and cytotoxic , antioxidant activities of new chalcone derivatives. Preethi KL, Kuttan G, Kuttan R described about antitumour activity of ruta graveolens extract. 5 5/28/2012

Methodology:

Methodology Scheme-1 1-(4-acetyl phenyl)-pyrrolidine-2,5-dione 6 5/28/2012

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Scheme-2a 7 5/28/2012

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Scheme-2b 8 5/28/2012

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Scheme-3 1-4(3-( subst.phenyl )-1 H -pyrazol-3-yl))phenyl)pyrrolidine-2,5-dione. 9 5/28/2012

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10 Sr.No Compound Colour Mol.Formula Mol.Wt Yield % M.P 0 C R f value 1. MKR-02 Yellow C 21 H 19 NO 5 365 52 147-148 0.6 2 MKR-03 Yellow C 22 H 21 NO 6 395 97 161-163 0.5 3 MKR-04 Yellow C 19 H 14 N 2 O 5 350 78 158-160 0.5 4 MKR-05 Yellow C 19 H 14 O 3 NCl 339 95 137-138 0.48 5 MKR-06 Brown C 20 H 17 NO 5 351 92 142-144 0.6 6 MKR-07 Brown C 19 H 14 N 2 O 5 350 92 132-134 0.6 7 MKR-08 Brown C 19 H 15 NO 4 321 91 162-164 0.5 8 MKR-09 Orange C 21 H 19 NO 4 349 85 132-134 0.5 9 MKR-23 Orange C 19 H 14 N 2 O 5 350 75 96-98 0.6 10 MKR-11 Yellow C 19 H 13 O 3 NCl 2 350 85 118-120 0.5 11 MKR-25 Yellow C 19 H 16 N 2 O 3 320 79 95-98 0.6 Physical data of chalcones 5/28/2012

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Physical data of derivatives: 11 Sr.No Compound Colour Mol.Formula Mol.Wt Yield % M.P 0 C R f value 1 MKR-15 Yellow C 19 H 13 O 3 NCl 2 350 85 118-120 0.5 2 MKR-14 Brown C 21 H 19 N 3 O 4 377 78 132-134 0.4 3 MKR-13 Brown C 22 H 21 N 3 O 5 407 62 110-112 0.5 4 MKR-19 Brown C 20 H 17 N 3 O 4 363 35 118-120 0.6 5 MKR-18 Yellow C 19 H 14 N 3 O 2 Cl 361 62 115-117 0.5 6 MKR-10 Black C 21 H 19 N 3 O 3 361 27 46-48 0.5 5/28/2012

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Spectral studies: MKR-02 1-4(3-(2,4-Dimethoxyphenyl) acryloyl )phenyl)pyrrolidine-2,5-dione UV ( λ max ) IR ( KBr cm -1 ) 1 H-NMR 365 3002 ( Ar C-H) 2927 (Ali C-H) 1639 (C=O) 1602 (C=C) 1307( OCH 3 ) 1168( C-N) 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, 2xOCH 3 ) ; δ 1.8 4H (s, 2xCH 2 of pyrrolidine dione ) 12 5/28/2012

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( Ar C-H) Ali C-H) (C=O) (C=C) OCH 3 C-N 13 5/28/2012

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MKR-03 1-4(3-(2,4-trimethoxyphenyl) acryloyl )phenyl)pyrrolidine-2,5-dione UV ( λ max ) IR ( KBr cm -1 ) 1 H-NMR 329 3100 (Ar C-H) 2936 (Ali C-H) 1633 (C=O) 1589 (C=C) 1280( OCH 3 ) 1178( C-N) δ 7.94 1H (s, CH=C H ) ; δ 7.95 1H (s, CO C H =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, 3xOCH 3 ); δ 1.8 4H (s, 2xCH 2 of pyrrolodine dione ) 15 5/28/2012

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MKR-05 1-4(3-(2-Chlorophenyl) acryloyl )phenyl)pyrrolidine-2,5-dione UV ( λ max ) IR ( KBr cm -1 ) 1 H-NMR 13 CNMR 317 3059 ( Ar C-H) 2923 (Ali C-H) 1649 (C=O) 1606 (C=C) 1178( C-N) δ 8.17 1H (s, CH=C H ) ; δ 8.09 1H (s, CO C H =CH) ; δ 6.62-7.95 8H (m, ArH ) δ 1.21-1.90 4H (s, 2xCH 2 of pyrrolidine dione ). δ 188.36 (C=O enone ), 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 C 6 H 4 -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 C 6 H 3 ] 18 5/28/2012

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Mass spectrum of MKR-05: 22 5/28/2012

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Compound code Structure Molecular weight(Proposed ) Observed(Positive Mode ) MKR-02 397 395(M+2) Base peak 297 23 5/28/2012

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MKR-14: UV ( λ max ) IR ( KBr cm -1 ) 314 3358 (N-H) 2977 ( Ar C-H) 2835 (Ali C-H) 1596 (C=N ) 1460 (C=C) 1208 (OCH 3 ) 1168 (C-N) 24 5/28/2012

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Biological activity:

Biological activity 1.Anticancer activity: Procedure: 1. Cells were aspirated from the peritoneal cavity of tumor bearing mice. 2. The cells were washed three times using PBS(phosphate buffer saline) 3.The viability of the cells were checked using trypan blue (cell viability should be above 98%) 4.The number of cells were counted using haemocytometer and after approximate dilution cell number adjusted to 1×10 -7 cell/ml 5. The experiment was setup by incubating different concentration of the drug with 1×10 6 cells 6. Final volume of the assay mixture was made upto 1ml using PBS and incubated at 37 0 C for about 3 hours. 7. 0.1ml of trypan blue was added after incubation and number of dead cell was counted using haemocytometer . 26 5/28/2012

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The number of stained and unstained cells was counted separately and percentage cell death was calculated using the formula: % cytotoxicity = No. of dead cell No.of live cell+No . of dead cell × 100 27 5/28/2012

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Drug conc Percent cell Death(DLA) µg/ml MKR-02 MKR-03 MKR-05 MKR-09 MKR-13 MKR-14 MKR-18 200 µg 57% 9% 15% 72% 21% 27% 84% 100 µg 39% 6% 10% 42% 14% 14% 75% 50 µg 25% 2% 7% 34% 5% 8% 60% 20 µg 15% 0 5% 20% 2% 5% 48% 10 µg 5% 0 0 8% 0 2% 33% 28 5/28/2012

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2.Antioxidant activity: Procedure: 1. Preparation of Control (DPPH) Solution. 2. Preparation of standard solution (Ascorbic acid) 3. Preparation of test or sample solutions 29 5/28/2012

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Compound code % Inhibition 10 µg/ ml 20 µg/ ml 30 µg/ ml 40 µg/ ml Ascorbic acid 63 68 72 79 MKR-02 52 58 64 71 MKR-03 53 57 63 69 MKR-04 51 59 64 73 MKR-05 60 62 69 75 MKR-06 47 49 52 59 MKR-07 48 49 51 57 MKR-08 32 38 41 44 MKR-09 17 20 22 28 MKR-11 42 46 49 52 MKR-16 32 35 36 39 MKR-23 21 23 27 31 MKR-25 18 19 22 26 30 Antioxidant activity of chalcones : 5/28/2012

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Compound code % Inhibition 10 µg/ ml 20 µg/ ml 30 µg/ ml 40 µg/ ml Ascorbic acid 63 68 72 79 MKR-10 21 23 27 31 MKR-13 31 35 36 39 MKR-14 52 54 58 61 MKR-15 47 49 51 54 MKR-17 40 41 44 48 MKR-18 50 53 54 61 MKR-19 49 51 53 57 MKR-20 33 38 39 42 31 Antioxidant activity of derivatives: 5/28/2012

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Graphical representation of antioxidant activity of 1-[4-(3-Subst phenyl- acryloyl )-phenyl]-pyrrolidine-2,5-dione and of 1-4(3-( Subst phenyl)-1 H -pyrazol-3-yl))phenyl)pyrrolidine-2,5-dione 32 5/28/2012

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3.Antibacterial activity: Methods for studying antimicrobial activity: Agar diffusion method . Tube dilution method . 33 5/28/2012

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Compound code Zone of inhibition (in mm) Staphylococcus aureus Bacillus subtilis Streptococcus pneumonia Salmonella typhi Ampicillin 39 40 38 40 MKR-02 29 32 28 38 MKR-03 33 36 31 34 MKR-04 32 34 30 33 MKR-05 36 38 32 36 MKR-06 26 22 21 23 MKR-07 18 20 20 17 MKR-08 15 18 16 20 MKR-09 - 18 13 - MKR-11 15 16 12 20 MKR-16 - 13 - 18 MKR-23 17 16 19 20 MKR-25 - - - 14 34 Antibacterial activity of chalcones : 5/28/2012

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Compound code Zone of inhibition (in mm) Staphylococcus aureus Bacillus subtilis Streptococcus pneumonia Salmonella typhi Ampicillin 39 40 38 40 MKR-10 25 23 22 19 MKR-13 31 30 32 30 MKR-14 - 15 13 - MKR-15 25 19 17 13 MKR-17 21 22 20 17 MKR-18 32 36 34 37 MKR-19 - 12 - 14 MKR-20 16 18 - - 35 Antibacterial activity of derivatives: 5/28/2012

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Graphical representation of antibacterial activity of 1-[4-(3-Subst phenyl- acryloyl )-phenyl]-pyrrolidine-2,5-dione and of 1-4(3-( Subst phenyl)-1 H -pyrazol-3-yl))phenyl)pyrrolidine-2,5-dione 36 5/28/2012

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Result and discussion: The synthesised compound like MKR-02, MKR-3, MKR-4, MKR-5, MKR-6, MKR-7, MKR-8, MKR-9, MKR-23, MKR-11 and MKR-25 exhibited bathochromic shift. The cyclised compound like MKR-10, MKR-13, MKR-14, MKR-18, MKR-19,MKR-20 exhibited hypsochromic shift due to loss of enone chromophore . MKR-02 and MKR-03 were synthesized by reacting 1-(4-acetyl-phenyl)-pyrrolidine-2,5-dione with substituted aromatic aldehyde in presence of potassium hydroxide and ethanol. The formation of MKR-02, and MKR-03 were confirmed by IR data. The prominent peaks observed were in the range of, 3000- 3100 ( Ar C-H str.), 2927-2935 (Ali C-H str.), 1633-1639 (C=O str.), 1589-1602 ( Ar C=C str.) , 1280-1307 (OCH 3 ) cm -1 and 1168-1178(C-N) respectively. 37 5/28/2012

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MKR-05 and (MKR-11) were synthesized by reacting 1-(4-acetylphenyl)pyrrolidine-2,5-dione. The formation of MKR-05 and MKR-11 were confirmed by IR data. The prominent peaks observed were in the range of, 3060-3226 ( Ar C-H str.), 2923-2925 (Ali C-H str.), 1649-1652 (C=O str.), 1599-1608 (CH=CH str.), and 1178-1221 (C-N.) cm -1 respectively. The formation of (MKR-02) was further confirmed by the 1 H NMR spectrum. The spectrum exhibited chemical shift in δ values ( ppm ), 7.5-8.13[(m, 4H, 2H of ArH+2H of CH=CH)], 6.40-6.7 (m, 3H, ArH of dimethoxy benzene), 3.84-3.88 (s, 6H, 2× OCH 3 ), 1.8(s, 4H, 2×CH 2 of pyrrolidine dione ). The formation of (MKR-03) was further confirmed by the 1 H NMR spectrum. The spectrum exhibited chemical shift in δ values (CDCl 3, ppm ), 7.94 (s, 1H, CH=C H ), 7.95 (s, 1H , CO C H =CH), 7.2-7.82 (m, 4H, ArH ), 6.60-6.85 (m, 2H,Ar of trimethoxy benzene), 3.8-3.9 (s, 9H, 3×-OCH 3 ), 1.8 (s,4H, 2×CH 2 pyrrolidine dione ), 38 5/28/2012

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The formation of (MKR-05) was further confirmed by the 1 H NMR spectrum. The spectrum exhibited chemical shift in δ values (CDCl 3, ppm ), 8.17 (s, 1H,CH=C H ), 8.09 (s, 1H, CO C H =CH), 6.62-7.95(m, 8H, ArH ), 1.21-1.90(s, 4H,2×CH 2 of pyrrolidine dione ). The formation of (MKR-05) was further confirmed by the 13 C NMR spectrum. The spectrum exhibited chemical shift in δ values (CDCl 3, ppm ), 188.36 (C=O enone), 151.56(C=O, succinimide ), 139.36(=CHC 6 H 4 Cl) , 135.66, 134.15, 125.36 [(Ca),(Cc) and ( Ce ), ( Cd ), ( Cb ) and ( Cf ) respectively of C6H4-succinamide]. 12813(Ch), 131.6, 131.07, 130.6, 128.74, 127.35 (Ca’), ( Cb ’),(Cc’), ( Cd ’ and Ce ’) Cf ’ respectively of 2 ClC 6 H 2 39 5/28/2012

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ANTI-CANCER ACTIVITY: The synthesized compound MKR-02, MKR-09 and MKR-18 have shown good anti-cancer activity at concentration 100 µg/ml and 200 µg/ml. The compound MKR-14 has shown moderate activity at concentration 200 µg/ml. The compound MKR-03, MKR-05 and MKR-13 did not exhibit prominent activity. 40 5/28/2012

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ANTIOXIDANT ACTIVITY: Compounds MKR-02, MKR-03, MKR-04, MKR-05, MKR-14, MKR-18 and MKR-19 exhibited maximum oxygen scavenging activity which is comparable to ascorbic acid. Compounds MKR-06, MKR-7, MKR-08, MKR-11, MKR-13, MKR-15, MKR-16, MKR-17 and MKR-20 exhibited moderate oxygen scavenging activity as compared to ascorbic acid. Compounds MKR-09, MKR-10, MKR-23 and MKR-25 exhibited minimum antioxidant activity. However none of the compound exhibited greater activity than the standard. 41 5/28/2012

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ANTI-BACTERIAL ACTIVITY: Compounds MKR-02. MKR-03, MKR-04, MKR-05, MKR-06, MKR-13 and MKR-18 exhibited maximum anti-bacterial activity when compared to ampicillin at concentration 100µg/ml. Compounds MKR-10, MKR-15 and MKR-17 showed moderate activity as compared to ampicillin. Compounds MKR-07, MKR-08, MKR-11, and MKR-23 showed very little anti-bacterial activity when compared to ampicillin. 42 5/28/2012

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Conclusion: The yield of the synthesized compound was found to be in the range from 56-97%. Structures of synthesized compounds was confirmed and characterized with the help of analytical data such as FTIR ,mass spectroscopy, 1 H NMR and C 13 NMR . All the synthesized compounds were screened for anti-cancer, antibacterial and antioxidant activity. 43 5/28/2012

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REFERENCES : Prasad YR, Kumar PP, Kumar PR, Rao AS. Synthesis and antimicrobial activity of some new chalcones of 2-acetyl pyridine. E. J Chem. 2008; 5(1):144-148 Tiwari B, Pratapwar AS, Tapas AR, Butle SR, Vatkar BS. Synthesis and antimicrobial activity of some chalcone derivatives. Int J ChemTech Res.2010; 2(1):499-503. Ahmed MR, Sastry VG,Bano N, Ravichandra S, Raghavendra M. Synthesis and cytotoxic , antioxidant activities of new chalcone derivatives. J Chem 2011; 4(2): 289-294 Preethi KL, Kuttan G, Kuttan R. Antitumour activity of Ruta graveolens extract.Asian Pacific J Cancer Prev. 2006; 7:439-443 44 5/28/2012

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THANK YOU 45 5/28/2012

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