1

CHAPTER 1

INTRODUCTION

1.1. DEFINITION OF NUTRACEUTICALS

Nutraceuticals can be defined as, "a food or part of a food that provides medical or

health benefits, including the prevention and / or treatment. Nutraceuticals must not only

supplement the diet but should also aid in the prevention and / or treatment of disease

and/or disorder”. The term "nutraceutical" was coined from "nutrition" and

"pharmaceutical" in 1989 by Stephen DeFelice1. About 2000 years ago, Hippocrates

correctly emphasized “Let food be your medicine and medicine be your food". Currently,

there is an increased global interest due to the recognition that “nutraceuticals” play a

major role in health enhancement. There are several definitions for nutraceuticals each of

them describes the different attributes of nutraceuticals.

Nutraceuticals can be defined as nonspecific biological therapies used to promote

wellness, prevent malignant processes and control symptoms.

Fig. 1.1. A graphical representation of nutraceuticals

2

Nutraceuticals can also be defined as natural bioactive, chemical compounds that

have health promoting, disease preventing and / or medicinal properties.

Most of the nutraceuticals have multiple bioactive compounds, which are used to

prevent or control the disease or symptom of the disease. The use of nutraceuticals, as an

attempt to achieve desirable beneficial outcomes with reduced side effects, as compared to

other therapeutic agents2,3. The preference for the discovery and production of

nutraceuticals over pharmaceuticals is well seen in pharmaceutical and biotechnology

companies.

1.2. CATEGORIES OF NUTRACEUTICALS

Nutraceuticals can be grouped into the following three broad categories4:

1. Substances with established nutritional functions such as vitamins, minerals,

amino acids and fatty acids - Nutrients

2. Herbs or botanical products as concentrates and extracts - Herbals

3. Reagents derived from other sources (e.g. pyruvate, chondroitin sulphate, steroid

hormone precursors) serving specific functions such as sports nutrition, weight-loss

supplements and meal replacements – Dietary supplements

Out of these three categories, “the herbs and botanical herbs or botanical products

as concentrates and extracts” are the important category for chemists, due to the vast

application i.e., identification of essence compound of a nutracuetical, application of lead

compound towards the SAR based drug discovery.

3

1.3. NUTRACEUTICAL MARKET

Nutraceutical and functional food ingredients are ingredients with human health

benefits beyond basic nutrition. The Indian nutraceutical market in 2007 was INR 18.75

billion and expected to grow by 20%. The global nutraceutical market was US$ 117.3

billion in 2007, where as in 2008, it was US$ 123.9 billion. Global nutraceutical market is

projected to grow US$ 147 billion by 2010. It is expected that nutraceutical market will

reach US$ 176.7 billion in 2013 with a CAGR 7.4%. The United States has been the major

market for nutraceuticals. India and China are becoming fastest growing markets.

Vitamins, minerals and nutrients constitute about 85% of the market while antioxidants and

anti-agents account for 10% and herbal extracts occupy 5% of the market globally5.

Pharmaceutical companies are now adopting the nutraceuticals due to the

overwhelming response of the customers as well as the less expensive and time consuming

nutraceuticals research process in drug discovery.

1.4. THE LIST OF IMPORTANT NUTRACEUTICALS

The list of nutraceuticals is very vast and the list is increasing everyday. The

nutraceuticals under category I such as vitamins, minerals, amino acids and fatty acids have

stablished chemistry and biological activity and thus not discussed here. This is a list of

important nutraceuticals of category II found in our regular diet6.

Table 1.1. List of important nutraceuticals

Sl.No. Herbal origin Nutraceuticals

1 Catechu Catechins, epicatechin

2 Garlic Alliin

4

3 Aloe Polysaccharides

4 Galangal Shagoal

5 Andrographis Andrographolides

6 Asparagus Saponins

7 Belladonna Atropine

8 Margosa tree Bitters

9 Thyme-leaved gratiola Bacosides

10 Seakale beet Betaines

11 Silk Cotton Tree Boswellic acid

12 Green Tea Polyphenols

13 Senna Sennosides

14 Climbing Staff tree Alkaloids

15 Gotu Kola Asiatic Acid, Asiaticosides

16 Veld grape Ketosterones

17 Coleus Forskohlin

18 Indian Bedellium Guggalsterones

19 Turmeric, Indian Saffron Curcuminoids

20 Indian Gooseberry Vitamin C

21 Indian Gooseberry Tannins

22 Indian Gooseberry Ellagic acid

23 Whitehead Bitters

24 Jambul, Rose Apple Saponins, Alkaloids

25 Garcinia HCA

26 Mangosteen Mangostin

5

27 Liquorice, Sweet Root Glycyrrhizin

28 Liquorice, Sweet Root Deglycyrrhizinated

29 Small Indian Ipecacuanha,

Gymnemic acid

30 Bitter Gourd Bitters, Charantin

31 Cow Itch Plant L-DOPA

32 Holy Basil, St. Joseph Wort

Tannins

33 Kidney Bean Activity 8000 units

34 Indian Long Pepper Piperine

35 Black Pepper Piperine

36 Indian Kino Tree Pterostillbene, Flavones

37 Pomegranate Ellagic acid

38 Kotalahimbatu Saponins, Flavones

39 Soapnut-tree Saponins

40 Arjuna Tannins, Arjunic acid

41 Belleric myroblan Tannins

42 Chebulic myroblan Tannins

43 Tinospora Gulancha Bitters

44 Small Caltrops Saponins

45 Fenugreek Saponins

46 Fenugreek 4-hydroxyisoleucine

47 Bellirica myrobalan, Chebulic Myrobalan & Indian Gooseberry

Tannins

48 Valerian rhizome Valeric acid

49 Winter Cherry Withanolides

50 Ginger Gingerols

6

1.5. THE ESSENTIAL NUTRACEUTICALS AND THEIR APPLICATIONS

Nutraceuticals list in Table 1.1. have positive effect on our health. But in most of

the cases, the mechanism of the nutraceuticals was not established well i.e., most of them

were used traditionally as medicines without proper scientific proof.

1.5.1. Alpha Carotene7

This is found in Kiwi Fruit, Mango, Peach, Cantaloupe, Apricots, Carrots the

richest source, Pumpkin second richest, Broccoli, Spinach, Kale, Brussels sprouts, and

Sweet potato. It protects many forms of cancer: cervical, liver, pancreas, skin, lung,

stomach, neuroblastoma and also protects against the development of cataracts. Carotene

supplements derived from Palm Oil are the richest supplemental sources of Alpha carotene.

Alpha Carotene

1.5.2. Anthocyanidins8

These compounds are found in all berries and red. These compounds have

antioxidant and anti-inflammatory. They strengthen connective tissue in the body and

reduce capillary fragility i.e., bruising and help to prevent edema. They help in the

prevention of cancer from spreading by strengthening the connective tissue and resist

tumor invasiveness.

7

O+

R3'

R4'

R5'

R3

R5

R6

R7

Anthocyanidins

1.5.3. Astaxanthin9:

This is found in some type of algaes. It is a carotenoid. It has anti-inflammatory

effects on nerve cells. It prevents bladder, colon and oral cancers in animals.

O

O

OH

HO

Astaxanthin

1.5.4. Catechin10

This compound comes under the polyphenolic natural product. It is like all other

polyphenolic natural product with a very good antioxidant component. It protects against

many types of cancers, liver from alcohol damage and is useful in the treatment of

hepatitis.

O

OH

OH

HO

OH

OH

Catechin

8

1.5.5. Curcumin11

Curcumin, a major yellow pigment found in the rhizome of cucuma longa. It is a

potent antioxidant, liver detoxifier and protector, gallstone prevention and cholesterol

lowering compound. It suppresses the damage to liver cells caused by hepatitis C and

stimulates glutathione by the liver. It is a potent cancer prevention and cancer treatment

compound. It stimulates apoptosis of cancer cells. It assists in stopping all stages of cancer

formation i.e., initiation, promotion and progression. Curcumin in preliminary studies

suggests that it is likely to inhibit prostate, breast, skin, colon, stomach, and liver cancers

and is suitable for use in conjunction with chemotherapy.

O

HO

O

OH

O

O

Curcumin

1.5.6. Ellagic Acid12

This is found in raspberries, pomegranates, cranberries, apples, grapes, cherries, and

strawberry. This helps to prevent various types of cancers in rodents, esophageal, lung, skin

and helps to stimulate the manufacture of glutathione. Ellagic acid is also very good in

cardiovascular protective.

9

O

O

O

O

OH

OH

HO

HO

Ellagic Acid

1.5.7. Isoflavones13

There are over 600 isoflavanoids. Daidzein, genistein, formononetic and

biochanin A are known for their estrogenic properties. Isoflavones have received a lot of

attention in the last decade in their support for menopause and in supporting conditions of

overexpression of estrogen. They also have been used by men in supporting prostate health.

O

O R

R'

Isoflavones

1.5.8. Lignans14

Lignans found primarily in the outer husk of the flaxseed. These block estrogen

receptors within the body, thereby inhibiting the toxic effects of excessive estrogens. They

inhibit the development of breast cancer and inhibit the development of colon cancer and

prostate cancer.

10

1.5.9. Limonene15

This is found in the spongy white inner parts of citrus fruit i.e., orange peel, lemon

peel, kumkuats and cranberry. This can dissolve gallstones. It inhibits the progression of

established breast cancer and in animal studies with rodents, it prevented the development

of pancreatic cancer and caused the regression of existing pancreatic cancer. In animal

studies with breast cancer, it caused the complete regression of the majority of advanced rat

breast cancers. Limonoids seem to work against cancer in three ways: prevent it from

forming, slower the growth of existing cancer and kill the cancer cells.

Limonene

1.5.10. Lutein16

This compound found in spinach, kale, broccoli, calendula marigold, egg yolk

sweet potato, brussel sprouts, green beans, cayenne pepper and palm oil. It protects the

eyes against the development of age-related Macular Degeneration. It helps in the

prevention of breast, colon, prostate and lung cancers.

OH

HO

H

Lutein

11

1.5.11. Lycopene17

This is found in many vegetables and fruits like tomato, grapefruit, watermelon

cayenne pepper, paprika, red grapes, the skin of red delicious apples, red papaya and

apricots are good sources. Prostate and testicles are major storage areas for men. It prevents

the body against prostate, bladder, breast, cervical, colon, endometrial, esophageal,

leukemia, liver, lung, mouth, pancreatic and stomach cancers.

Lycopene

1.5.12. Omega 3 Fatty Acids18

These are found in salmon and sardines and also in albacore tuna, flax seed. Omega

3 plays a critical role in the brain and in cell membrane fluidity. They are potent controllers

of the inflammatory processes.

HO

O

Omega 3 Fatty Acid

1.5.13. Quercetin19

This is found in red onions, apples and the skins of russet potatoes, red wine, green

tea, black tea, apples, grapes, pears, kiwi, califlower, spinach, broccoli, kale, cabbage,

12

cayenne, green beans, okra, fennel and squash. It helps to prevent cataracts. It has

significant antitumor activity against various form of cancer i.e., brain, breast, colon,

leukemia, lung, ovarian, squamous cell carcinoma and it stimulates apoptosis cellular death

in cancer cells. It is best known for its anti-inflammatory, anti-allergy and for allergic

asthma. It is the best single nutritional strategy for the treatment of any kind of allergy. It

appears to protect brain cells against oxidative stress. It can prevent infections caused by

viruses. It has also antioxidant, anti-cancer, anti-inflammatory and anti-allergy properties

also.

O

O

OH

OH

OH

OH

HO

Quercetin

1.5.14. Resveratrol20

It is found in red wine, dark grape juice, dark muscadines, raisins and whole seeded

dark grapes the skin and the seeds, cranberries, mulberries and peanuts. It helps in the

prevention of atherosclerosis and inhibits abnormal blood clotting. It lowers total serum

cholesterol increasing HDL and prevents the oxidation of LDL cholesterol. It may be one

of the most potent Cox-2 inhibiting anti-inflammatory substances found in nature. It has

major cancer inhibiting effects. It is also important in helping fight leukemia, colon cancer,

skin cancer, prostate cancer, melanoma and thyroid cancer where it stimulates apoptosis.

13

OH

OH

HO

Resveratrol

1.5.15. Rutin21

It is found in bee pollen, red wine, buckwheat, yerba mate, garlic, fennel and

hawthorne. It strengthens the blood vessels and prevents bruising. It is useful in treating

hemorrhoids. It has been shown helpful for people with Glaucoma by strengthening the

connective tissue of the eye and is useful for allergies and inflammation like quercetin

though not as powerful.

O

O

O

OH

OH

OH

HO

O OH

OHHO

HOOH

O

H3COHO

Rutin

1.5.16. Theophiline22

This is found in green tea. It is very helpful for the treatment of asthma. It has

anticancer activity also.

14

HN

NN

N

O

O

Theophiline

1.6. TURMERIC AND CURCUMIN

1.6.1. Curcuma longa

Turmeric, a source of vital nutraceutical curcumin is a rhizomatous herbaceous

perennial plant of the ginger family, Zingiberaceae. Its orgin is tropical South Asia. The

rhizome of this plant is the most useful part of the plant for culinary and medicinal

purposes. Turmeric is used as a dietary spice, coloring agent in foods and textiles, and a

treatment for a wide variety of ailments. The most active component of turmeric is

curcumin, which makes up 2 to 5% of the spice23. The characteristic yellow color of

turmeric is due to the curcuminoids24. The world's largest producer and most important

trading center of turmeric in Asia is Erode, TamilNadu.

15

Fig. 1.2. Turmeric plant – Turmeric Rhizome - Turmeric Powder

Taxonomy24

Kingdom : Plantae

Phylum : Magnoliophyta

Class : Liliopsida

Order : Zingiberales

Family : Zingiberaceae

Genus : Curcuma

Species : Curcuma longa

16

1.6.2. Chemical composition of turmeric

Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates

(69.4%) and moisture (13.1%). The essential oil (5.8%) obtained by steam distillation of

rhizomes has a-phellandrene (1%), sabinene (0.6%), cineol (1%), borneol (0.5%),

zingiberene (25%) and sesquiterpines (53%)25. Curcumin (diferuloylmethane) (3 – 4%) is

responsible for the yellow colour, and comprises curcumin (94%), demethoxycurcumin

(6%) and bisdemethoxycurcumin (0.3%) 26.

Curcumin was first isolated in 1815 and its chemical structure was determined by

Roughley and Whiting27 in 1973. It has a melting point at 183°C with molecular formula of

C21H20O6, and its molecular weight is 368.37. It forms a reddish - brown salt with alkali

and is soluble in ethanol, methanol, dichloromethane, ethylacetate, chloroform acetic acid

and with various solvents.

1.6.3. Biological activity of turmeric and its compounds

The turmeric and its various compounds possess a variety of biological activities.

Fifty percent ethanolic extract of curcuma longa shows hypolipemic action28 in rats and

also possess antitumour activity29. Turmeric powder has healing effect on both aseptic and

septic wounds in rats and rabbits30. It also shows chemoprotection in experimental

forestomach and oral cancer models of mice. Alcoholic extract and turmeric shows

antibacterial activity31. The crude ether and chloroform extracts of curcuma longa stem are

also reported to have antifungal activity32. The extracts of the rhizomes of curcuma longa

have been in use from the vedic ages33.

17

Fig. 1.3. Pubmed citations on curcumin from 1990-2010

Curcumin, a secondary metabolite and the main yellow compound of cucuma longa

rhizome which is the main component of turmeric powder is widely used as a traditional

medicine in widespread in several parts of Asia34. Due to its various biological activities,

curcumin is one of the compounds mostly modified and numerous numbers of analogues

were made towards the optimization of various biological activities. The pubmed citations

on curcumin from 1990 to 2010 say clearly the importance of curcumin (Fig. 1.3. and 1.4.).

18

Fig. 1.4. Curcumin and its various biological activities

1.7. PHARMACOLOGICAL ACTION OF CURCUMIN

1.7.1. Antioxidant effect

An antioxidant is a molecule capable of inhibiting the oxidation of other molecules.

Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing

agent. The antioxidant activity of curcumin was reported35 as early as 1975. It acts as a

scavenger of oxygen free radicals36. It protects haemoglobin from oxidation37. In vitro,

curcumin can significantly inhibit the generation of ROS. Curcumin exerts powerful

19

inhibitory effect against H2O2 induced damage in human keratinocytes and fibroblasts38 and

in NG 108-15 cells39. It also decreases lipid peroxidation in rat liver microsomes,

erythrocyte membranes and brain homogenates40.

1.7.2. Anti-inflammatory activity

Anti-inflammatory refers to the property of a substance or treatment that reduces

inflammation. Curcumin is effective against carrageenin-induced oedema in rats and

mice41,42,43 . The antirheumatic activity of curcumin has been established in patients who

showed significant improvement of symptoms after administration of curcumin44.

Curcumin offers antiinflammatory effect through inhibition of NFκβ activation45.

Curcumin has been shown to reduce the TNF-α-induced expression of the tissue factor

gene in bovine aortic-endothelial cells by repressing activation of both AP-1 and NFκβ46.

The anti-inflammatory role of curcumin is mediated through downregulation of

cyclooxygenase-2 and inducible nitric oxide synthetase through suppression of NFκβ

activation47. Curcumin also enhances wound-healing in diabetic rats and mice48.

1.7.3. Anticarcinogenic effect

Curcumin is a potent anticarcinogenic compound through various mechanisms.

Colon carcinoma is prevented by curcumin through arrest of cell-cycle progression

independent of inhibition of prostaglandin synthesis49. Curcumin suppresses human breast

carcinoma through multiple pathways. Its antiproliferative effect is estrogen dependent in

ER-positive MCF-7 cells. Curcumin also suppresses tumour growth through various

20

pathways. Nitric oxide and its derivatives play a major role in tumour promotion. Curcumin

inhibits iNOS and COX-2 production50 by suppression of NFκβ activation47. Recently, in

Jurkat cells, curcumin has been shown to prevent glutathione depletion, thus protecting

cells from caspase-3 activation and oligonucleosomal DNA fragmentation51 in curcumin

exerts both pro and antimutagenic effects. At 100 and 200 mg / kg body weight doses,

curcumin has been shown to reduce the number of aberrant cells in cyclophosphamide -

induced chromosomal aberration in Wistar rats52. Turmeric also prevents mutation in

urethane models53.

1.7.4. Anticoagulant activity

Curcumin shows anticoagulant activity by inhibiting collagen and adrenaline -

induced platelet aggregation in vitro as well as in vivo in rat54.

1.7. 5. Antifertility activity

Curcumin inhibits 5α-reductase, which converts testosterone to 5α-

dihydrotestosterone, thereby inhibiting the growth of flank organs in hamster55. Curcumin

also inhibits human sperm motility and has the potential for the development of a novel

intravaginal contraceptive56. Petroleum ether and aqueous extracts of turmeric rhizomes

show 100% antifertility effect in rats when fed orally57. Implantation is completely

inhibited by these extracts58.

21

1.7.6. Antidiabetic effect

Curcumin prevents galactose-induced cataract formation at very low doses59. Both

turmeric and curcumin decrease blood sugar level in alloxan-induced diabetes in rat60.

Curcumin also decreases advanced glycation end products induced complications in

diabetes mellitus61.

1.7.7. Antibacterial activity

It has been observed that both curcumin and the oil fraction suppress the growth of

several bacteria like Streptococcus, Staphylococcus, Lactobacillus, etc62. The aqueous

extract of turmeric rhizomes has antibacterial effects63. Turmeric and curcumin possess

moderate activities against E.Coli, S.aureus, V.cholera, S.typhi and P.aeuroginosa64,65.

1.7.8. Antifungal effect

Ether, ethanol, chloroform extracts and oil of curcuma longa have antifungal

effects66,67. Turmeric oil is also active against Aspergillus flavus, A. parasiticus, Fusarium

moniliforme and Penicillium digitatum68. Curcumin has moderate antifungal activity

against Cardiac albicans64.

1.7.9. Antiprotozoan activity

The ethanol extract of the rhizomes has anti-Entamoeba histolytica activity.

Curcumin has anti-Leishmania activity in vitro69. Several synthetic derivatives of curcumin

22

have anti-Leishmania amazonensis effect70. Anti-Plasmodium falciparum and anti-

Leishmania are the major effects of curcumin have also been reported71.

1.7. 10. Antiviral effect

Curcumin shows anti-HIV activity by inhibiting the HIV-1 integrase needed for

viral replication72. It inhibits EBV 73.

1.7. 11. Antifibrotic effect

Curcumin suppresses bleomycin-induced pulmonary fibrosis in rats74. Oral

administration of curcumin at 300 mg/kg dose inhibits bleomycin-induced increase in total

cell counts and biomarkers of inflammatory responses. It also suppresses bleomycin-

induced alveolar macrophage-production of TNF-α, superoxide and nitric oxide. Thus

curcumin acts as a potent antiinflammatory and antifibrotic agent.

1.7.12. Antivenom effect

Ar-turmerone, isolated from curcuma longa, neutralizes both haemorrhagic activity

of Bothrops venom and 70% lethal effect of Crotalus venom in mice75. It acts as an

enzymatic inhibitor of venom enzymes with proteolytic activities76.

1.8. PHARMACOKINETIC STUDIES ON CURCUMIN

Curcumin, when given orally or intraperitoneally to rats, is mostly egested in the

faeces and only a little in the urine77,78. Only traces of curcumin are found in the blood

from the heart, liver and kidney. Curcumin, when it is added to the isolated hepatocytes, is

23

quickly metabolized and the major biliary metabolites are glucuronides of

tetrahydrocurcumin and hexahydrocurcumin79,80. After metabolism in the liver, curcumin is

mainly excreted through bile.

1.8.1. Clinical studies and medicinal applications of turmeric and curcumin

Curcumin is used for the treatment of biliary disorders, anorexia, cough, diabetic

wounds, hepatic disorders, rheumatism and sinusitis in traditional Indian medicine81.

Turmeric powder is used to treat wounds, bruises, inflamed joints and sprains82. Data are

also available showing that the powder, when applied as capsules to patients with

respiratory disease, gives relief from symptoms like dyspnoea, cough and sputum83. In

patients undergoing surgery, oral application of curcumin reduces post-operative

inflammation84. Recently, curcumin has been formulated as slow-release biodegradable

microspheres for the treatment of inflammation in arthritic rats85.

1.8.2. Safety evaluation with turmeric and curcumin

The average intake of turmeric by Asians varies from 0.5 to 1.5 g/day/person,

which produces no toxic symptoms86. Male and female Wistar rats, guinea pigs and

monkeys were fed with turmeric at much higher doses (2.5 g/kg body weight) than

normally consumed by humans. No changes were observed in the appearance and weight

of kidney, liver and heart80. Also, no pathological or behavioural abnormalities were

noticed and no mortality was observed.

24

1.9. CURCUMIN DERIVATIVES, ANALOGUES AND VARIOUS BIOLOGICAL

ACTIVITIES

Curcumin has the following possibilities for structural alteration as shown in

Fig. 1.5. Alterations of structure at all these molecular architectural sites are attempted.

Fig. 1.5. Curcumin and possible structural modification

The modification of the basic structure of curcumin can be classified into two

categories. These are:

1. Curcumin derivatives

2. Curcumin analogues

1.10. CURCUMIN DERIVATIVES

Compounds that derived from curcumin, by utilizing the functional groups such as

phenol, 1,3-diketone, active methylene, alkenyl double bond are classified as curcumin

derivatives. The curcumin derivatives are further divided in to two groups. They are

1. Curcumin derivatives by organic reaction

2. Curcumin derivatives by complex formation

25

1.10.1. Curcumin derivatives by organic reaction

The curcumin derivatives are generally synthesized by derivatization, starting from

curcumin. The phenolic hydroxy group is acylated, alkylated, glycosylated, and amino

acylated87-101. The methoxy group is demethylated to hydroxy groups102. The active

methylene group of is acylated or alkylated or substituted by an arylidene group 103. The

hydrogenation of the C7 linker double bonds and the carbonyl groups affords the simplest

of the analogues, such as dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin and

octahydrocurcumin, which are obtained by the reduction of curcumin104-107. The central

1,3-diketone is converted to pyrazole, oxazole by reacting the curcumin with hydrazine,

hydroxylamine respectively108-111.

N NH

O

OH

O

HO

N N

O

OH

O

HO

Aryl

N O

O

OH

O

HO

O HN

O

OH

O

HO

O

HN

O HN

O

OH

O

HO

NH

O O

O

OH

O

HO

O O

O

Opyranoside

O

Opyranoside

O O

O

OH

O

N N

O

OH

O

R

HO

HO

NH2

NH

O

O

HO

O

OH

Fig. 1.6. Curcumin derivatives

26

The monosemicarbazone112, bisthiosemicarbazone113 and an ethylene diamine

adduct 114 of curcumin have also been synthesised. The reduction of alkene bonds followed

by the masking of 1,3-diketone allows several heterocyclic compounds to synthesis115. The

piperidones also synthesised by converting the alkene and keto group with amine under

microwave conditions116.

1.10.2. Curcumin derivatives by complex formation

Metal complexes of curcumin are synthesized by the reaction of curcumin with a

metal salt. Boron has long been known to form a complex with curcumin117. The complex

resulting from combination of a molecule of curcumin, oxalic acid, and a boron atom,

sourced from boric oxide or acid, is known as rubrocurcumin. The complexation of two

curcumin molecules with a boron atom affords rosocyanin. Complexes of copper118-120,

iron, manganese 121-125, palladium126, vanadyl127, gallium, and indium 128,129 have been

reported.

1.11. CURCUMIN ANALOGUES

Curcumin analogues are synthesised from smaller synthons like araldehydes and

acetylacetone, cylic ketones like piperidone, cyclohexanone etc. Several approaches like

converting the central 1,3-diketone in to phenyl, heteroaryl, aliphatic chains, extending the

chain length, etc., in view of finding interesting biological properties have been attempted.

The five carbon analogues are synthesized from piperidone, acetone with aldehydes. The

seven carbon analogues are synthesized from variouos synthons lik acetyl acetone, 2-

27

acetylcycloakanones. The extended chanin lengths like C9, C11 or longer chains also

attempted in view of the increased biological activity. The total numbers of such analogues

now synthesized are too many to depict conveniently130-164.

O O

RR

O O

RR

O O

RR

O

R R

O

R R

O

R R

NH

O

R R

O

R R

O

Five Carbone linker

Six Carbon linker

RR

28

NH

O

O O

O O

HN

HN

OO

HN

HN

OO

n

R

R

R

R

R

R

R

RR

R

Extend Long Chains

Fig. 1.7. Curcumin analogues

1.12. BIOLOGICAL ACTIVITIES OF CURCUMIN ANALOGUES AND

DERIVATIVES

Most of the curcumin based compounds were screened for the antioxidant, anti-

inflammatory, anticancer activities. The anti inflammatory behaviour of curcumin is

improved a lot by its analogues. The hydrazinocurcumin possess more antiangiogenic

activity than curcumin itself. 2,6-bis(2-fluorobenzylidene) piperidone (EF24) shows more

antiangiogenesis than curcumin. Curcumin analogues possess more antioxidant activity due

to the hydroxyl and central beta diketo groups scavenging activity of free radicals. The

detailed discussion of antioxidant activity of curcumin derivatives is discussed in

Chapter 4.

29

1.13. SCOPE AND OBJECTIVE

The main scope and objective of the present study is:

i) To synthesize the 3,5-diarylidene-4-piperidone and corresponding

sulfonamide, carboxamide derivatives. To characterize the compound with

the assistance of 1H NMR, 13C NMR and LCMS data

ii) To evaluate the 3,5-diarylidene-4-piperidone and corresponding

sulfonamide, carboxamide derivatives against the gram positive and gram

negative bacterias

iii) To establish SAR analysis and improve the biological activities by

bioisostere concept

iv) To analyse the turmeric phytochemically, to isolate and characterize the

curcuminoids

v) To synthesize the heteroarylhydrazinocurcumin and arylhydrazinocurcumin

from curcumin with the help of microwave reaction condition to achieve

good yield as well as reduced reaction time. To characterize the compound

with the assistance of 1H NMR, 13C NMR and LCMS data

vi) To evaluate the novel heteroarylhydrazinocurcumins against in vivo

antioxidant assays considering curcumin as standard

30

1.14. REFERENCES

1. Brower, V. Nutraceuticals: poised for a healthy slice of the healthcare market? Nat.

Biotechnol. 1998, 16, 728-731.

2. Nelson, N. J. Purple carrots, margarine laced with wood pulp? Nutraceuticals move into

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