SYNTHESIS AND BIOLOGICAL ACTIVITIES OF O...

SYNTHESIS AND BIOLOGICAL ACTIVITIES OF O- AND C-PRENYLATED

FLAVONOID DERIVATIVES

NUR EDELIN BINTI MOHD FAUZI

A thesis submitted in fulfillment of the

requirements for the award of the degree of

Master of Science (Chemistry)

Faculty of Science

Universiti Teknologi Malaysia

MARCH 2017

iii

With lots of love,

Parents and Grandparents

The siblings,

Siti Umairah

Fairuz Wirdani

Muhammad Abbas

Muhammad Umar

Wonderful husband,

Muhammad Shahrul bin Po’at

For always standing by my side through ups and downs

iv

ACKNOWLEDGEMENTS

With the name of Allah the Most Gracious and Merciful. All praise and

gratitude be given to Him for giving me great strength, patience and courage to finish

what I choose to start.

First of all, I would like to express my deepest appreciation to Assoc. Prof.

Dr. Farediah Ahmad for her supervision, advice, and guidance from the beginning

until now. She will always be the best teacher ever for not giving up on me and

always supporting me.

To my fellow postgraduate colleagues, Athirah, Nuzul, Mala, Saidu, and

others (members of MPKO 1 and MPKO 2), for the valuable advice in science

discussion, commentary and friendship, thank you a lot.

It is a pleasure to pay tribute also to the data collection collaborators. To Mr.

Amin Mr. Azmi, Mr. Rashidi and Mr. Subri, I would like to thank for their assistance

in obtaining the data of all the compounds.

Last but not least, for all whose involved in helping to accomplish this

journey, all of you have been an auxiliary through all the time. Thank you.

v

ABSTRACT

Chalcones scaffolds have attracted many researchers to investigate their

synthetic routes, potential biological activities and their roles as intermediates for

naturally occurring flavanoid skeletons. This study focused on the synthesis of

chalcones bearing the O-, C-prenyl and chromane as substituents. The target

compounds were purified by chromatographic methods and the structures of these

compounds were determined by using infrared (IR), nuclear magnetic resonance

(NMR) and mass spectrometry (MS) spectroscopies. The prenylated precursors were

synthesized starting from 2,4-dihydroxyacetophenone (65) and 2,4,6-

trihydroxyacetophenone (93). Prenylation of 2,4-dihydroxyacetophenone using

prenyl bromide has been successfully accomplished to produce 2-hydroxy-4-O-

prenylacetophenone (101). A reaction of 2,4,6-trihydroxyacetophenone with prenyl

bromide in the presence of base resulted in a mixture and the chromatographic

purification gave 2,4,6-trihydroxy-3-C-prenylacetophenone (132) and 2,4-dihydroxy-

5,6-chromanacetophenone (133). Compound (133) was prenylated into 2-hydroxy-4-

O-prenyl-5,6-chromanacetophenone (136). C-prenylated acetophenone (132) was

then converted to 2-hydroxy-3-C-prenyl-4,6-dimethoxyacetophenone (137) using

methyl iodide in the presence of potassium carbonate. Claisen-Schmidt condensation

of O- and C-prenylated acetophenone with individual benzaldehydes, namely 4-

(N,N-dimethyl)aminobenzaldehyde (61), 2-methoxybenzaldehyde (126), 4-

isopropylbenzaldehyde (127), 3,4-dimethoxybenzaldehyde (128) and 4-

chlorobenzaldehyde (129) resulted in the formation of two series of chalcones, each

consisting of five chalcones. These two series differ in the existence of prenyl

substituents on ring A of the chalcone structure. Five chalcones bear O-prenyl and

five others bear C-prenyl substituent with both series having the same substituents on

ring B consisting of 4-(N,N-dimethyl)amino, 2-methoxy, 4-isopropyl, 3,4-dimethoxy

and 4-chloro substituents. Chromanochalcone (152) was the sole compound

successfully synthesized with the aid of prenylation of free hydroxyl group of the

chromanacetophenone (133) precursor. All the synthetic compounds were screened

for antibacterial activity by the micro dilution method against two bacteria strains,

namely Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram

negative (Pseudomonas aeruginosa and Escherichia coli). The compounds were also

tested for 15-LOX assay using Lipoxygenase inhibitory screening assay kit (Item No.

760700). All the synthetic compounds did not show activity against the bacteria

tested, while compound (138) and (145) showed moderate lypoxygenase activity at

100 M concentration with 53.9% and 50.9% inhibition, respectively.

vi

ABSTRAK

Rangka kalkon telah menarik ramai penyelidik untuk mengkaji laluan

sintesis, keupayaan aktiviti biologi dan peranannya sebagai bahan perantara untuk

rangka flavanoid semulajadi. Kajian ini memfokuskan kepada sintesis kalkon yang

mempunyai penukarganti O-, C-prenil dan kromano. Sebatian sasaran ditulenkan

dengan kaedah kromatografi dan struktur semua sebatian ditentukan dengan

menggunakan kaedah spektroskopi inframerah (IM), resonans magnetik nuklear

(RMN) dan spektrometri jisim (SJ). Prekursor terprenil telah disintesiskan bermula

daripada 2,4-dihidroksiasetofenon (65) dan 2,4,6-trihidroksiasetofenon (93).

Pemprenilan 2,4-dihidroksiasetofenon menggunakan prenil bromida telah

dilaksanakan dengan jayanya bagi menghasilkan 2-hidroksi-4-O-prenilasetofenon

(101). Tindak balas 2,4,6-trihidroksiasetofenon dengan prenil bromida dengan

kehadiran bes telah menghasilkan satu campuran, dan penulenan kromatografi

memberikan 2,4,6-trihidroksi-3-C-prenilasetofenon (132) dan 2,4-dihidroksi-5,6-

kromanasetofenon (133). Sebatian (133) telah diprenilkan kepada 2-hidroksi-4-O-

prenil-5,6-kromanasetofenon (136). C-prenilasetofenon (132) kemudian diubah

kepada 2-hidroksi-3-C-prenil-4,6-dimetoksiasetofenon (137) menggunakan metil

iodida dengan kehadiran kalium karbonat. Kondensasi Claisen-Schmidt O- dan C-

prenilasetofenon dengan benzaldehid individu, iaitu 4-(N,N-

dimetil)aminobenzaldehid (61), 2-metoksibenzaldehid (126), 4-isopropilbenzaldehid

(127), 3,4-dimetoksibenzaldehid (128) dan 4-klorobenzaldehid (129) telah

menghasilkan dua siri kalkon, tiap-tiap satu terdiri daripada lima kalkon. Dua siri ini

berbeza dari segi kewujudan prenil pada gelang A struktur kalkon. Lima kalkon

mempunyai O-prenil dan lima kalkon yang lain mempunyai penukar ganti C-prenil

dengan kedua-dua siri mempunyai penukar ganti yang sama pada gelang B yang

terdiri daripada penukar ganti 4-(N,N-dimetil)amino, 2-metoksi, 4-isopropil, 3,4-

dimetoksi and 4-kloro. Kromanokalkon (152) adalah sebatian tunggal yang berjaya

disintesis dengan bantuan pemprenilan kumpulan hidroksil bebas pada prekursor

kromanasetofenon (133). Semua sebatian sintetik telah disaring untuk aktiviti

antibakteria menggunakan kaedah pencairan mikro terhadap dua jujukan bakteria

iaitu Gram positif (Staphylococcus aureus dan Bacillus subtilis) dan Gram negatif

(Pseudomonas aeruginosa dan Escherichia coli). Sebatian juga telah diuji untuk

cerakin 15-LOX menggunakan kit cerakin saringan perencatan lipoksigenase (Item

No. 760700). Semua sebatian sintetik tidak menunjukkan aktiviti terhadap bakteria

yang diuji, manakala sebatian (138) dan (145) menunjukkan aktiviti lipoksigenase

sederhana pada kepekatan 100 M dengan masing-masing mempunyai nilai

perencatan sebanyak 53.9% dan 50.9%.

vii

TABLE OF CONTENTS

CHAPTER TITLE PAGE

DECLARATION ii

DEDICATION iii

ACKNOWLEDGMENTS iv

ABSTRACT v

ABSTRAK vi

TABLE OF CONTENTS vii

LIST OF TABLES xii

LIST OF SCHEMES xiii

LIST OF FIGURES xvi

LIST OF ABBREVIATIONS xvii

LIST OF APPENDICES

xix

1 INTRODUCTION 1

1.1 General Introduction 1

1.2 Problem Statement 2

1.3 Objectives of Study 3

1.4 Scope of Study 3

2 LITERATURE REVIEW 5

2.1 Flavonoids 5

2.2 Chalcones 5

2.3 Biosynthesis of Chalcones 6

2.4 Prenylated Chalcones 9

viii

2.5 Chromanochalcones and Pyranochalcones 11

2.6 Chemical Synthesis of Chalcones

Derivatives

13

2.6.1 KOH and NaOH as Catalyst 13

2.6.2 BF3.Et2O and K2CO3 as Catalyst 19

2.6.3 DBU, Pyridine or Piperidine as

Catalyst

21

2.6.4 Suzuki-Miyaura Reaction 24

2.6.5 Heterogenous and Ecofriendly

Synthesis Methods

25

2.7 Biological Activities of Chalcones 26

3 RESULTS AND DISCUSSION 30

3.1 Retrosynthetic Analysis 30

3.2 Synthesis of Chalcone Intermediates 31

3.3 Prenylation of Acetophenone 31

3.3.1 Prenylation Using DBU as

Catalyst

32

3.3.2 Prenylation Using K2CO3 as

Catalyst

40

3.3.3

Prenylation of 2,4-dihydroxy-5,6-

chromanoacetophenone (133) by

Using DBU

42

3.4 Synthesis of Methylated Acetophenone 43

3.5

Synthesis of Series of Prenylated Chalcones 45

3.5.1 Synthesis of 2'-Hydroxy-4-(N,N-

dimethyl)amino-4'-O-

prenylchalcone (125)

46

3.5.2

Synthesis of 2'-Hydroxy-2-

methoxy-4'-O-prenylchalcone

(138)

48

3.5.3 Synthesis of 2'-Hydroxy-4-

isopropyl-4'-O-prenylchalcone

52

ix

(139)

3.5.4 Synthesis of 2'-Hydroxy-3,4-

dimethoxy-4'-O-prenylchalcone

(140)

54

3.5.5

Synthesis of 2'-Hydroxy-4-chloro-

4'-O-prenylchalcone (141) 55

3.6 SSynthesis of C-Prenylchalcone Derivatives 56

3.6.1 Synthesis of 2'-Hydroxy-4',6'-

dimethoxy-4-N,N-

dimethyl)amino-3'-C-


57

3.6.2

Synthesis of 2'-Hydroxy-2,4',6'-

trimethoxy-3'-C-prenylchalcone

(143)

59

3.6.3

Synthesis of 2'-Hydroxy-4',6'-

dimethoxy-4-isopropyl-3'-C-


60

3.6.4

Synthesis of 2'-Hydroxy-

3,4,4',6'-tetramethoxy-3'-C-


62

3.6.5

Synthesis of 2'-Hydroxy-4',6'-

dimethoxy-4-chloro-3'-C-


63

3.7

Comparison of Yields for the Synthesized

of O-and C-Prenylated Chalcones

66

3.8

Synthesis of 2'-Hydroxy-4-(N,N-

dimethyl)amino-4'-O-prenyl-5,6-

chromanochalcone (152)

67

3.9 Alternative Method for Chalcone Synthesis 70

3.10 Antibacterial Activity 74

3.11 Lipoxygenase Activity 74

4 EXPERIMENTAL 76

4.1 General Introduction 76

4.2

Synthesis of Prenylated Acetophenone

77

x

Using DBU as Catalyst

4.2.1

Prenylated Precursor from 2,4-

Dihydroxyacetophenone (65)

77

4.2.2

Prenylated Precursor From 2,4,6-

Trihydroxyacetophenone (93)

78

4.3 Synthesis of Prenylated Acetophenone

Using K2CO3 as Catalyst

80

4.3.1 Prenylated Precursor from 2,4-

Dihydroxyacetophenone (65)

80

4.3.2

Prenylated Precursor from 2,4,6-

Trihydroxyacetophenone (93)

80

4.4

Synthesis of Chromanoacetophenone (133)

by Using DBU and K2CO3

82

4.5

Prenylation of 2,4-dihydroxy-5,6-

chromanacetophenone (133) by Using DBU

83

4.6

Synthesis of Methylated C-

prenylacetophenone

83

4.7

General Procedure for Synthesis of O-

Prenylated Chalcones Derivatives

84

4.8 General Procedure for Synthesis of C-

Prenylated Chalcones Derivatives

87

4.9

Synthesis of 2'-Hydroxy-4-(N,N-



90

4.10 Attempted Synthesis of Chromanochalcone

via Grinding Method

91

4.11 Attempted Synthesis of Hydroxylated

Chalcone Using Piperidine

92

4.12

Attempted Synthesis Hydroxylated C-

Prenylated Chalcones using BF3.OEt2

92

4.13 Antibacterial activity 93

4.13.1 Chemicals and Microorganisms 93

4.13.2

Minimum Inhibitory

Concentration (MIC) and

Minimum Bactericidal

94

xi

Concentration (MBC)

4.14 Lipoxygenase Activity 95

4.14.1 Chemicals and Instrumentation 95

4.14.2 15-Lipoxygenase Inhibitory

Activity

95

5 CONCLUSION AND RECOMMENDATIONS 97

5.1 Conclusion 97

5.2 Recommendations 98

REFERENCES 99

APPENDICES 113

xii

LIST OF TABLES

TABLE NO. TITLE PAGE

2.1 Chalcones with C-prenyl substituents 28

3.1 Data of 1H NMR and

13C NMR spectra for compound

(101) and (131)

35

3.2 Stoichiometric equivalence of reagents for synthesis of

prenylated compounds

41

3.3 NMR data tabulation for compound (137)

44

3.4 NMR (1H and

13C) data of compound (138)

49

3.5 NMR (1H and

13C) data of compound (139) 53

3.6 NMR (1H and

13C) data of compound (142) 58

3.7 1H NMR and

13C NMR spectrum of compounds (143-

146)

64

3.8 Yield and melting point of chalcones (125, 138-146) 66

3.9 13

C NMR and DEPT of compound (152) 69

3.10 15-Lipoxygenase Inhibition by chalcones

75

xiii

LIST OF SCHEMES

SCHEMES TITLE PAGE

2.1 Biosynthesis pathways of chalcones 7

2.2 Biosynthetic pathway of xanthohumol (9) in plants 9

2.3 Synthesis of chalcones (46) via Claisen-Schmidt

condensation

14

2.4 Synthesis of chalcone (49), O-prenylated (50) and O-

geranylated derivatives (51)

14

2.5 Synthesis of chalcone derivatives (57-59) 15

2.6 Synthesis of chalcones via Claisen-Schmidt

condensation using KOH in EtOH

16

2.7 Synthesis of geranylated chalcones 17

2.8 Synthesis of xanthohumol (9) 18

2.9 Formation of acylated chalcones (80) by means of

BF3.Et2O

19

2.10 Chelation and cyclization of C-prenylated chalcone 20

2.11 Prenylation of flavonoids using K2CO3 21

2.12 Chalcone synthesis via Julia-Kocienski olefination 22

2.13 DBU as catalyst for alkylation 22

2.14 Formation of acyl chromene (99) and

chromenochalcones (100)

23

2.15 Synthesis of chalcone using piperidine 24

2.16 Suzuki-Miyaura reaction for synthesis of chalcone 25

2.17 Synthesis of chalcones using NaOH under solvent free

condition

25

xiv

2.18 Synthesis of chalcones using NaOH-Al2O3 26

3.1 Retrosynthetic pathway of chalcone (125) 30

3.2 Prenylation of 2,4-dihydroxyacetophenone (65) 32

3.3 Prenylation of 2,4,6-trihydroxyacetophenone (93) 37

3.4 Mechanism of C-prenyl cyclization into chromane 38

3.5 Mechanism of prenylation using DBU as base catalyst 39

3.6 Prenylation using DBU with different stoichiometry of

reagents

40

3.7 Prenylation of 2,4-dihydroxyacetophenone (65) using

K2CO3

41

3.8 Prenylation of 2,4,6-trihydroxyacetophenone (93) using

K2CO3

41

3.9 Prenylation of 2,4-dihydroxy-5,6-chromanacetophenone

(133)

42

3.10 Methylation of compound (132) 43

3.11 Mechanism for the formation of chalcone (149) 46

3.12 Reaction for the formation of (125) 47

3.13 Synthesis of 2'-hydroxy-2-methoxy-4'-O-prenylchalcone

(138)

48

3.14 Mass fragmentation pattern of compound (138) 51

3.15 Synthesis of 2'-hydroxy-4-isopropyl-4'-O-


52

3.16 Synthesis of 2'-hydroxy-3,4-dimethoxy-4'-O-


54

3.17 Synthesis of 2'-hydroxy-4-chloro-4'-O-prenylchalcone

(141)

55

3.18 Synthesis of 2'-hydroxy-4',6'-dimethoxy-4-(N,N-

dimethyl)amino-3'-C-prenylchalcone (142)

57

3.19 Synthesis of 2'-hydroxy-2,4',6'-trimethoxy-3'-C-


59

3.20 Synthesis of 2'-hydroxy-4',6'-dimethoxy-4-isopropyl-3'-

C-prenylchalcone (144)

60

xv

3.21 Mass fragmentation pattern of C-prenylated compound

(144)

61

3.22 Synthesis of 2'-hydroxy-3,4,4',6'-tetramethoxy-3'-C-


62

3.23 Synthesis of 2'-hydroxy-4',6'-dimethoxy-4-chloro-3'-C-


63

3.24 Cannizaro reaction on benzaldehyde 67

3.25 Retrosynthetic route of synthesis pathway for compound

(152)

68

3.26 Attempt of chalcone synthesis via grinding method 70

3.27 Attempt of chalcone synthesis using piperidine as base 71

3.28 Attempt of synthesis of C-prenylated chalcone using

BF3.Et2O

71

3.29 Proposed mechanism of prenyl cyclization to chromane

substituent

72

xvi

LIST OF FIGURES

FIGURES TITLE PAGE

2.1 Biosynthetic pathway for prenylated flavonoids 8

3.1 Comparison spectra of O-prenylated acetophenone

(101) and C-prenylated acetophenone (131)

34

3.2 Electron delocalization of phenoxide 2,4-

dihydroxyacetophenone (65)

36

3.3 Spectra of chromane acetophenone (133) (a) and

expected chalcone (b)

73

xvii

LIST OF ABBREVIATIONS

BF3-Et2O boron trifluoride etherate

13C carbon-13

CD3COCD3 deuterated acetone

CDCl3 deuterated chloroform

CHCl3 chloroform

d doublet

DBU 1,8-diazobicyclo [5.4.0] undec-7-ene

dd doublet of doublets

DEPT Distortionless Enhancement by Polarization Transfer

EIMS Electron Impact Mass Spectrometry

Et2O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

1H proton

HCl hydrochloric acid

HMBC heteronuclear multiple bond correlation

HMQC heteronuclear multiple quantum coherence

Hz hertz

iNOS inducible nitric oxide synthase

IR infrared

IM inframerah

J coupling constant

K2CO3 potassium carbonate

KBr potassium bromide

KOH potassium hydroxide

lit. Literature

LOX Lipooxygenase

xviii

m/z mass to charge ratio

m multiplet

M molar

MBC minimum bactericidal concentration

Me2SO4 dimethyl sulphate

MeOH methanol

MgSO4 magnesium sulphate

MHz megahertz

MIC minimum inhibition concentration

MOM methoxylmethyl ether

m.p melting point

MS mass spectrometry

NaOH sodium hydroxide

NMR nuclear magnetic resonance

ppm parts per million

Rf retention factor

RMN resonans magnetik nuklear

SD standard deviation

s singlet

sept septet

SM spectrum jisim

t triplet

THP tetrahydropyranyl acetal

TLC thin layer chromatography

δ chemical shift

λ lambda

xix

LIST OF APPENDICES

APPENDIX TITLE PAGE

1 1H NMR spectrum of 2,4-O-diprenylacetophenone

(130)

114

2 IR spectrum of 2-hydroxy-4-O-prenylacetophenone

(101)

115

3 1H NMR spectrum of 2-hydroxy-4-O-

prenylacetophenone (101)

116

4 13

C NMR spectrum of 2-hydroxy-4-O-


117

5 1H NMR spectrum of 2,4-dihydroxy-C-


118

6 13

C NMR spectrum of 2,4-dihydroxy-3-C-


119

7 IR spectra of 2,4,6-trihydroxy-C-


120

8 1H NMR of 2,3,6-trihydroxy-C-prenylacetophenone

(132)

121

9 13

C NMR spectrum of 2,4,6-trihydoxy-C-


122

10 IR spectrum of 2,4-dihydroxy-5,6-

chromanoacetophenone (133)

123

11 1H NMR spectrum of 2,4-dihydroxy-5,6-

chromanoacetophenone (133)

124

12 1H NMR spectrum of 2,6-dihydroxy-4-O-


125

13 1H NMR spectrum of 2,6-dihydroxy-3-C-4-O-

diprenylacetophenone (135)

126

xx

14 1H NMR spectrum of 2-hydroxy-4-O-prenyl-5,6-

chromanacetophenone (136)

127

15 IR spectrum of 2-hydroxy-3-C-prenyl-4,6-

dimethoxyacetophenone (137)

128

16 1H NMR of 2-hydroxy-3-C-prenyl-4,6-


129

17 13

C NMR spectrum of 2-hydroxy-3-C-prenyl-4,6-


130

18 IR spectrum of 2'-hydroxy-4-(N,N-

dimethyl)amino-4'-O-prenylchalcone (125)

131

19 1H NMR spectrum of 2'-hydroxy-4-(N,N-


132

20 13

C NMR spectrum of 2'-hydroxy-4-(N,N-


133

21 IR spectrum of 2'-hydroxy-2-methoxy-4'-O-


134

22 1

H NMR spectrum of 2'-hydroxy-2-methoxy-4'-O-


135

23 13

C NMR spectrum of 2'-hydroxy-2-methoxy-4'-O-


136

24 HMQC spectrum of 2'-hydroxy-2-methoxy-4'-O-


137

25 MS spectrum of 2'-hydroxy-2-methoxy-4'-O-


138

26 IR spectrum of 2'-hydroxy-4-isopropyl-4'-O-


139

27 1H NMR spectrum of 2'-hydroxy-4-isopropyl-4'-O-


140

28 13

C NMR of 2'-hydroxy-4-isopropyl-4'-O-


141

29 HMQC spectrum of 2'-Hydroxy-4-isopropyl-4'-O-


142

30 IR spectrum of 2'-hydroxy-3,4-dimethoxy-4'-O-


143

31 1H NMR spectrum of 2'-hydroxy-3,4-dimethoxy- 144

xxi

4'-O-prenylchalcone (140)

32 13

C NMR spectrum of 2'-hydroxy-3,4-dimethoxy-

4'-O-prenylchalcone (140)

145

33 DEPT spectrum of 2'-hydroxy-3,4-dimethoxy-4'-

O-prenylchalcone (140)

146

34 IR spectrum of 2'-hydroxy-4-chloro-4'-O-


147

35 1H NMR spectrum of 2'-hydroxy-4-chloro-4'-O-


148

36 13

C NMR spectrum of 2'-hydroxy-4-chloro-4'-O-


149

37 IR spectrum of 2'-hydroxy-4',6'-dimethoxy-4-(N,N-

dimethyl)amino-3'-C-prenylchalcone (142)

150

38 1H NMR spectrum of 2'-hydroxy-4',6'-dimethoxy-

4-(N,N-dimethyl)amino-3'-C-prenylchalcone (142)

151

39 13

C NMR spectrum of 2'-hydroxy-4',6'-dimethoxy-

4-(N,N-dimethyl)amino-3'-C-prenylchalcone (142)

152

40 HMQC spectrum of 2'-Hydroxy-4',6'-dimethoxy-4-

(N,N-dimethyl)amino-3'-C-prenylchalcone (142)

153

41 IR spectrum of 2’-hydroxy-2,4’,6’-trimethoxy-3’-C-prenylchalcone (143)

154

42 1H NMR spectrum of 2'-hydroxy-2,4',6'-

trimethoxy-3'-C-prenylchalcone (143)

155

43 13

C NMR spectrum of 2'-hydroxy-2,4',6'-

trimethoxy-3'-C-prenylchalcone (143)

156

44 IR spectrum of 2'-hydroxy-4',6'-dimethoxy-4-

isopropyl-3'-C-prenylchalcone (144)

157


4-isopropyl-3'-C-prenylchalcone (144)

158

46 13


4-isopropyl-3'-C-prenylchalcone (144)

159

47 HMQC spectrum of 2'-Hydroxy-4',6'-dimethoxy-4-


160

48 MS spectrum of 2'-hydroxy-4',6'-dimethoxy-4-


161

xxii

49 IR spectrum of 2'-hydroxy-3,4,4',6'-tetramethoxy-

3'-C-prenylchalcone (145)

162

50 1H NMR spectrum of 2'-hydroxy-3,4,4',6'-

tetramethoxy-3'-C-prenylchalcone (145)

163

51 13

C NMR spectrum of 2'-hydroxy-3,4,4',6'-


164

52 HMQC spectrum of 2'-hydroxy-3,4,4',6'-


165

53 IR spectrum of 2'-hydroxy-4',6'-dimethoxy-4-

chloro-3'-C-prenylchalcone (146)

166


4-chloro-3'-C-prenylchalcone (146)

167

55 13


4-chloro-3'-C-prenylchalcone (146)

168

56 DEPT spectra of 2'-hydroxy-4',6'-dimethoxy-4-

chloro-3-C-prenylchalcone (146)

169

57 IR spectrum of 2'-hydroxy-4-(N,N-



170

58 1H NMR spectrum of 2'-hydroxy-4-(N,N-



171

59 13

C NMR spectrum of 2'-hydroxy-4-(N,N-

dimethyl)amino-4'-O-prenyl-5',6'-


172

60 DEPT spectra of 2'-hydroxy-4-(N,N-



173

61 HMQC spectrum of 2'-hydroxy-4-(N,N-



174

62 1H NMR spectrum as a result of grinding method

175

63 1H NMR spectrum as a result of synthesized

chalcone using piperidine

176

xxiii

64 1H NMR spectrum as a result of synthesized

chalcone using BF3.Et2O

177

CHAPTER 1

INTRODUCTION

1.1 General Introduction

Flavonoids are abundance group of polyphenolic substances which can be

extracted in most plants and sometimes presence as glycosides [1]. Multiple

combination of substituent such as hydroxyl, oxygen, methyl groups and sugars

attached to these structures create the various classes of flavonoids (1), flavonols (2),

flavanones (3), flavones (4), flavan-3-ols (5), anthocyanidins (6) and isoflavones (7).

Flavonoids have shown capability as potential antitumor, antineoplastics activities,

antimicrobial and antimalarial agents [1].

OO O

O O O

A

B O

C1'

6'

5'

8

7

65 4

3

2 2'

4'

3'

1

(1)O

OH

O

OH

O

OOHOH

(2) (3) (4)

(7)(6)(5)

Chalcone is the simplest flavonoid with a fifteen-carbon skeleton (C6-C3-C6)

(8) which possessed two phenyl rings connected by three carbon bridges [2]. The

synthesized chalcones were obtained via Claisen-Schmidt condensation with

2

association of cross aldol condensation of appropriate aldehydes and ketones,

catalysed by base or acid and enclosed by dehydration [3].

O

A

B6

1

4

1'

3

2

5

3'

6'

2'

5'

4'

(8)

Chalcone (8) are intermediates in the biosynthesis of flavonoids that

widespread in plants and with an array of bioactivities [2]. Derivatives of chalcone

are physiologically active compounds and become the substrates for the valuation of

various organic syntheses [2]. Lipophilic prenyl side-chain attached to a chalcone

moiety has been attracting the attention of the scientific community because of their

myriad biological activities [4] which include O-prenylation, C-prenylation and

chroman group [5]. Natural prenylated chalcones such as xanthohumol (9) exhibit

numerous pharmacological properties such as antibacterial [6], antitumor [7],

antihistaminic [8], antioxidant [9], and antiplasmodial activity [10].

HO OCH3

OH O

OH

(9)

1.2 Problem Statement

Owing to their simple structures and ease of preparation, chalcones

intermediates for the synthesis of large number of derivatives of flavonoids. Besides

prenylation, the pharmacological properties of chalcones also related to the presence,

number and position of hydroxyl and methoxyl groups in both A and B ring. Hence,

3

the synthesis of prenylated derivatives which include O-prenyl, C-prenyl, and

chromane chalcones bearing hydroxyl and methoxyl substituents is undertaken. The

previous mentioned structural moieties are expected to display significant biological

activities.

1.3 Objectives of Study

The objectives of this study are:

1. To synthesis, purify and elucidate the acetophenone derivatives with O-

prenyl, C-prenyl and chromane as the side chains.

2. To synthesis, purify, elucidate the series of O-prenyl, C-prenyl and

chromanochalcones.

3. To screen the antibacterial and anti-inflammatory activities (LOX) of the

synthesized chalcones.

1.4 Scope of Study

The initial reactions were carried out by synthesizing O-prenyl, C-

prenylacetophenone and chromanacetophenone from 2,4-dihydroxyacetophenone

and 2,4,6-trihydroxyacetophenone using prenyl bromide in the presence of either 1,8-

diazabicycloundec-7-ene (DBU) or K2CO3 as base without the use of protecting

group. Mixtures of compounds were purified by recrystallization techniques or silica

gel column chromatography (CC). Structures of O-prenyl, C-prenyl and

chromanacetophenone were determined using IR and NMR (1D and 2D).

Acetophenone derivatives were subjected to methylation using methyl iodide in

K2CO3 followed by purification and structural elucidation. All characterized

acetophenone derivatives were subjected to Claisen-Schmidt reaction with

benzaldehyde derivatives which include benzaldehyde bearing substituents 4-(N,N-

dimethyl)amino, 2-methoxyl, 4-isopropyl, 3,4-dimethoxyl, and 4-chloro to form

4

chalcones. The reaction mixtures were purified by CC and the pure compounds were

elucidated spectroscopically by IR, NMR and MS. The synthesized chalcones were

screened for antibacterial and anti-inflammatory activities. Minimum inhibition

concentration (MIC) using microdilution method was used as the tool to determine

the antibacterial activity of the synthesized compounds against the Gram-positive

and Gram-negative bacteria. Lipoxygenase assay (LOX) was used to screen the anti-

inflammatory activity of the synthesized chalcones.

99

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