11 chapter 3 Synthesis and biological...

Chapter:-3 Synthesis and biological evaluation of fluorinated chalcones

8

CHAPTER-3 Synthesis and biological evaluation

of fluorinated Chalcones


9

2.1 Introduction

The term "Chalcone" was first coined by Kostanecki and Tambor1, who did pioneering

work in the synthesis of natural coloring compounds. The chemistry of chalcones has generated

intensive precise studies all over the world, especially interesting for their biological and

industrial applications. Due to presence of chromophore these compounds are colored

compounds. They are known as benzalacetophenones or benzylidene acetophenones.

Chalcones are characterized by their possession of a structure who is having aromatic

rings attached with aliphatic chain.

O

“Chalcone” Fig-2.1

The chalcones were known from different names like phenyl styryl ketones,

beanzalacetophenone, α-phenyl acrylphenone, γ-oxo-α,γ-diphenyl-α-propylene and α-phenyl-α-

benzoethylene.

2.1.1 Synthetic aspect

Chalcone formation

For making chalcones a very good method is available called Claisen-Schimidt condensation

which involves aryl methyl ketones with aryl aldehyde in presence of alcoholic alkali2.

Alternative synthetic routes for better yield, shorter reaction time to synthesize new

analogs


10

Various modifications have been applied to Claisen-Schimidt condensation to get better

yield and to synthesize biologically active analogs. Different catalysts have been reported to

increase the yield of the reaction. Microwave synthesis strategies have also applied to shorten the

reaction time. Solid phase synthesis and combinatorial chemistry has made possible to generate

library of chalcone derivatives.

Solid-Phase Synthesis

During the past two decades, combinatorial chemistry has appeared as one of the most

valuable tools used to accelerate drug discovery and lead optimization processes. The

emergence of this new field has promoted the transfer of solution-phase functional group

transformations to the solid phase.

A. R. Katritzky and coworker have synthesized chalcone derivatives by using sodium

methoxide as a catalyst and Wang resin as a solid support3. Jian Cao and group reported

polymer-supported selenium-induced solid - phase synthesis4. Recently Kamal Ahmed et al

demonstrated solid-phase synthetic protocol for the chalcone and its derivatives5.

Liquid-Phase Synthesis

In the solid phase synthesis there are some disadvantages are there. Due to hard in

monitor reaction at the big scale solid phases 6 are used.

Recently S. Yongjia et al reported soluble polymer-supported synthesis of chalcone

derivatives7. Saravanamurugan and coworker used ZSM-5 catalyst and Liquid phase synthesis

strategy for the derivative preparation8. E. V. Stoyanov and group demonstrated liquid phase

synthesis of 2'-hydroxychalcone derivatives9.

2.1.2 Microwave Assisted Synthesis

Reactions in microwave is very important instrument in chemistry because of faster

reaction rate, selectivity & higher yields10.


11

Solvent free experiments are most popular in chemistry now. Coworker and k. mogilaiah

have done reaction of chalcone with P.T.S.A in microwave without solvent11, with other

reference Katade S. made reaction in microwave of chalcone with good yields12.

2.1.3 Catalysts

The other catalysts employed in synthesis and some time with advantages are alkali of

different strength13,14, hydrochloric acid15,16, phosphorous oxychloride17, piperidine18, anhydrous

aluminium chloride19, boron trifluoride20, amino acids21, perchloric acid22 etc. recently S. Ryo

and group reported synthesis using Ruthenium as a catalyst and get better yield23.

Chalcones can also be synthesized by condensing several other reagents instead of an aldehyde

and ketone.

1. Nencki reaction with cinnamic acid on an aromatic compounds24.

2. Diazo coupling of phenyl diazonium chloride with benzoyl acrylic acid25.

3. Friedel craft's cinnamoylation26.

4. Fries rearrangement of aryl cinnamates27.

2.2 Reaction mechanism

The following two mechanisms have been suggested for the synthesis of chalcones.

(A) Base catalyzed

(B) Acid catalyzed

(A) Base catalyzed:


12

Two alternative mechanisms were advanced for the reaction of benzaldehyde with acetophenone

in the presence of a basic catalyst28.

CH3

O

R+ OH

- CH2-

O

R+ OH2

H

O

R1

C+

H

O-

R1

CH2-

O

R

C+

H

O-

R1 + C

H

O-

R1

CH2 C

O

R

C

H

O-

R1

CH2 C

O

R + OH2C

H

OH

R1

CH2 C

O

R + OH-

C

H

OH

R1

CH2 C

O

R- H2O

CHR1

CH C

O

R

Fig-2.2

The intermediate aldol type products formed readily undergoes dehydration even under mild

condition, particularly when R and R’ are aryl groups.

(B) Acid catalyzed:

The formation of chalcones by the acid catalyzed condensation of acetophenones and

aldehydes has been studied29. The rate of reaction depends on the first power of the concentration

of aldehyde and the Hammet acidity function. Also the condensation step has been shown to be

the rate determining step in this reaction. The following mechanism seems to be operable.


13

CH3

O

R

CH2

OH

R

H

O

R1 H

O+

R1

H

CH2

OH

RH

O+

R1

H

+ R C CH

H

OH

C

R1

OH

R C CH

H

O+

C

R1

OHHOH

H

R C C

H

C

R1

O+

H H

R C C

H

C

R1

O

R C CH

H

O+

C

R1

OHHOH

Fig-2.3

2.2.1 Therapeutic importance

Chalcones are potential biocides, some naturally occurring antibiotics and amino

chalcones probably own their activities because the of α,β-unsaturated carbonyl. Few of them are

as below.

1. Antitumor30-31

2. Anticancer32-33

3. Antiviral and Antitubercular34

4. Anti HIV35

5. Fungicidal36-37

6. Antiinflammatory38

7. Antimicrobial39-40

8. Antimalarial41-42

9. Insecticidal43-44


14

10. Antiproliferation45

11. Antiparasitic46

12. Antiplasmodial47

Nakahara Kazuhiko et al.48 have synthesized chalcones as carcinogen inhibitors.

Antitubercular agents of chalcone derivatives have been prepared by Lin Yuh-Meei et al.49 Ko

Horng-Huey et al.50 have reported chalcones as anti-inflammatory agents. Some of the chalcones

have been reported for their use for treatment of glaucoma51 and showed antifungal,52 aldose

reductase inhibitors,53 anticancer54 activities. Satyanarayana M. et al.55 have synthesized

chalcone derivatives as anti hyperglycemic activity.

Mudalir and Joshi56 reported insecticidal activity of some phenoxy chalcones. Ko et al57.

have prepared some new chalcones for potent inhibition of platelet aggregation. Ziegler et al58.

reported some chalcones as antiparasitic. The antimalarial activities of chalcones have also been

reported by Xue et al59 and Dominguez et al60. Seo et al61. have synthesized chalcones

derivatives and reported them as a-glucosidase inhibitors. Larsen and co-worker62 and Wu et al63.

have reported anti-plasmodial activity and Boeck and et al64 have reported anti leishmanial

activity of some chalcones. Analogs containing nitro, fluorine or bromine group respectively

displayed increased selectivity against the parasites as compared with natural chalcone.

Shao-Jie Wang et al.65 have synthesized chalcones derivatives (II) and reported them as a

Aldose Reductase Inhibitors.


15

O

R1

R2

R3COOH

(II)

R1= CH3, OCH3

R2= H, CH3, OCH3, Cl, F

R3=H, OH, CH3

Recently Ni Liming et al.66 have synthesized chalcones and screened for their

antiinflammatory and cardiovascular activity. Kumar Srinivas et al.67 have synthesized chalcones

as a antitumor agent. Ko Horng-Huey et al.68 have prepared chalcones as antiinflammatory agent.

Nakahara Kazuhiko et al.69 have synthesized chalcones and tested as carcinogen inhibitors.

Antitubercular agents of chalcone derivatives have been prepared by Lin Yuh-Meei et al.70

A. Nagaraj and C. Sanjeeva Reddy71 reported Antimicrobial, Antifungal Activity of some

bis-chalcones (III).

O O

HO OHR R

R= H, 4-OCH3, 4-Cl, 2-Cl, 4-NO2, 4-Br

(III)

Fig-2.4

Furthermore, Alcaraz M. J. et al.72 have described the role of nuclear factor-kappa B and

heme oxygenase-1 in the action of an anti-inflammatory Chalcone derivative in RAW 264.7

cells. Nerya O. et al73 have prepared some new chalcones as potent tyrosinase inhibitors (IV).


16

O

O

OCH3

OH

OCH3

(IV)

Dong Hwan Shon et al.74 have synthesized and investigated the anti-inflammatory

activity of 2,4,6-tris(methoxymethoxy)chalcone derivatives. Liu Mei et al.75 have prepared

chalcones and screened for antimalarial activity. Opletalova Veronika et al.76 have synthesized

chalcones and tested as cardiovascular agents. Moreover, it has been found that chalcone

derivatives possesses nitric oxide inhibitor77-78 anti HIV79-80 and antiproliferative81-82 activities.

Moreover, Khatib S. et al. synthesized some novel chalcones as potent tyrosinase

inhibitors (IV). Ko H. H. et al. have prepared some new chalcones for potent inhibition of

platelet aggregation. Ziegler H. L. et al. reported chalcones as an antiparasitic. Go M. L. et al.

have described the synthesis and biological activities of chalcones as antiplasmodial. A new class

of sulfonamide chalcones (V) synthesized and their glycosidase inhibitory activity were

investigated.

(V)

O

OHHO

OH

OH

O

(V)

HNSH3C R

R=3-OH,3,4-OH

O

O


17

Chalcones have been proved to be an important intermediate for the synthesis of

many heterocyclic compounds in organic chemistry. These facts prompted us to synthesize some

novel chalcone derivatives bearing substituted benzaldehyde moiety, in order to achieving better

therapeutic agents.

With the biodynamic activities of chalcones and as a fine synthon for different

fluorinated compounds, the awareness has been paying attention on the creation of new

chalcones. With a observation to obtained compounds having better therapeutic activity, new

synthesized (E)-3-(3,5-bis(trifluoromethyl) phenyl)-1-phenylprop-2-en-1-one by the

condensation of 1-(3,5-bis(trifluoromethyl)phenyl)ethanone with various aromatic aldehydes by

using alkali as catalyst.

Recognizing these facts, we have synthesised four new series of (E)-3-(3,5-

bis(trifluoromethyl) phenyl)-1-phenylprop-2-en-1-one (TV -101 to 115) The structures of all the

newly synthesized compounds were elucidated by FT-IR, mass spectra, 1H NMR and elemental

analyses. The newly synthesized compounds were subjected to antimicrobial activity and anti

cancer activity.

2.2 Reaction Scheme: A) (E)-3-(3,5-bis(trifluoromethyl) phenyl)-1-phenylprop-2-en-1-one.

CF3

F3CCH3

O

R

CHOKOH

Methanol

O25 hrs

RCF3

F3C

R= TV 101 to 115

Fig-2.5


18

2.3.1 Physical Data Table Series-1:

Code R1 M.F. M.

W.

M.P.

ºC

Yield % R f1 Rf2

TV-101 4-Cl C17H9ClF6 379 189 67 0.45 0.68

TV-102 4-CH3 C18H12F6O 358 201 58 0.48 0.60

TV-103 4-OCH3 C18H12F6O2 374 203 77 0.40 0.69

TV-104 4-F C17H9F7O 362 186 68 0.50 0.65

TV-105 4-Br C17H9BrF6O 423 221 74 0.49 0.69

TV-106 3,4DiOCH C19H14F6O 404 204 56 0.59 0.61

TV-107 4, 3-DiCl C17H8Cl2F6O 413 224 76 0.40 0.68

TV-108 3-OCH3 C18H12F6O2 374 212 71 0.48 0.62

TV-109 3-Cl C17H9ClF6 379 195 80 0.45 0.68

TV-110 3-Br C17H9BrF6O 423 182 77 0.50 0.69

TV-111 2-Cl C17H9ClF6 379 242 58 0.49 0.60

TV-112 2-F C17H9F7O 362 212 60 0.45 0.68

TV-113

2,4-

DiCH3

C19H14F6O 372 224 62 0.43 0.65

TV-114 2-OCH3 C18H12F6O2 374 209 66 0.47 0.76

TV-115 H C17H10F6O 344 200 76 0.49 0.68

Table-2.1

TLC Solvent system Rf1: Hexane: Ethyl acetate – 7:3;

Rf2: Chloroform: Methanol - 9:1.


19

2.4 Plausible Reaction Mechanism

CH3O

CH2HO

HO

R1H

O+

R1

H

CH2

HO

HO+

R1

H

C CH

H

OHC

R1

OH

C CH

H

O+

CR1

OHHHO

H

CC

H

CR1

O

C CH

H

O+

CR1

OHHHO

H

CC

H

CR1

O+ H

+

CF3

F3C F3C

CF3

F3C

CF3

F3C

F3C

F3C

F3C

F3C

F3C

F3C

F3C

F3C

F3C

Fig-2.6

2.5 Experimental

2.5.1 Materials and Methods

Open capillary tubes are used for melting points. TLC has been checked for formation of

compounds regularly and spots were seen by iodine. FT-IR-8400 instrument is using for IR

spectra. Shimadzu GC-MS-QP-2010 model used for Mass spectra. Brucker Ac 400 MHz

spectrometer was used for 1H NMR.


20

2.5.2 Procedure for (TV- 101 to 115)3-[(bis-3,5(methyltrifluoro)phenyl]-1-(substituted phenyl)-

propenone.

A mixture of the 3,5 Bis (trifluoromethyl)acetophenone (0.01 Moles), substituted

benzaldehydes (0.01 Moles) and potassium hydroxide (0.2 Moles) was heated in methanol (10

ml) for 25 hrs. Cooling was applied & methanol was added. Solid was came after stand overnight

reaction & filtered. (E)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-chlorophenyl)propenone, which

were recrystallized from ethanol.

2.5.2.1(E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(4-chlorophenyl)propenone (TV-101)

Yield: 67%; mp 189ºC; Analytical Calculation for C17H9ClF6O: Carbon, 53.92; Hydrogen, 2.40;

Cl, 9.36; Florine, 30.10; O, 4.22; Found: C, 53.17; H, 2.15; Cl, 9.12; F, 30.01; O, 4.10%;

Infrared (cm-1): 3049 (aromatic ring of C-H stretching), 1651 (C=O stretching ), 1622, 1564 and

1519 (C=C stretching), 1640 (C=C vinyl stretching) 1203 (C-O-C stretching of ether ) 1078

(aromatic ring of C-H in plane deformation), 825 (1,4-disubutituion C-H out of plane bending),

1012 (C-F stretching); MS: m/z 379; 1H NMR (DMSO-d6) δ ppm: 7.02-7.14 (m, 2H, Hab), 7.21-

7.36 (m, 2H, Hcd), 7.44-7.55 (d, 2H, Hef), 7.65 (s, 1H, Hg), 7.78-7.79 (s, 1H, Hh), 8.37 (s, 1H, Hi).

2.5.2.2 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-p-tolylpropenone (TV-102)

F3C

CF3

O

Cl


21

Yield: 58%; mp 201ºC; Analytical Calculation for C18H12F6O: Carbon, 60.34; Hydrogen, 3.38;

Fluorine, 31.82; O, 4.47; Found: Carbon, 60.11; Hydrogen, 3.12; Fluorine, 11.82; O, 4.21%; MS:

m/z 358.

2.5.2.3 (E)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-methoxyphenyl)propenone(TV-103)

Yield- 77%; mp 203ºC; Anal. Calcd. for C18H12F6O2: Carbon, 57.76; Hydrogen, 3.23; Fluorine,

30.46; O, 8.55; Found: Carbon, 57.54; Hydrogen, 3.02; Fluorine, 30.21; O, 8.23%; MS: m/z 374;

2.5.2.4 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(4-fluorophenyl)propenone (TV-104)

F3C

CF3

O

CH3

F3C

CF3

O

OCH3

F3C

CF3

O

F


22

Yield- 68%; mp 186ºC; Analytical Calculation. for C17H9F7O: Carbon, 56.37; Hydrogen, 2.50;

Fluorine, 36.71; O, 4.42; Found: Carbon, 56.24; Hydrogen, 2.14; Fluorine, 36.35; O, 4.12 %;

MS: m/z 362.

2.5.2.5 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(4-bromophenyl)propenone(TV-105)

Yield- 74%; mp 221ºC; Analytical. Calculation for C17H9BrF6O: Carbon, 48.25; Hydrogen, 2.14;

Bromine, 18.88; Fluorine, 26.94; Oxygen, 3.78; Found: Carbon, 48.12; Hydrogen, 2.00;

Bromine, 18.54; Fluorine, 26.42; Oxygen, 3.21%; MS: m/z 423.

2.5.2.6 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(3,4-dimethoxyphenyl)propenone(TV-106)

Yield- 56%; mp 204ºC; Analytical Calculation for C19H14F6O3: Carbon, 56.44; Hydrogen, 3.49;

Fluorine, 28.19; Oxygen, 11.87; Found: Carbon, 56.16; Hydrogen, 3.21; Fluorine, 28.01;

Oxygen, 11.64%; MS: m/z 404.

F3C

CF3

O

Br

F3C

CF3

O

OCH3

OCH3


23

2.5.2.7 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(3,4-dichlorophenyl)propenone(TV-107)

Yield- 76%; mp 224ºC; Analytical Calculation for C17H8Cl2F6O: Carbon, 49.42; Hydrogen, 1.95;

Chlorine, 17.16; Fluorine, 27.59; Oxygen, 3.87; Found: Carbon, 49.12; Hydrogen, 1.84;

Chlorine, 17.01; Fluorine, 27.24; Oxygen, 3.56%; MS: m/z 413.

2.5.2.8 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(3-methoxyphenyl)propenone(TV-108)


Fluorine, 30.46; Oxygen, 8.55; Found: Carbon, 57.55; Hydrogen, 3.05; Fluorine, 30.22; Oxygen,

8.21%; MS: m/z 374.

2.5.2.9(E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(3-chlorophenyl)propenone(TV-109)

F3C

CF3

O

Cl

Cl

F3C

CF3

O

OCH3

F3C

CF3

O

Cl


24

Yield- 80%; mp 195ºC; Analytical Calculation for C17H9ClF6O: Carbon, 53.92; Hydrogen, 2.40;

Chlorine, 9.36; Fluorine, 30.10; Oxygen, 4.22; Found: Carbon, 53.13; Hydrogen, 2.11; Chlorine,

9.11; Fluorine, 30.00; Oxygen, 4.09% MS: m/z 379.

2.5.2.10 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(3-bromophenyl)propenone (TV-110)

Yield- 77%; mp 182ºC; Analytical Calculation for C17H9BrF6O: Carbon, 48.25; Hydrogen, 2.14;

Bromine, 18.88; Fluorine, 26.94; Oxygen, 3.78; Found: Carbon, 48.04; Hydrogen, 2.01;

Bromine, 18.34; Fluorine, 26.44; Oxygen, 3.12%; MS: m/z 423.

2.5.2.11 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(2-chlorophenyl)propenone (TV-111)

F3C

CF3

O

Br

F3C

CF3

O Cl


25

Yield- 58%; mp 242ºC; Analytical Calculation for C17H9ClF6O: Carbon, 53.92; Hydrogen, 2.40;

Chlorine, 9.36; Fluorine, 30.10; Oxygen, 4.22; Found: Carbon, 53.18; Hydrogen, 2.11; Chlorine,

9.12; Fluorine, 30.04; Oxygen, 4.11% MS: m/z 379.

2.5.2.12 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(2-fluorophenyl)propenone (TV-112)

Yield- 60%; mp 212ºC; Analytical Calculation for C17H9F7O: Carbon, 56.37; Hydrogen, 2.50;


4.12% MS: m/z 362.

2.5.2.13 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(2,4-dimethylphenyl)propenone (TV-113)



4.12%; MS: m/z 372.

2.5.2.14 (E)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(2-methoxyphenyl)propenone (TV-114)

F3C

CF3

O F

F3C

CF3

O

CH3

CH3


26



8.21%; MS: m/z 374.

2.5.2.15 (E)-3-[bis-3,5(methyltrifluoro)phenyl]-1-(phenyl)propenone (TV-115)



4.65%; MS: m/z 344.

2.6 Spectral discussion

2.6.1 Mass spectral study

Shimadzu GC-MS-QP-2010 model was using for mass spectra. Proper fragmentation

came in spectral studies. Molecular weight peaks came of respective compounds. It has given

below.

F3C

CF3

O OCH3

F3C

CF3

O


27

2.6.1.1 Mass fragmentation pattern for TV-101

O

F3C

Cl

O

CF3

F3C

CF3

F3C

O

O

F3C

O

CF3

F3C

Cl

m/z=344

m/z=310

m/z=214

m/z=208

m/z=276

Cl

m/z=112 m/z=378

Fig-2.7


28

2.6.2 IR spectral study

Shimadzu FT-IR-8400 model records IR spectra using KBr pellet method. Various

functional groups present in molecule were identified by characteristic frequency obtained for

them. For chalcones TV-101 to 115, confirmatory bands for aliphatic carbonyl groups were

observed at 1690- 1550cm-1 respectively. C=C stretching of aromatic ring is at 1525. Another

characteristic C-F stretching band of CF3 ring was observed at 1095-1000 cm-1, C-Cl stretching

band observed at 790-761 which suggested formation of desired products TV-101 to 115.

2.6.3 1H NMR spectral study

In 1H NMR DMSO-d6 used as a solvent with Brucker 400 MHz spectrometer & TMS

used as a standard. Synthesis compounds structures were proven by all protons and their

chemical shifts.

1H NMR spectra confirmed the structures of chalcones TV-101 to 115 on the basis of

following signals: a singlet for the aromatic proton at 7.0-7.5 δ ppm, dublet for the -CH proton

connected to fluoro ring at 8.4 δ ppm and dublet for -CH proton connected to chloro benzene

ring at 7.7 δ ppm, respectively.


29

Mass spectrum of TV-101

Fig-2.8

IR spectrum of TV-101

Fig-2.9

F3C

CF3

O

Cl

M.W.- 378

F3C

CF3

O

Cl


1H NMR spectrum of TV-101

Expanded 1H NMR spectrum of TV

Synthesis and biological evaluation of fluorinated chalcones

Fig-2.10

H NMR spectrum of TV-101

Fig-2.11

Synthesis and biological evaluation of fluorinated chalcones

30


31

2.7 References

1. S. V. Kostanecki, J. Tambor, Monoxyohalcones, Ber. Duch. Chem. Ges., 32, 1921

(1899).

2. Vyas D. H., Dhaduk M. F., Tala S. D., Akbari J. D., Joshi H. S., (2007), Synthesis and

biological activity of some pyrazoline derivatives Indian J. Het. Chem., 17(2), 169-172

(2007).

3. Katritzky A. R., Chassaing C., Barrow S. J., Zhang Z., Forood B. (2002), Solid-Phase

Synthesis of 4,6-Disubstituted and 3,4,6-Trisubstituted Pyrid-2-ones, J. Combi. Chem.,

4(4), 249-250 (2002).

4. J. Cao, E. Tang, X. Huang, Wu Lu Ling, X. Huang, Chinese Chem. Lett., 17(7), 857-858

(2006).

5. Kamal A., Shankaraiah, N., Prabhakar S., Ch. R. Reddy, N. Markandeya, K. L. Reddy, V.

Devaiah (2008), Solid-phase synthesis of new pyrrolobenzodiazepine–chalcone

conjugates: DNA-binding affinity and anticancer activity, Bioorg. Med. Chem. Lett.,

18(7), 2434-2439 (2008).

6. Toy P. M., Janda K. D., (2000), Soluble Polymer Supported Organic Synthesis, Chem.

Res., 33, 546-554 (2000).

7. Yongjia S., Lianbing R., Jianwei Wu, (2008), Novel Method for

Soluble‐Polymer‐Supported Synthesis of 3,4,5‐Trisubstituted Isoxazoles, Syn. Comm.,

38(4), 583-594 (2008).

8. Saravanamurugan S., Palanichamy M., Arabindoo B., Murugesan V., (2004), Liquid

phase reaction of 2′-hydroxyacetophenone and benzaldehyde over ZSM-5 catalysts J.

Mol. Catal. A: Chemical, 218(1), 101-106 (2004).

9. Stoyanov E. V., Champavier Y., Simon A., Jean-Philippe B., (2002), Efficient

liquidPhase synthesis of 2′-Hydroxychalcones, Med. Chem. Lett., 12(19), 2685-7 (2002).


32

10. (a) Caddick S., (1995), Microwave assisted organic reactions, Tetrahedron, 51(38),

10403-10432 (1995); (b) Deshayes S., Liagre M., Loupy A., Luche J., (1999), A. Petit;

Microwave activation in phase transfer catalysis Tetrahedron, 55(36), 10851-10870

(1999); (c) Lidstrom P Tierney J., Wathey B., Westman J.; (2001), Microwave assisted

organic synthesis—a review, Tetrahedron, 57(45), 9225-9283 (2001).

11. Mogilaiah K., Sakram B., Kavitha S., (2007), Ptsa catalysed Claisen Schmidt

condensation in solvent free condisions under microwave irradiation, Het. Comm., 13(1),

43-48 (2007).

12. Katade S., Phalgune U., Biswas S., Wakharkar R., Deshpande N., Microwave studies on

synthesis of biologically active chalcone derivatives, Indian J. Chem.: B, 47B(6), 927-

931 (2008).

13. H. Rupe, D.Wasserzug, Several condensing agents used are alkali of different strength

hydrogen chloride Ber. Duch. Chem. Ges., 34, 3527 (1901).

14. T. Szell; Several condensing agents used are alkali of different strength phosphorous

oxychloride, Chem. Ber., 92, 1672 (1959).

15. R. E. Lyle, L. P. Paradis Several condensing agents used are alkali of different strength

piperidine, J. American Chem. Soc., 77, 6667 (1955).

16. S. A. Hermes, Several condensing agents used are alkali of different strength aluminium

chlorides, Chem. Abstr., 70, 96422h (1969).

17. Szell and Sipos, Ann., 64 (1), 113 (1961)

18. D. S. Breslow and C. R. Hauser, J. Am. Chem. Soc., 62, 2385 (1940)

19. C. Kuroda and T. Matsukuma, C. A., 26, 2442

20. S. Fujise and H. Tatsuta, J. Chem. Soc. Japan, 63, 632, (1940)

21. G. V. Jadhav and V. G. Kulkami, Curr. Sci. (India), 20, 42 (1951)


33

22. P. L. Cheng, P. Fournari and Triouflet, J. Am. Bull. Soc. Chem France, 10, 2248, (1963),

C. A., 60, 1683 (1964)

23. Ryo S., Tamio H., (2008), Ruthenium-catalyzed 1,4-Addition of Organoboronic Acids to

α,β-Unsaturated Ketones, Chem. Lett., 37(7), 724-725 (2008).

24. Bergellini and Morantonic Atti, Alad, Linli, Nencki reaction with cinnamic acid on an

aromatic compounds, Brit. Chem. Abstr., 8(i), 801 (1908).

25. H. S. Mehra and K. B. L. Mathur, Diazo coupling of phenyl diazonium chloride with

benzoyl acrylic acid, J. Indian Chem. Soc., 32, 465 (1955).

26. Christian and Amin; An Improved Method for the Synthesis of p-Alkylamino-p'-

arilinodiphenyl Sulphides" Sulphoxides &. Sulphones J. Sci. Ind. Research, 14B, 421

(1955).

27. M. Dzurilla, P. Kristian, K. Gyoryoya, Fries rearrangement of aryl cinnamates, Chemicke

Zvesti, 24(3), 207-217 (1970).

28. D. S. Noyce, W. A. Pryor, A. H. Bottini, the base catalyzed condensation of

acetophenones and aldehydes has been studied, J. Am. Chem. Soc., 77, 1402-1405 (1955).

29. A. B. Linke and D. E. Eveleigh, Z. Naturorsch, 30B, 740 (1975)

30. Andreas T., Theodara K., Christos R., Vassilios R., "1-(2-Alkoxy-5- carboxyphenyl)-a,β-

unsaturated ketones’’. Their preparation and application in therapeutics., PCT Int. Appl.,

WO 9954278 pp 22 (1999).

31. Han Y., Riwanto M., Go M.-L., Rachel P. L., (2008), Modulation of breast cancer

resistance protein (BCRP/ABCG2) by non-basic chalcone analogues Eur. J. Pharm. Sci.,

35(1-2), 30-41 (2008).

32. Achanta G., Modzelewska A., Feng Li., Khans S. R., Huang P., (2006), A Boronic-Ch

alcone Derivative Exhibits Potent Anticancer Activity through Inhibition of the

Proteasome Mol. Pharmacol., 70(1), 426-433 (2006).


34

33. Lall N., Hussein A. A., Meyer J. J. M., (2006), Antiviral and antituberculous activity of

Helichrysum melanacme constituents Fitoterapia, 77(3), 230-232 (2006).

34. Cheenpracha S., Karalai C., Ponglimanont C., Tewtrakul S., (2006), Anti-HIV-1 protease

activity of compounds from Bioorg. Med. Chem., 14 (6), 1710-1714 (2006).

35. Pedersen A. K., Fitz G., Garret A., (1985), Preparation and analysis of deuterium-

labeledaspirin: Application to pharmacokinetic studies, J. Pharm. Sci., 74(2), 188-192

(1985).

36. Lahtchev K. L., Batovska D. I., Parushev St. P., Ubiyvovk V. M., Sibirny A. A., (2008),

Antifungal activity of chalcones: A mechanistic study using various yeast strains Eur. J.

Med. Chem., 43(10), 2220-2228 (2008).

37. Talley J. J., Sikorski J. A., Graneto M. J., Carter J. S., Norman B. H., Devadas B., (2002),

Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-

lipoxygenase inhibitors U. S. Pat. Appl. Publ. US 20020058810 pp 54 (2002).

38. Dimmock J. R., Manavathu E. K., (2000), Mannich bases of conjugated styryl ketones U.

S. Pat. US 6017933 pp 23 (2000).

39. Katade S., Phalgune U., Biswas S., Wakharkar R., Deshpande N., Microwave studies on

40. Synthesis of biologically active chalcone derivatives., Indian J. Chem., 47B(6), 927-931

(2008).

41. Dominguez J. N., Leon C., Rodrigues J., Gut J., Rosenthal P. J., (2005), Synthesis and

antimalarial activity of sulfonamide chalcone derivatives, Il Farmaco, 60 (4), 307-311

(2005).

42. Go M. L., Liu M., Wilairat P., Rosenthal P. J., Kevin J., Kirk K., (2004), Antiplasmodial

Chalcones Inhibit Sorbitol-Induced Hemolysis of Plasmodium falciparum-Infected

Erythrocytes, J. Med. Chem., 45(8), 1735 (2002).

43. S. R. Modi, H. B. Naik, Oriental J. Chem., 10(1), 85-86 (1994).


35

44. Grosscurt A.C., Van H.R., Wellinga K. (1979), 1-Phenylcarbamoyl-2-pyrazolines, a new

class of insecticides. 3. Synthesis and insecticidal properties of 3,4-diphenyl-1-

phenylcarbamoyl-2-pyrazolines J. Agri. Food. Chem., 27(2), 406-409 (1979).

45. Bombardelli E., Piero V.; (1998), Chalcones possedantune activity proliferante PCT Int.

Appl. WO 9858913 pp 18.

46. Ziegler H. L., Hansen H. S., Staerk D., Christensen S. B., Hagerstrand H., (2004), The

Antiparasitic Compound Licochalcone A Is a Potent Echinocytogenic Agent That

Modifies the Erythrocyte Membrane in the Concentration Range Where Antiplasmodial

Activity Is Observed. Antimicrob. Agents Chemother. 48(10), 4067-4071.

47. Go M. L., Liu M., Wilairat P., Rosenthal P. J., Kevin J., Kirk K., (2004),

AntiplasmodialChalcones Inhibit Sorbitol-Induced Hemolysis of Plasmodium

falciparum-Infected Erythrocytes Antimicrob. Agents Chemother., 48(9), 3241-3245. N.

Kazuhiko, G. Torakoontiwakon, M. Kameyama, O. Hiroshi, Y. Mitsuru, T. Toujirou,

Jpn. Kokai Tokkyo Koho JP, 2003040829 pp 6 (2003).

48. Lin Y. M., Zhou Y., Flavin M. T., Zhou Li-M., Nie W., C Fa. Chen; (2002), Chalcones

and flavonoids as anti-Tuberculosis agents, Bioorg. Med. Chem., 10(8), 2795-2802.

49. Ko H. H., Tsao L. T., Yu K. L., Liu C. T., Wang J. P., Lin C. N., (2003), Structure–

activity relationship studies on chalcone derivatives: the potent inhibition of chemical

mediators release, Bioorg.Med. Chem., 11(1), 105-111.

50. Eiichi B. B. Kalashnikov, I. P. Kalashnikova, Russ. J. Gen. Chem., 68(8), 1343-1344

(1998).

51. Walavalkar Toru O., Yoshihito O., Shoji S., Nobuyuki N., Susumu I., (1999),Jpn.

KokaiTokkyo Koho New Chalcone and Pharmaceutical Containing the compound, JP

11349521 pp 7.

52. Pratap R., Satyanarayana M., Nath C., Raghubir R., Puri A., Chander R., Tiwari

P.,Tripathi B., Srivastava A., (2006), Oxy substituted chalcones as antihyperglycemic and


36

antidyslipidemic agents, U.S. Pat. Appl. Publ. US 2006142303,pp. 19. V. R. Mudalir and

V. Joshi; Ind. J. Chem., 34B(5), 456-57 (1995).

53. H. H. Ko, H. K. Hsieh, C. T. Liu, H. C. Lin, C. M. Teng and C. N. Lin; prepared some

new chalcones for potent inhibition of platelet aggregation, J. Pharm. Pharmacol.,

56(10), 1333-37 (2004).

54. Ziegler H. L., Hansen H. S., Staerk D., Christensen S. B., Hagerstrand H., (2004), The

Antiparasitic Compound Licochalcone A Is a Potent Echinocytogenic Agent That

Modifies the Erythrocyte Membrane in the Concentration Range Where Antiplasmodial

Activity Is Observed, Antimicrob. Agents Chemother., 48(10), 4067-71 (2004).

55. C. X. Xue, S. Y. Cui, M. C. Liu, Z. D. Hu and B. T. Fan; The antimalarial activities of

chalcones have also been reported, Eur. J. Med. Chem., 39(9), 745-53 (2004).

56. Dominguez J. N., Leon C., Rodrigues J., Gut J., Rosenthal P. J., (2005), Synthesis and

antimalarial activity of sulfonamide chalcone derivatives, IlFarmaco, 60 (4), 307-311. W.

D. Seo, J. H. Kim and K. H. Park Bioorg. Med. Chem., 15(24), 5514-16 (2005).

57. M. Larsen, H. Kromann, A. Kharazmi and S. F. Nielsen; have reported anti-plasmodial

activity, Bioorg. Med. Chem., 15(21), 4858-61 (2005).

58. X. Wu, R. T. Edward, L. Kostetski, N. Kocherginsky, A. L. C. Tan, P. Wilairat and M. L.

Go; have reported anti-plasmodial activity, Eur. J. Pharma. Sci., 27(2-3), 175-87 (2006).

59. P. Boeck, C. Alves and B. R. Bergmann; have reported anti leishmanial activity of some

chalcones, Bioorg. Med. Chem., 14(5), 1538-45 (2006).

60. Shao-Jie Wang, Ju-Fang Yan, Dong Hao, Xin-Wen Niu and Mao-Sheng Cheng; have

synthesized chalcones derivatives (I) and reported them as a Aldose Reductase Inhibitors.

Molecules, 12, 885-895 (2007).

61. Ni Liming, K. J. Worsencrott, M. D. Weingarten, C. Q. Meng and J. A. Sikorski; have

synthesized chalcones and screened for their antiinflammatory and cardiovascular

activity, U. S. US WO, 02, 41336 (2002); Chem. Abstr., 139, 85160 (2003).


37

62. K. Kumar Srinivas, E. Hager, C. Pehit, H. Gurulingoppal, N. E. Davidson and S. R.

Khan; J. Med. Chem., 46(14), 2813-15 (2003); Chem. Abstr., 139, 117464 (2003).

63. Ko Horng-Huey, Tsao Lo-Ti, Yo Kum-Lung, Cheng-Tsung, Wong J. P. and Lin C. N.;

have synthesized chalcones as a antitumor agent, Bioorganic & Medicinal Chemistry,

11(1), 105-111 (2003); Chem. Abstr., 139, 30144 (2003).

64. Nakahara Kazuhiko, G. Torakoontiwakon, M. Kaneyama, Ono Hiroshi and Yoshida

Mitsuru; Jpn. Kokai Tokkyo Koho JP, 03, 040829 (2003); Chem. Abstr., 138, 158753

(2003).

65. Lin Yuh-Meei, Zhou Yasheen, M. T. Flavin, L. M. Zhou, W. Nie F. C. Cheng,

synthesized chalcones and tested as carcinogen inhibitors Bioorganic & Medicinal

Chemistry, 10(8), 2795-2802 (2002); Chem. Abstr., 138, 66146 (2003).

66. A. Nagaraj and C. Sanjeeva Reddy; reported Antimicrobial, Antifungal Activity of some

bis-chalcones J. Iran. Chem. Soc., 5(2), 262-267 (2008).

67. M. J. Alcaraz, A. M. Vicente, A. Araico, J. N. Dominguez and M. C. Terencio; have

described the role of nuclear factorkappa B and heme oxygenase-1 in the action of an

anti-inflammatory Chalcone derivative i Br. J. Pharmacol., 142(7), 1191-9 (2004).

68. O. Nerya, R. Musa, S. Khatib, S. Tamir and J. Vaya; have prepared some new chalcones

as potent tyrosinase inhibitors (III) Phytochemistry., 65(10), 1389-95 (2004).

69. Sung Hee Lee, Geom Seog Seo and Dong Hwan Shon; have synthesized and investigated

the antiinflammatory activity of 2,4,6-tris(methoxymethoxy)chalcone derivatives,

European Journal of Pharmacology, 532(1-2), 178-186 (2006).

70. Liu Mei, Wilairat Prapon and GO Mei-Lin; prepared chalcones and screened for

antimalarial activity, J. Med. Chem., 45(8), 1735 (2002); Chem. Abstr., 139, 94746

(2003).

71. Opletalova Veronika, Jahodar L., Jun D and Opletal L.; have synthesized chalcones and

tested as cardiovascular agents Ceska a Slovenska Farmacie, 52(1), 12-19 (2003); Chem.

Abstr., 138, 265043 (2003).


38

72. Rojas. Javier, J. N. Dominguez, J. E. Charris, Lobo Gricela, M. Paya and L. Ferrandiz ;

chalcone derivatives possesses nitric oxide inhibitor, Eur. J. Med. Chem., 37(8), 699-705

(2002); Chem. Abstr., 138, 122472 (2003).

73. Rojas Javier, M. Paya, J. N. Qominguez and F. M. Luisa; chalcone derivatives possesses

nitric oxide inhibitor, Bioorg. & Med. Chem. Letters, 12(15), 1951-54 (2002); Chem.

Abstr., 138, 39068(2003).

74. N. N. Mateeva, R. N. Kode and K. K. Redda; chalcone derivatives possesses nitric oxide

anti HIV, J. Heterocycl. Chem., 39(6), 1251-58 (2002); Chem. Abstr., 138, 401568

(2003).

75. Wu Jiu-Hong, Wang Xi-Hong, Yi Yang-Huy, Lee Kuo-Hsiung; chalcone derivatives

possesses nitric oxide anti HIV, Bioorg. & Med. Chem. Jeff., 13(10), 1813-1815 (2003);

76. G. A. Potter and P. C.; Butter PCT chalcone derivatives possesses nitric oxide

antiproliferative, Int., Appl. WO, 03, 028713 (2002) (Cl. A61K03100).

77. Potter G. A., Ijaz Taeeba; chalcone derivatives possesses nitric oxide, PCT Int. Appl. WO,

03, 029176 (Cl. C07 C049-84) (2002).

78. Khatib S., Nerya O., Musa R., Shmuel M., Tamir S., Vaya J.; synthesized some novel

chalcones as potent tyrosinase inhibitors, Bioorg Med Chem., 13(2), 433-41(2005).

79. Ko H. H., Hsieh H. K., Liu C. T., Lin H. C., Teng C. M., Lin C. N; have prepared some

new chalcones for potent inhibition of platelet aggregation, J Pharm Pharmacol., 56(10),

1333-7(2004).

80. Ziegler H. L., Hansen H. S., Staerk D., Christensen S. B., Hagerstrand H.; reported

chalcones as an antiparasitic, Antimicrob Agents Chemother., 48(10), 4067-71(2004).

81. Go M. L., Liu M., Wilairat P., Rosenthal P. J., Saliba K. J., Kirk K.; have described the

synthesis and biological activities of chalcones as antiplasmodial Antimicrob Agents

Chemother., 48(9), 3241-5(2004).


39

82. Woo Duck Seo, Jin Hyo Kim and Ki Hun Park; A new class of sulfonamide

chalconessynthesized and their glycosidase inhibitory activity were investigated,

Bioorganic & Medicinal Chemistry Letters, 15(24), 5514-5516 (2005).

11 chapter 3 Synthesis and biological...

Documents

Transcript of 11 chapter 3 Synthesis and biological...