Chemical and Biotransformation studies of Some Bioactive ...shodhganga.inflibnet.ac.in/bitstream/10603/10457/5/... · (1998 ); Walton and Brown (1999 )]. For instance, several bioactive

Chemical and Biotransformation......... General Introduction

1

Chemical and Biotransformation studies of Some Bioactive Phenolics

and Heterocyclic compounds

Is not Nature both the model and educator, not only of the artist but also of the chemist, ofthe latter even to a higher degree as he set himself higher goals? Through his synthesis, hewants to reproduce the chemical compounds created by Nature; to grasp and imitate theirmechanism of formation; and further wants to supplement Nature by producing substancesnot created by Nature………………………………………………………………………Walton

1.1. Introduction

Since the crack of dawn, nature has remained a quintessential repository of bewildering

array of structurally and functionally diverse organic compounds with interesting

bioactivities [King and Oxford (1999); Clardy and Walsh (2004)]. In fact a vast majority of

plant derived molecules, termed as secondary metabolites, [Dixon (2001)] find applications

in pharmaceutical, agrochemical, flavor and aroma industries [Paul (1997); You-Ping

(1998); Walton and Brown (1999)]. For instance, several bioactive compounds like

podophyllotoxin, taxol, curcumin, morphine etc. (Figure 1) have been isolated from various

natural sources.

O OH

HO

H3CO

OH

OCH3

O

O

H3CO

OCH3

OCH3

OH

OH

O

Ac O OHO

HOAcOBz

O

NH

O

O

OH

Podophyllotoxin

Curcumin

Taxol

O

O

O

HO

NH

HO

HH

Morphine

Figure 1

Although, nature provides vital clues for biologically active lead candidates, however, a big

gap exists between the demand and supply of such natural products as nature on its own is

not capable of fulfilling the demand of these compounds. This is mainly due to the scarcity

of the natural resources which further gets compounded due to meager percentage of the

desired compounds in these resources. For example, taxol- a complex diterpene natural

product- is currently considered the most leading compound for cancer chemotherapy.

Unfortunately, taxol is obtained in poor yields from the very slow growing yew trees


2

[Matthew (1995)]. Thus, the synthesis of rare and important bioactive natural molecules has

become indispensable to meet their burgeoning global demand [Nicolaou and Snyder

(2004)]. Further, chemical modification of abundantly available secondary metabolites from

plants has proved useful in the semi-synthesis of biologically active natural products and

their analogues. For example- chemical modification of salicylic acid (isolated from the

willow tree, Salix alba) provided aspirin (Scheme 1) which turned out to be a much more

effective and safer than the former.COO H

OHCOO H

OAc

Salicylic acid Aspirin

O

O O

+

Acetic anhydride

+ C H 3COOH

Scheme 1

Over the past few years, fresh challenges have placed organic synthesis at the defining

moment [Gartner et al. (2003); Li and Trost (2008)] wherein the search for innovative

solutions for reduction of chemical steps, wastes and energy has become the central

objective due to the deleterious environmental impact of some of the current chemical

practices. This new approach has received extensive attention and goes by many names

including “Green Chemistry, Environmentally Benign Chemistry, Clean Chemistry and

Benign by Design Chemistry” [Anastas and Warner (1998); Trost (2002); Li and Trost

(2008)]. In the present scenario, this study aimed to address some of the above challenges of

Green Chemistry by focusing on a few important classes of phenolics and some heterocyclic

compounds.

1.2. Brief description and significance of phenolics and heterocyclic compounds

taken up in this study

1.2.1. Phenolics

‘Phenolics’ or ‘phenolic compounds’ embraces a diversified group of aromatic

phytochemicals with one or more hydroxyl groups attached to the aromatic ring and

represent a striking example of metabolic plasticity enabling plants to adapt to changing

biotic and abiotic environments. These occur ubiquitously in plants [Pridham (1960);

Harborne (1982); Harborne and Turner (1984); Nicholson and Hammerschmidt (1992);

Beckman (2000)] and are classified according to the number of carbon atoms in conjunction

with the basic phenolic skeleton. Generally, there are simple phenols, phenolic acids (both

benzoic and cinnamic acid derivatives), coumarins, flavonoids, stilbenes, hydrolysable &

condensed tannins, lignans and lignins etc [Mann et al. (1994)].


3

1.2.1.1. Biosynthesis of phenolics

The biosynthetic route for the preparation of phenolics involving phenylalanine ammonia-

lyase (PAL) as a key biosynthetic catalyst is well known. Phenylalanine acts as precursor

for the synthesis of a number of phenolics [Shahidi (2002); Naczk and Shahidi (2004);

Shahidi and Naczk (2004)] (Figure 2); which is in turn synthesized by the shikimate

pathway.

C3C6

C3C6

C3C6 C2C6 C6

C3C6 C6

C3C6 C6

C3C6

C3C6

C3C6

C2C6 C6

Phenylalanine

PAL

Cinnamic acid

3-malonyl CoA

Stilbenes

Chalcones

3-malonyl CoA

Chalcone synthase

Flavonoids

Stilbene synthasePhenyl propanoid

Lignins

Lignans2

n

n

Suberins, Cutins

nProanthocyanidins

- Flavones- Flavonols- Flavonones- Isoflavonoids- Aurones- Anthocyanins

Figure 2: Outline of biogenesis of phenylpropanoids, stilbenes, lignans, lignins, suberins,

cutins, flavonoids and tannins from phenylalanine (PAL) [Naczk and Shahidi (2004)]

Phenylalanine undergoes deamination into cinnamic acid which serves as a precursor for

phenylethanoids (C6-C2 unit) and phenylpropanoids (C6-C3 unit). Stilbenes and chalcones

are formed biosynthetically from phenylpropanoid linkage to corresponding malonyl


4

coenzyme A. Chalcones are easily converted into isomeric flavonoids which comprise of six

major subgroups in most plants: the flavones, flavonols, flavonones, flavans, aurones and

anthocyanins. Likewise, lignans are composed of two phenylpropanoid units. One well

known example is podophyllotoxin from the rhizomes of Podophyllum hexandrum, which is

in clinical use in modified form for the treatment of certain cancers. Phenylpropanoids can

also polymerize to give rise to lignins and suberins while polymeric chalcones are known as

proanthocyanidins.

1.2.1.2. Biological significance of phenolics

Phenolics are considered as secondary metabolites that are synthesized by plants during

normal development [Harborne (1982); Bravo (1998); Crozier et al. (2009)] and in response

to stress conditions such as infection, wounding, UV radiation [Kondratyuk and Pezzuto

(2004)], pathogens and predators [Bravo (1998)] and as attractants for pollinators [Shahidi

and Naczk (2004)]. In food, phenolics contribute to the bitterness, astringency, color, flavor,

odor, and oxidative stability of products [Alasalvar et al. (2001)]. In addition, health-

protecting activities of phenolics such as anti-allergenic, anti-inflammatory, antimalarial,

antimicrobial, antioxidant [Lampe (1999)], anti-thrombotic, anti-diabetic, cardioprotective

and vasodilatory effects [Benavente-García et al. (1997); Samman (1998); Middleton et al.

(2000); Puupponen-Pimiä et al. (2001); Manach et al. (2005); Rawat et al. (2011)] are of

great importance to mankind [Shahidi and Naczk (2004)] and has resulted in the

mobilization of scientific community towards the exploration of newer bioactivities for this

class of compounds.

Among all, the focus of the present study will remain on exploring the antioxidant,

antimicrobial, antimalarial activities and colorant properties of phenolic compounds.

1.2.1.2.1. Phenolics as antioxidants

Antioxidant compounds in food as health-protecting factor is a current hot trend that is

capturing everyone’s imagination with images of a new magic bullet or fountain of youth.

Antioxidants are micronutrients that have gained interest in recent years due to their ability

to neutralize the actions of free radicals [Cadenas and Packer (1996)] that destabilize other

molecules and lead to cardiovascular disease, cancer, diabetes, arthritis and various

neurodegenerative disorders [Sies (1996); Kokate and Purohit (2004)]. Many synthetic

antioxidants like BHA (Butylated hydroxy anisole) and BHT (Butylated hydroxy toluene)

are used in food industry. However, both consumers’ preference and toxicological

investigations have diverted the interest in research towards natural antioxidants. In this

direction, the current research focuses on investigating the antioxidant action of phenolic


5

compounds such as flavonoids, anthocyanins, stilbenes etc. as a natural replacement for

synthetic antioxidants [Kroon and Williamson (2005)] (Table 1). It is believed that the

ability of phenolic compounds to quench free radicals arises because of both their acidity

(ability to donate protons) and their delocalized π-electrons (ability to transfer electrons

while remaining relatively stable) characteristic of benzene rings [Rice-Evans et al. (1996)].

Table 1: Some anti-oxidative phenolics and their sources

Phenolics Source

Catechins Tea, red wine

Flavanones Citrus fruits

Flavonols Onions, olives, tea, apples, wine

Anthocyanidins Cherries, strawberries, grapes, colored fruits

Caffeic acid Grapes, olives, coffee, tomatoes, plums

1.2.1.2.2. Phenolics as antimicrobials

With the current trend on increasing awareness for more efficient antimicrobials with fewer

side-effects on human health, the plant-derived agents have been attracting much interest as

natural alternatives to synthetic compounds because microbes slowly develop resistance

against antibiotics [Samy and Gopalakrishnakone (2010)]. Plants have an almost limitless

ability to synthesize aromatic substances, most of which are phenols or their oxygen-

substituted derivatives [Geissman (1963)]. In many cases, these substances serve as plant

defense mechanisms against predation by microorganisms, insects, and herbivores. The

mechanisms thought to be responsible for phenolic toxicity to microorganisms include

enzyme inhibition by the oxidized compounds, possibly through reaction with sulfhydryl

groups or through more nonspecific interactions with the proteins [Mason and Wasserman

(1987)]. A wide variety of phenolics such as catechol, phenolic acids, catechins, flavones,

flavonoids, flavonols and quinones (Figure 3) [Tsuchiya et al. (1996); Aziz et al. (1998);

Bisignano et al. (1999); Chan (2002); Srinivas et al. (2003); Wen et al. (2003)] have been

reported to inhibit various pathogenic microorganisms.


6

OH

OH

CH=CH-COOH

HO

OH

OH

CatecholCaffeic acid

HO

OCH3

Eugenol

O

O

Quinone

O

OH

HO

O

Chrysin

OHO

OH

OH

OH

OH

Catechin

H3CO

HO

NH

CH3

CH3

O

Capsaicin

Figure 3

1.2.1.2.3. Phenolics as antimalarials

Malaria management has become problematic because of the emergence of multidrug-

resistant strains of Plasmodium falciparum over the past few decades. In view of the success

with the two important chemotherapeutic agents- quinine and artemisinin- isolated from

plants, there is great interest in plant chemicals which may have anti-infective properties for

Plasmodium species [Saxena et al. (2003)]. In this context, several classes of phenolics have

provided vital breakthrough, but the most important and diverse biopotency has been

observed in chalcones and flavonoids. For example: Licochalcone A isolated from

Glycyrrhiza inflate [Chen et al. (1994)], 5-Prenylbutein isolated from Erythrina abyssinica

[Yenesew et al. (2004)] and xanthohumol along with its seven derivatives from Humulus

lupulus [Frölich et al. (2005)] have been identified as potent inhibitor of protease activities

of Plasmodium. Subsequently, several synthesized derivatives of chalcones and flavonoids

have been reported for in vitro antimalarial activity against Plasmodium strains (Figure 4)

[Dominguez et al. (2001); Liu et al. (2001); Wu et al. (2002); Araico et al. (2006); Lim et

al. (2007)]. These studies have provided necessary impetus to design novel chalcone based

entities for antimalarial studies.


7

beta-Hydroxydihydrochalcone

O

OH O OH

CH3O O OCH3

OOH OH

1,8-Dihydroxy-3-isoprenyloxy-6-methylxanthone

O

OH

O

HO

OH

Lonchocarpol A

O

OH

HO

O

Liquiritigenin

Figure 4

1.2.1.2.4. Phenolics as pigments

An important role of phenolics, particularly flavonoids, is to serve as visual signals for

insects and animals for pollination and seed dispersal through display of a variety of flower

and fruit colors [Lattanzio et al. (2006)]. For example, anthocyanins are mainly responsible

for the bluish-purple and red colors in plants, chalcones and aurones contribute to yellow

color in a number of plants while phenolic pigments benzoquinones, naphthoquinones and

anthraquinones provide variable colors ranging from orange to red to brown [Lattanzio et

al. (2006)]. In an approach towards revival of natural dyes owing to the consumer

perception that `natural is best', exploration of newer plant sources is on increase for the

isolation of phenolic rich colored compounds/fractions [Nishida and Kobayashi (1992a);

(1992b); Indrayan and Sharma (1999); Onal et al. (1999); Bhuyan and Saikia (2005)].

Structures of some commercially important natural colorants are shown in Figure 5.

GluO OH

O

OH

OGlu

HO OGlu

O

OHO

O

OHO

OH

OH

CH3

OHOOH

HO

OH O OH

HO CH3

O

O

CH3

OH

Isobutrin

Apigenin

Hypericin

Plumbagin

Carthamone

Figure 5


8

1.2.1.3. A brief description of some of the phenolic compounds taken up in the

present study is given below

1.2.1.3.1. Phenolic acids and phenolic aldehydes

These compounds are represented by C6-C1 basic skeleton and are in general considered as

derivatives of benzoic acid or benzaldehyde. For example, gallic acid and vanillin (Figure 6)

are well known examples of phenolic acids and phenolic aldehydes, respectively.C HO

OC H 3

OH

C OO H

HO

OH

OH

C OO H

OH

O

O

C HO

V an illin P ip ero n al G allic acid p -C o u m aric ac id

Figure 6: Examples of phenolic acid/aldehydes

Significance

Phenolic acids/aldehydes are generally produced in plants as a response for defending

injured parts against pathogens [Harborne et al. (1999)] and are considered essential for the

growth and reproduction of plants. In addition, these compounds are responsible for the

fragrance and flavor of various phenolic natural products. For instance, vanillin (4-hydroxy-

3-methoxybenzaldehyde, Figure 6) extracted from the pods of orchid Vanilla planifolia, is

one of the most important flavoring agents used in food and pharmaceutical industry

worldwide [Tilay et al. (2010)]. Similarly, vanillic acid and p-hydroxybenzoic acid also find

application as flavoring agents. Recent interest in phenolic aldehydes and phenolic acids

stems from their potential protective role, through ingestion of fruits and vegetables, against

oxidative damage diseases (e.g. coronary heart disease, stroke, and cancers).

1.2.1.3.2. Styrenes

Styrenes denote organic compounds possessing C6-C2 skeleton and possesses a vinylene

substituted aromatic ring; thus also called vinyl benzenes.

Significance

Styrenes are a highly useful class of compounds having wide ranging industrial, medicinal

and synthetic applications. Several FEMA GRAS (Flavor and Extract Manufacturers

Association Generally Regarded As Safe) approved flavoring agents in food and

pharmaceutical industry are hydroxy derivatives of styrenes, for example, 4-hydroxy-3-

methoxystyrene (4-vinylguaiacol) and 4-hydroxystyrene (4-vinylphenol) (Figure 7).

Another important member of the class is 4-hydroxy-3,5-dimethoxyphenylethene (canolol)

which is reported to possess antioxidant and antimutagenic properties [Kuwahara et al.

(2004)]. Similarly, several substituted styrenes are known to possess biological activities


9

like antibacterial, antifungal, hypolipidemic and antimutagenic activities [William et al.

(1996); Vuorela et al. (2004)], which have increased their pharmacological importance.

OCH3 OCH3

HOHO

H3CO

HO

4-Hydroxystyreneor 4-vinylphenol

4-Hydroxy-3-methoxystyreneor 4-vinylguaiacol

FEMA GRAS No. 3739FEMA GRAS No. 2675

4-Hydroxy-3,5-dimethoxystyreneor Canolol

Antioxidant

Figure 7: Commercially important styrenes

In addition, styrenes act as versatile synthons for the synthesis of other bioactive

compounds in numerous reactions e.g. in Heck reaction for the synthesis of stilbenes

[Beletskaya and Cheprakov (2000)], in hydroformylation reaction for the synthesis of

carbonyls [Kohlpaintner and Frohning (1996)] etc. Another important application of

styrenes involves their use as precursors for the synthesis of polymers [Stuart et al. (1994);

Atsushi et al. (1998); Bonnet et al. (1999); Campos et al. (2000)] and photoresists etc.

1.2.1.3.3. Phenylpropenes

Phenylpropenes, the second largest group of plant volatiles, are one of the major

components of plant derived essential oils [Benzoukian (1986)] and have a phenyl ring and

a three carbon side chain with at least one double bond. These display interesting functional

and chemical reactivities influenced by the variation in the isomeric forms (, β and γ) and

the substitution pattern.

Significance

A variety of phenylpropenes are used as condiments and herbal remedies since ancient

times due to their high flavor and fragrant attributes [Gang et al. (2001); Springob and

Kutchan (2009)] as well as antimicrobial properties. In plants, these primarily function as

attractants of pollinators and seed dispersals or as defense compounds. Some of the

naturally occurring phenylpropenes are shown in Figure 8.OCH3

H3COOCH3

HOH3CO

H3CO O

O

-AsaroneIsoeugenol IsosafroleTrans-anethole

Figure 8: Some naturally occurring phenylpropenes

Another major utility of phenylpropenes is their use as abundantly available feedstock for

the synthesis of value added products such as cinnamaldehydes, neolignans, benzaldehydes


10

etc (Figure 9) [Lee et al. (2004); Leite et al. (2004); Freire et al. (2005); Joshi et al. (2005);

Kasana et al. (2007); Sinha et al. (2010)].

Phenylpropenes

Propiophenones Neolignans

Dihydro derivatives

Oxidation

Hydrogenation

Cinnamaldehydesalpha-Asarone

OMe

MeOOMe

HOOMe O

O

OMe

MeOOMe

HOOMe O

O

Figure 9: Synthetic utility of various naturally occurring phenylpropenes for synthesis of

value added compounds

1.2.1.3.4. Propiophenones

Propiophenones (1-phenylpropan-1-ones) (C6-C3 unit) are a class of phenolic compounds

containing a ketonic group in the side chain. A large number of hydroxy, methylenedioxy or

methoxy substituted propiophenones are found in nature [Harborne et al. (1999)], some of

which are listed in Figure 10.OCH3

H3CO

OCH3

HO

OCH3

O

O

O

O

O

O

3,4-Methylenedioxy-propiophenone

2,4,5-Trimethoxy-propiophenone

4-Hydroxy-3-methoxy-propiophenone1-Phenylpropiophenone

Figure 10

Significance

Phenylpropanones find demand in flavor and perfumery industries [Steffen (1994)] e.g. 1-

phenylpropiophenone is used in lilac and also blends well with cananga, amylsalicylate,

anisaldehyde and lavandin oil etc. The compounds possess a wide range of biological

activities such as choleretic, anti-PAF, H3-receptor antagonist, antifungal and hypolipidemic

activities [Suri et al. (1987); Krause et al. (1998); Zacchino et al. (1999)]. In addition,


11

propiophenones are also utilized as synthons for the production of various useful bioactive

molecules [Perry (1973); Hoegberg et al. (1990)].

1.2.1.3.5. Phenylbut-3-en-2-ones

The 1-phenylbut-3-en-2-ones are characterized by a C6-C4 skeleton and fall in the category

of α,β-unsaturated carbonyl compounds. Enones are an important class of compounds

because of their bioactivity such as anticandidial effect [Tabakova et al. (1999)] and

antioxidant activity [Weber et al. (2005)]. Many of the compounds have high commercial

value also. For example: 4-phenylbut-3-en-2-one is a food additive permitted for direct

addition to food for human consumption. More significantly, the compounds afford

synthetically useful building blocks in organic synthesis for further elaboration such as

Michael addition [Wang et al. (2006)].

1.2.1.3.6. Flavonoids

Flavonoids (from the Latin word flavus meaning yellow), also collectively known as

Vitamin P and citrin, are a broad class of low molecular

weight polyphenolic compounds. The two benzene rings are

joined by a linear three carbon chain (represented as C6 - C3

- C6 system) (Figure 11). Figure 11

Flavonoids are widely distributed in the leaves, seeds, bark and flowers of plants and are

easily recognised as flower pigments in most angiosperm families (flowering plants). Red or

blue colored berries, tea, wines, and certain vegetables are the major sources of flavonoids

in the human diet [Carando et al. (1999); Prior and Cao (1999); Stewart et al. (2000)].

The chemical structure of flavonoids are based on a C15 skeleton with a CHROMANE ring

bearing a second aromatic ring B in position 2, 3 or 4 (Figure 12).

O

A C B

1

2

3

456

7

8 2' 3'

4'

5'6'

Figure 12

In a few cases, the six-membered heterocyclic ring C occurs in an isomeric open form or is

replaced by a five-membered ring, example: AURONES (2-benzyl-coumarone) (Figure 13).

A C

B

O1

2

34

5

6

72'

3' 4'

5'

6'

Figure 13

A B2

34

56

2'

3'

4'

5'

6'

12 3


12

Various subgroups of flavonoids are classified according to the substitution patterns of ring

C (Figure 14). The distinguishing feature among the general flavonoid structural classes is

the presence or absence of an unsaturated bond in conjugation with an oxo function.

A C

B

O

A C

B

O

O

A C

B

O

O

A C

B

O

OH

O

A C

B

A

B

O

O

O

OH

Flavones

F lavonones

A nthocyan id ins

C halcones

F lavono ls

(+ )-C atech in , (-)-E p icatech in

K aem pfero l, Q uercetin

A pigen in , C hrysin

N aring in , H esperetin

Licochalcone, X an thohum ol

C yan id in , D elph in id in

C lass S tru ctu re E xam p les

Flavano ls

+

Figure 14: Major classes of flavonoids

Significance

The role of flavonoids as the major red, blue, yellow and purple pigments in plants has

gained these secondary metabolities a great deal of attention over the years [Carando et al.

(1999); Prior and Cao (1999); Stewart et al. (2000)]. In addition, these compounds provide

protection against ultraviolet radiations, pathogens, and herbivores [Harborne and Williams

(2000)]. The protective effects of flavonoids in biological systems are ascribed to their

capacity to transfer electrons to free radicals, chelate metal catalysts [Ferrali et al. (1997)],

activate antioxidant enzymes [Elliott et al. (1992)], reduce alpha-tocopherol radicals

[Hirano et al. (2001)] and inhibit oxidases [Cos et al. (1998)].

1.2.1.3.6.1. Chalcones

Chalcones are 1,3-diphenyl-2-propene-1-ones in which two aromatic rings are linked by a

three carbon α,β-unsaturated carbonyl system. Chalcone is derived from three acetates and

cinnamic acid as shown below (Figure 15).


13

HO OH

OH O

Cinnamic acid

3 x acetate(or malonate)

Figure 15

Generally, chalcones are synthesized by Claisen-Schmidt condensation of aldehyde and

ketone using base catalysis (Scheme 2). Recently, improved conditions using organolithium

bases in a polar solvent [Daskiewicz et al. (1999)] and microwave-assisted approaches

[Kumar et al. (2010)] have also been developed.

O

OHC

KOH

RT, 24 h

O

R1 R2R1R2

+

Scheme 2

Significance

Chalcones are key precursors in the synthesis of many biologically important heterocycles

such as open chain flavonoids, isoflavonoids, benzothiazepine, pyrazolines, 1,4-diketones,

and flavones [Rahman (2011)]. Chalcone and its derivatives have attracted increasing

attention due to numerous pharmacological applications among which antimalarial [Chen et

al. (1994); Motta et al. (2006); Lim et al. (2007), Begum et al. (2011)], anticancer [Go et al.

(2005); Achanta et al. (2006); Romagnoli et al. (2008); Kamal et al. (2010)], antiprotozoal

(antileishmanial and antitrypanosomal) [Lunardi et al. (2003)], anti-inflammatory [Zhang et

al. (2010); Yadav et al. (2011)], antibacterial [Bhatia et al. (2009)], antifilarial [Awasthi et

al. (2009)], antifungal [Lahtchev et al. (2008)], antimicrobial [Trivedi et al. (2007)],

larvicidal [Yadav et al. (2011)], anticonvulsant [Kaushik et al. (2010)], antimitotic

[Romagnoli et al. (2008)] and antioxidant [Vogel et al. (2008); Sivakumar et al. (2011)]

activities have been reported. They have also shown inhibition of the enzymes, especially

mammalian alpha-amylase [Najafian et al. (2010)], cyclo-oxygenase (COX) [Zarghi et al.

(2006)] and monoamine oxidase (MAO) [Chimenti et al. (2009)]. It is perceived that the

presence of a reactive ,β-unsaturated keto function in chalcones is found to be responsible

for their antimicrobial activity while the antimalarial property of chalcones results from

their ability to inhibit parasitic cysteine protease, an enzyme used by the parasite for the

degradation of host hemoglobin for its nutritional purposes.


14

1.2.1.3.7. Naphthoquinones

Naphthoquinones are one of the secondary metabolic groups widespread in nature, where

they mostly appear as chromatic pigments. They have been found in higher plants such as

Plumbaginaceae, Juglandaceae, etc. [Zhong et al. (1984); Binder et al. (1989)], fungi

(Marasmius gramium and Verticillium dahliae) [Medentsev and Akimenko (1998)] and

microorganisms (Streptomyces and Fusarium) [Moore and Hopke (2001)].

Naphthoquinones display very significant pharmacological properties [Babula et al.

(2007)]- they are cytotoxic, have significant antibacterial, antimalarial, antifungal, antiviral,

insecticidal, anti-inflammatory, and antipyretic properties [Ali et al. (1995); Kapadia et al.

(1997); Higa et al. (1998); Likhitwitayawuid et al. (1998); Kayser et al. (2000); Sasaki et al.

(2002)]. Pharmacological effects to cardiovascular and reproductive systems have been

demonstrated too [Elangovan et al. (1994); Srinivas et al. (2004)]. The mechanism of their

effect is highly large and complex - they bind to DNA and inhibit the processes of

replication, interact with numerous proteins (enzymes) and disturb cell and mitochondrial

membranes or interfere with electrons of the respiratory chain on mitochondrial membranes

[Fujii et al. (1992); Floreani et al. (1996); Song et al. (1999)]. Plant extracts containing

naphthoquinones have been used for a long time in traditional medicines for cancer and

rheumatoid arthritis treatment, for mitigation of toothache, for treatment of diarrhoea, skin

diseases and digestion malfunction [Babula et al. (2006)]. Chemical structures of some

bioactive napthoquinones are shown in Figure 16.O

O

OH

O

O

O

O

O

O

CH3

Lawsone 1,4-Naphthaquinone

OH

Juglone

OH

Plumbagin

Figure 16

1.2.2. Heterocyclic compounds

Aromatic compounds which contain heteroatoms (e.g. O, N, S) as part of the cyclic

conjugated π-system are called heterocyclic compounds. The remarkable ability of

heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely

contributed to their unique value as traditional key elements of numerous drugs [Varma

(1999); Eicher and Hauptmann (2003); Polshettiwar and Varma (2008)]. In the family of

heterocyclic compounds, nitrogen-containing compounds are of great significance to life

because their structural subunits exist in many natural products such as vitamins, hormones,


15

antibiotics and alkaloids, as well as pharmaceuticals, herbicides, dyes etc. [Bur and Padwa

(2004); Hulme et al. (2005); Garuti et al. (2007); Gil and Braese (2009)].

Among the various nitrogen heterocycles, dihydropyrimidinone derivatives have emerged

as one of the most pharmacologically important compounds because of their promising

biological effects, including antiviral, antibacterial, antitumor, anti-inflammatory activities

[Kappe (1993); (2000)]. Recently appropriately functionalized dihydropyrimidinones were

found to emerge as calcium channel modulators [Atwal et al. (1990)], orally active

antihypertensive agents [Rovnyak et al. (1992); Plunkett and Ellman (1997); Dömling

(1998); Schreiber (2000)] and α1a– adrenoceptor selective antagonists [Sidler et al. (1999);

Weber et al. (1999)]. The identification of dihydropyrimidinone monastrol (Figure 17) as a

specific inhibitor of mitotic kinesin Eg5 motor protein has provided a new lead for the

development of anticancer drugs [Mayer et al. (1999)]. Furthermore, several marine natural

products with interesting biological activities containing the dihydropyrimidine-5-

carboxylate core have recently been isolated [Heys et al. (2000)]. Most notable among these

are the batzelladine alkaloids A and B (Figure 17) which inhibit the binding of HIV

envelope protein gp-120 to human CD4 cells and, therefore, are potential new leads for

AIDS therapy [Patil et al. (1995)].

NH2

H2NHN

O O

NHN

NH

O

O

NH

N

(CH2)6CH3H3C

HH

Batzelladine B (Anti-HIV agent)

3

6

NH

NH

HO

S

C2H5OOC

H3C

Monastrol (mitotic kinase inhibitor)

Figure 17

1.3. Current challenges in synthesis of phenolics and heterocyclic compounds

Just less than two centuries ago, organic compounds were believed to be only accessible

through biological processes under the influence of ‘‘vital forces’’ [Bruce (2004)]. Today,

many molecules of great complexity can be synthesized readily. The total syntheses of

natural products with extremely high complexity such as vitamin B12 [Nicolaou and

Sorensen (1996)] and palytoxin [Armstrong et al. (1989)] in the laboratory are testimonials

of triumph of organic synthesis. However, despite such enormous achievements, we are

facing great challenges in future chemical synthesis as the present state-of-the-art processes

for synthesizing chemical products are highly inefficient [Li and Trost (2008)]. The concept

of atom economy [Trost (1991)] and E factor [Sheldon (1994)] provided a quantifiable


16

measure of such inefficiency and draws environmental and health concerns related to the

chemical wastes. Since its birth over a decade ago the field of “Green Chemistry” has been

specifically designed to meet such challenges in chemical synthesis [Anastas and Warner

(1998); Horváth and Anastas (2007)].

1.3.1. Green Chemistry“Industrial vomit…..fills our skies and seas, pesticides and herbicides filter into our foods. Twisted

automobile carcasses, aluminium cans, non-returnable glass bottles and synthetic plastics form

immense middens in our midst as more and more of our detritus resists decay. We do not even begin

to know what to do with our detritus resists decay we do not even begin to know what to do with our

radioactive wastes – whether to pump them into the earth, shoot them into outer space, or pour them

into the oceans. Our technological powers increase, but the side effects and potential hazards also

escalate.” -Alvin Toppler, Future Shock 1970

Throughout the 1990s, as pollution prevention moves to the forefront of environmental

stewardship, there has been a move away from the ‘command and control’ approach to a

more scientifically-based and economically beneficial approach known as “Green

Chemistry” or “Sustainable Chemistry” [Warner et al. (2004)]. Approaches to Green

Chemistry are varied: the use of benign solvents, the development of biodegradable

products, and the generation of non-toxic substances all contribute to pollution prevention

[Kappe and der Eycken (2010)]. Although hazardous substances and steps remain in some

processes, even incremental changes make a positive contribution to pollution prevention

[Li and Trost (2008)].

In 1998, Anastas and Warner proposed a set of guiding principles to achieve the goals of

green chemistry which are stated as below:

1. It is better to prevent waste than to treat or clean up waste after it has been created.

2. Synthetic methods should be designed to maximize the incorporation of all materials

used in the process into the final product.

3. Wherever practicable, synthetic methods should be designed to use and generate

substances that possess little or no toxicity to human health and the environment.

4. Chemical products should be designed to preserve efficacy of function while reducing

toxicity.

5. The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made

unnecessary wherever possible and innocuous when used.


17

6. Energy requirements should be recognized for their environmental and economic

impacts and should be minimized. Synthetic methods should be conducted at ambient

temperature and pressure.

7. A raw material or feedstock should be renewable rather than depleting whenever

technically and economically practicable.

8. Unnecessary derivatization (use of blocking groups, protection/ deprotection, temporary

modification of physical/chemical processes) should be minimized or avoided if

possible, because such steps require additional reagents and can generate waste.

9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.

10. Chemical products should be designed so that at the end of their function they break

down into innocuous degradation products and do not persist in the environment.

11. Analytical methodologies need to be further developed to allow for real-time, in-process

monitoring and control prior to the formation of hazardous substances.

12. Substances and the form of a substance used in a chemical process should be chosen to

minimize the potential for chemical accidents, including releases, explosions, and fires.

In summary, an ideal synthesis is generally regarded as one in which the target molecule

(natural or designed) is prepared from readily available, inexpensive starting materials in

one simple, safe, environmentally acceptable, and resource-effective operation that proceeds

quickly and in quantitative yield (Figure 18).

IdealSynthesis

SimpleTotal

conversion

One pot

Readily availablestarting materials

Environmentallyacceptable

Resourceefficient

Safe

Quantitativeyield

Figure 18: Ideal Chemical synthesis

In 2005, Ryoji Noyori identified three key developments in Green Chemistry: use of

supercritical carbon dioxide as green solvent, aqueous hydrogen peroxide for clean

oxidations and the use of hydrogen in asymmetric synthesis [Noyori (2005)]. It is not

possible to achieve all these goals simultaneously in a chemical reaction and the role of

chemist is to identify pathways, which optimize the balance of desirable attributes. Thus, in

this context, the present studies especially involve the application of following green tools.


18

Catalysis: Bio- and Organo-catalysis

Solvents: Ionic liquids and water

Chemical feedstocks: Use of readily available starting materials

Reactions: Tandem/Cascade and Multi-component reactions

Energy conservation : Use of microwave

1.3.1.1. Catalysis

The area of catalysis is sometimes referred to as the “foundational pillar” of Green

Chemistry [Anastas et al. (2001)]. Catalytic reactions [Manzer (1994); Hoelderich (2000)]

often reduce energy requirements and increase selectivity; they may permit the use of

renewable feedstocks or minimize the quantities of reagents needed [Anastas and Kirchhoff

(2002)]. Thus, catalysis is expected to remain a cornerstone in building a sustainable

chemical community through Green Chemistry [Anastas et al. (2000)]. Nowadays, the

catalytic potential of biocatalysts (enzymes and whole cells) and organocatalysts for organic

synthesis is being more and more looked at.

1.3.1.1.1. Biocatalysis

Through millions of years of evolution and ‘‘sustainability,’’ nature has developed its own

catalysts for achieving highly efficient and selective transformations. Exploiting the

potential usefulness of these catalysts of nature i.e. enzymes [Bisht et al. (1994); Wong and

Whitesides (1994); Prasad et al. (1999)], whole cells [Faber (1997); Kamal et al. (2011)],

and catalytic antibodies [Lerner et al. (1991)] for organic synthesis has provided powerful

and parallel tools in the synthetic chemist’s toolbox. Isolated enzymes have the advantage

of not being contaminated with other enzymes present in the cell while the use of whole cell

biocatalysis combines these benefits with simple catalyst preparation as it avoids separation

and purification of the enzyme [Sheldon (1994); Pfruender et al. (2006)]. Indeed

biocatalysis fits very well into the Green Chemistry and sustainable chemistry concepts: the

processes are inherently very benign as they are run at low or moderate temperatures,

preferably natural substrates and no toxic chemicals are used in the process [Schmid et al.

(2001)]. Further biocatalytic processes are normally very selective and do not need

protection-deprotection steps, all of which leads to a high atom economy [Schmid et al.

(2001)]. The significant features of biocatalysis are:

Alternative to conventional chemistry

Enzymes offer a wide range of reactions in aqueous and non-aqueous conditions

Particularly useful in chiral synthesis

Can function in green solvents such as ionic liquids, CO2 etc


19

An illustrative example of the benefits to be gained by replacing conventional organic

chemistry by biocatalysis is provided by the manufacture of 6-aminopenicillanic acid (6-

APA), a key raw material for semi-synthetic penicillin and cephalosporin antibiotics, by

hydrolysis of penicillin G [Bruggink et al. (1998); Wegman et al. (2001)] (Scheme 3).HN

O N

S

O

H H

COO H

N

Cl N

S

O

H H

COO H

H2N

N

S

O

H H

COO H

1. Me3SiCl2. PCl5 / CH2Cl2

PhNMe2 -40oC

1. n-BuOH, -40oC2. H2O, 0oC

Pencillin acylaseH2OPencillin G

37oC

6-APA

Scheme 3: Enzymatic versus chemical deacylation of penicillin G

The realization that many enzymes, particularly lipases, can catalyze alternate reactions

other than their natural role has led to rapid expansion of the biocatalysis [Kumar et al.

(2011)]. The enzyme active-site is optimized by evolution for a specific chemical

transformation and specific substrate recognition, but despite this, many enzymes perform

alternative activities or accept alternative substrates by showing “promiscuous” behavior

[Hult and Berglund (2007)]. For instance, in a recent report [Li et al. (2008)] (Scheme 4),

aldol reaction has been performed using porcine pancreas lipase (PPL).

CHO

R1

O

H2O

O

R1

OH

+

R1 =p-NO2, o-NO2, m-NO2, p-CN

Porcine pancreas lipase

Scheme 4

1.3.1.1.2. Organocatalysis

Organocatalysis is the acceleration of chemical reactions with a sub-stoichiometric amount

of an organic compound which does not contain a metal atom. The interest in this field has

increased spectacularly as result of both the novelty of the concept and the fact that

efficiency of many organocatalytic reactions meets the standards of established organic

reactions [Dalko and Moisan (2004)]. The vast majority of organocatalytic reactions are

amine based reactions [Westermann (2003a); (2003b)] with amino acids, peptides,

alkaloids, and synthetic nitrogen-containing molecules as catalysts. L-Proline and other


20

amino acid-derived organocatalysts or their analogues act through the formation of

enamines [List (2004)] or iminium salts [Erkkila et al. (2007)] (Scheme 5).

R1X

R2

O YH

R2R1

O

NH

COO H

N COO H

R1

R2

N

R1

R2

OH

O

Y

X

N

R1

R2

O-H

O

Y

X

+

Y

XElectrophile(aldehyde, ketone,azodicarboxylate....)

+ H2O

Scheme 5

Chiral urea or thiourea derivatives, which act as hydrogen-bond catalysts [Connon (2008)]

or chiral Brønsted acids, represent a special class of organocatalysts [Connon (2006)]. In the

last few years, the scope of organocatalytic reactions has been expanded considerably.

Typical C-C, C-N coupling reactions, such as aldol condensation [Saito and Yamamoto

(2004)], Manich reaction [Còrdova (2004)], Michael addition [Alexakis and Andrey

(2002)], α-amination [Duthaler (2003)] etc have been carried out efficiently with amino acid

derived catalysts. Furthermore, organocatalytic methods have great practical potential in

devising multicomponent and tandem sequences [Ramachary and Barbas (2004); Enders et

al. (2006)] (Scheme 6).

O

R1

R3 R2

NO2

R2NO2

OR1 R3

O

R2NO2

+A C

B

R3

R1

O

NH

Ph

PhOTM S

NH

Ph

PhOTMS

(S), 20 mol%Toluene

0oC to RT-H2O

Toluene0oC to RT

-H2O

(R), 20 mol%

Scheme 6: Asymmetric, organocatalytic three component multistep reaction cascade

1.3.1.2. Solvents

Auxiliary substances, such as solvents, are used to promote a reaction but are not

incorporated into the final product. As such, they become part of the waste stream and many


21

pose an environmental hazard [Sheldon (2005)]. Certain chlorinated organic solvents, for

example, are suspected human carcinogens, while chlorofluorocarbons (CFCs) are known to

deplete the stratospheric ozone layer [Anastas et al. (2000)]. Thus, as the introduction of

cleaner technologies has become a major concern throughout both industry and academia,

the search for alternatives to the most damaging solvents has become one of the primary

objectives of sustainable chemistry. The development of Green Chemistry redefines the role

of a solvent: An ideal solvent facilitates the mass transfer but does not dissolve! In addition,

a desirable green solvent should be natural, nontoxic, cheap, and readily available. More

desirably, it should have additional benefits of aiding the reaction, separation, or catalyst

recycling [Li and Trost (2008)]. There are four principal green strategies to avoid using

conventional organic solvents: No solvent (heterogeneous catalysis), water, ionic liquids

and supercritical fluids.

1.3.1.2.1. Ionic liquids

The field of ionic liquids began in 1914 with an observation by Paul Walden who reported

the physical properties of ethylammonium nitrate ([EtNH3][NO3]), which was formed by

the neutralization of ethylamine with concentrated nitric acid [Walden (1914)]. However,

research into ionic liquids boomed only after an article by Michael Freemantle -“Designer

solvents - ionic liquids may boost clean technology development” [Freemantle (1998)]

which effectively launched a renaissance in scientific and engineering interest in both

“salts” and “liquids”. Ionic liquids are now being defined as liquids composed entirely of

ions that are fluid around or below 100°C; thus replacing the older phrase “molten salts”

[Rogers and Seddon (2003)]. It is assumed that ionic liquids have no detectable vapor

pressure, and therefore contribute no volatile organic components to the atmosphere

[Rogers and Voth (2007)]; but this is not the only reason for using ionic liquids. Another is

that at least a million binary ionic liquids and 1018 ternary ionic liquids are potentially

possible [Seddon (1999)]. This diversity enables the solvent to be designed and tuned

[Freemantle (1998)] to optimize yield, selectivity, substrate solubility, product separation

and even enantioselectivity. Most common ionic liquids are formed through the

combination of an organic heterocyclic cation and an inorganic or organic anion. Typical

cations and anions of ionic liquids are shown in Figure 19. Ionic liquids can be highly

conducting [Ohno (2003)], form versatile biphasic systems for separations [Gutowski et al.

(2003)], are media for a wide range of organic and inorganic reactions [Rogers and Seddon

(2003); Wasserscheid and Welton (2003)], and are the basis for at least one industrial

process, called the BASIL process [Seddon (2003)].


22

N N R NR

NR2R1

NR1 R4

R3R2P

R1 R4

R3R2

NR1 R2

NNR1

R2

N SS

R2R1

R3

1-alkyl-3-methylimidazolium

N-alkyl-pyridinium

N-alkyl-N-methyl-piperidinium

Tetraalkyl-ammonium

Tetraalkyl-phosphonium

N-alkyl-N-methyl-pyrrolidinium

1,2-dialkyl-pyrazolium

N-alkyl-thiazolium

Trialkyl-sulfonium

R1,2,3,4 = CH3(CH2)n (n = 1,3,5,7,9); aryl etc.

Some possibleanions

water-immiscible water-miscible[PF6]-

[NTf2]-[BR1R2R3R4]-

[BF4]-

[OTf]-

[N(CN)2]-

[CH3CO2]-

[CF3CO2]-; [NO3]-

Br-; Cl-; I-[AlCl4]-

Some possiblecations

Figure 19: Some commonly used ionic liquid systems [Plechkova and Seddon (2008)]

After the seminal work by Klibanov in the early 1980s [Zaks and Klibanov (1985);

Klibanov (1986)], ionic liquids have emerged as a new paradigm for biocatalysis (Scheme

7). Due to the poor solubility of many precursors and their intermediates in the aqueous

reaction medium as well as toxic effects on the biocatalyst, a strong need was felt for

alternative solvents. Though initial background to the interest in ionic liquids was the desire

to replace volatile organic solvents; nevertheless increased enantioselectivity and stability

was also noticed in case of isolated enzymes [Yang and Pan (2005)] while efficiency of

whole cell biocatalytic process was enhanced profoundly [Pfruender et al. (2004)].

O

C7H15CO OHO

C7H15CO HO

H2O2H2O

[bmim]BF4rt, 24 h

CAL-B

Scheme 7: Perhydrolysis mediated by Candida antarctica lipase B (CAL-B) in ionic liquid

[van Rantwijk et al. (2003)]

Of late, amino acids based functional ionic liquids (AAILs) are attracting considerable

attention from industrial and academic community as “green solvent” [Tao et al. (2005);


23

(2006)]. Amino acids contains both an amino group and a carboxylic acid residue in a single

molecule, with various side groups and a chiral carbon atom, thus acting as suitable

candidates for synthesis of ionic liquids (Scheme 8). The merit of AAILs is their low cost,

biodegradability and biological activity [Ohno and Fukumoto (2007)].

H3N+ COO-

R

R

H3N+ COOHN N OH

R

R

H2N COO-

R

N COORS

F3C O

O

As cation

As anion

cation

X-

native

X-+

modified

cation

Scheme 8

1.3.1.2.2. Water

It is obvious that water is the most inexpensive and environmentally benign solvent. Since it

was reported that Diels–Alder reactions [Rideout and Breslow (1980)] could be greatly

accelerated by using water as a solvent instead of organic solvents (Scheme 9), there has

been considerable attention dedicated to the development of organic reactions in water [Li

(2005); Li and Chan (2007); Lindstrom (2007)].

O

COCH3

COCH3

H2O ++

Scheme 9

Several other advantages for choosing water as a solvent are following:

Water is the cheapest and most abundant solvent available.

Environmentally benign by being non flammable and non toxic.

If biphasic reaction system is used, organic substrates can be isolated by a simple

phase separation.

Water has the highest value for specific heat capacity, enabling the more facile

control of an exothermic reaction.

Water has a network of hydrogen bonds which can influence the reactivity of the

substrates.

Other interesting properties of water are that additives such as salts can be used.


24

Surfactants & cyclodextrins can be added, the pH can be varied and co-solvents or

biphasic reaction systems can be utilized.

Importantly, products can be isolated by filtration.

Water is the traditional solvent for biocatalysis as it does not inactivate enzymes and

therefore chemo-enzymatic strategy can be considered.

1.3.1.3. Chemical feedstocks: Use of readily available starting materials

One area to address when evaluating a synthetic transformation whether or not it is

environmentally benign is what material is being employed as feedstock. Presently, the

main feedstock of chemical products comes from non-renewable petroleum that is being

depleted rapidly both for chemical and energy needs. The utilization of benign, renewable

feedstock is a needed component for addressing the global depletion of resources [Gupta et

al. (2010)]. Therefore, the feasibility and benefits of using bio-based feedstock instead of

petroleum based feedstock, is actively being researched in both academia and the chemical

industry. Biological feedstocks provide several advantages including the fact that they are

derived from renewable sources, often are highly oxidized and functionalized which,

generally, allows for cleaner types of transformations such as reductions. For example, the

conventional synthesis of catechol begins with benzene, a known carcinogen, which is

obtained from petroleum, a non-renewable feedstock. Using genetically-engineered

Escherichia coli, catechol may be obtained in a single step from D-glucose (Scheme 10).

The biocatalytic pathway not only eliminates the use of hazardous substances present in the

synthesis of catechol but also decreases the energy demands of the reaction [Draths and

Frost (1998)].

OO H

O H

O H

O H

O H

O H

O HE . c o li A B 2 8 3 4 /P K D 1 3 6 /P K D 9 .0 6 9 A

D -G lu c o seC a te c h o l

3 7 o C

Scheme 10

On the other hand, the use of abundantly available plant derived raw materials as synthons

is highly advantageous as these often provide convenient templates to efficiently build up a

wide array of high valued scaffolds. For instance, a series of antimalarial methoxylated

chalcones were synthesized from natural β-asarone rich Acorus calamus (Scheme 11)

[Kumar et al. (2010)].


25

OCH 3

H3COOCH 3

R

O

A B

OOCH 3

H3COOCH 3

R

OCH 3

H3COOCH 3

O

R

OCH 3

H3COOCH 3

O

NR'

R

OCH3

H3COOCH3

beta-Asarone

R = Cl, Br, I , OCH3, CN, NO2 etc.R' = H, allyl etc.

Scheme 11

1.3.1.4. Reactions

Reactions play the most fundamental role in synthesis. The ideology of Green Chemistry

calls for the development of new chemical reactivities and reaction conditions that can

potentially provide benefits for chemical syntheses in terms of resource and energy

efficiency, product selectivity, operational simplicity as well as health and environmental

safety [Li and Trost (2008)]. In this context, tandem/cascade and multicomponent reactions

(MCR) have drawn great interest due to high atom economy and high selectivity associated

with them [Singh and Singh (2011)].

1.3.1.4.1. Tandem/Cascade reactions

Of fundamental importance to greener syntheses is the development of tandem and cascade

reaction processes that incorporate as many reactions as possible to give the final product in

one operation [Li and Trost (2008)]. Evidently, a multistep approach would generate

considerable waste due to use of large amounts of solvents, reagents and energy etc. In

contrast it would be more beneficial if a single operational sequence could be developed to

afford the formation of several bonds without isolation of reaction intermediates and

addition of reagents. The cascade reactions have been classified according to the mechanism

of the single steps which may be of the same or of different types and which can include

cationic, anionic, radical, pericyclic, transition metal-catalyzed, or redox transformations

[Tietze and Rackelmann (2004)].

Thus, the following two general classes of cascade reactions are possible:

Homo-cascade reactions: a combination of reactions of the same mechanism

Hetero-cascade reactions: a sequence of reactions with different mechanisms

A well-known example of tandem/cascade reaction is Jamison’s synthesis of the core piece

of ‘‘ladder’’ polyether marine natural products through a biomimetic cascade cyclization in

neutral water (Scheme 12).


26

O

HO

H3CO

O

O

H

H

O

O

HOH

HHOH3C

HH

HHH

H2O

70oC

Scheme 12

1.3.1.4.2. Multicomponent reactions

Multicomponent reactions (MCRs) are convergent reactions, in which three or more starting

materials react to form a product, where basically all or most of the atoms contribute to the

newly formed product (Scheme 13).

C

B

A

D

C

B

A

D

4CR+

Scheme 13

MCR strategies offer significant advantages over conventional linear-type syntheses in

terms of speed, diversity, and efficiency [Zhu and Bienayme (2005)]. The challenge is to

conduct an MCR in such a way that the network of pre-equilibrated reactions channel into

the main product and do not yield side products. The result is clearly dependent on the

reaction conditions: solvent, temperature, catalyst, concentration, the kind of starting

materials and functional groups [Dömling (2005)]. MCRs have great contribution in

convergent synthesis of complex and important organic molecules from simple and readily

available starting materials, paticularly heterocyclic scaffolds for the creation of diverse

chemical libraries of “drug-like” molecules for biological screening [Hulme et al. (2005)].

One prominent MCR that produces an interesting class of nitrogen heterocycles is the

venerable Biginelli dihydropyrimidinone synthesis (Scheme 14).

OR1

O O

H2N NH2

XRCHO

NH

NHR1OOC

R

X+

H+

EtOH,

Scheme 14

1.3.1.5. Energy conservation

According to one of the Green Chemistry principles- ‘Energy requirements should be

recognized for their environmental and economic impacts and should be minimized’. The


27

traditional manner of heating reaction mixtures on a laboratory scale typically involved the

use of mantles, oil baths or hot plates by applying a reflux set-up. This form of heating is

rather slow and inefficient method for transferring energy into a reaction mixture, as it

depends on convection currents and on the thermal conductivity of the various materials that

must be penetrated. Moreover, it often results in the temperature of the reaction vessel being

higher than that of the reaction mixture leading to wastage of energy. Consequently, the

chemical transformations should be designed to reduce the required energy input in terms of

mechanical, thermal and other considerations and the associated environmental impacts of

excessive energy usage. In this regard, Microwave and Ultrasound are emerging

technologies with a great potential for academia and industrial applications as a safe heating

source [Varma (2001); Hayes (2002); Appukkuttan and der Eycken (2006); Kumar et al.

(2007); Kalia and Kaith (2008); Malik et al. (2008)].

1.3.1.5.1. Microwave assisted organic synthesis (MAOS)

Microwave-assisted organic synthesis has been known since 1986 [Gedye et al. (1986);

Giguere et al. (1986)]. This “non-conventional” synthetic method has shown broad

applications as a very efficient way to accelerate the course of many organic reactions,

producing high yields and higher selectivity, lower quantities of side products and,

consequently, easier work-up and purification of the products (Scheme 15) [Kappe (2004);

(2008); Appukkuttan and der Eycken (2006); Polshettiwar and Varma (2008)].

NH

R

NH2

X XK2CO 3,H 2O

N

N

RN

HN

R+

Microwave+

major minorR = H, CH3, Cl; X= Cl, Br, I, OTs

Scheme 15: MW-assisted synthesis of 4,5-dihydro-pyrazole

The recognition of this technique as an integral part of green synthesis is established from

the fact that almost thousand publications have appeared on microwave mediated chemical

reactions. Microwave heats some certain substances not others due to selective absorption

of microwave by polar molecules. Reactions can be classified in two catagories in

microwave: (a) Reaction with solvent (b) Solvent free reactions.

Two additional attractive areas to study microwave heating are: a) biocatalysis (Scheme 16)

and b) application of ionic liquids (Scheme 17). Both classified under “Green Chemistry”

show synergy with microwave heating [Yadav and Lathi (2004); Lévêque and Cravotto

(2006)]. Important factors to work with ionic liquids are their high boiling points and low

volatility. Extremely fast heating rate curves (up to 10°C per second) are observed for ionic


28

liquids under microwave irradiation, due to the presence of ions which strongly interact

with the electromagnetic waves.

O

O

H H

NH2

NH

O

+ +1 mol% (S)-proline

DMSO , MW

Scheme 16: Asymmetric Mannich reaction under MW

X

ROB u

O

OBu

O

R

PdCl 2

Ionic liquidBase, M W

+

Scheme 17: Heck reaction in an ionic liquid heated by microwave irradiation

Some of the principal benefits of MAOS include:

Drastic reduction in reaction times

Improved yields and selectivity

Higher energy efficiency

Possibility of solventless reactions

Operational simplicity

1.4. Objectives of the present study

In the above context, it is evident that the compounds belonging to phenolic and

heterocyclic family are of immense importance in the domains of food, flavors and

pharmaceuticals. In an urgent need to develop new environment friendly methodologies for

the synthesis of some biologically important phenolic and heterocyclics, due emphasis will

be given to the utilization of concepts and tools of green chemistry which includes reducing

the consumption of solvents, energy conservation (use of microwave), utilization of

abundantly available compounds as precursors, multicomponent reactions and biocatalysis.

Further, stress will also be given on the isolation, chromatographic evaluation and

application of phenolics from plant sources.

Hence, the objective of the thesis entitled “Chemical and biotransformation studies of

some bioactive phenolics and heterocyclic compounds” involves studies towards phenolic

acids/aldehydes, styrenes, chalcones, coumarins and 3,4-dihydropyrimidin-2(1H)-ones.

For the sake of presentation, the work has been divided into following sections:

Chapter 1 Biocatalytic oxidative C=C bond cleavage and C-C bond formation studies on

phenolic derivatives in ionic liquid media


29

Chapter 2 Synthesis of allylated chalcones and their derivatives with enhanced solubility

for antimalarial and pesticidal activity

Chapter 3 Green synthesis of some bioactive heterocyclic compounds from natural

precursors

Chapter 4 Isolation, chromatographic evaluation and application of phenolic rich

colored compounds/fractions from plants

1.5. References:

Achanta, G., Modzelewska, A., Feng, L., Khan, S.R. and Huang, P. (2006). A boronic-

chalcone derivative exhibits potent anticancer activity through inhibition of the

proteasome. Molecular Pharmacology 70: 426-33.

Alasalvar, C., Taylor, K.D.A., Oksuz, A., Garthwaite, T., Alexis, M.N. and Grigorakis, K.

(2001). Freshness assessment of cultured sea bream (Sparus aurata) by chemical,

physical and sensory methods. Food Chemistry 72: 33-40.

Alexakis, A. and Andrey, O. (2002). Diamine-catalyzed asymmetric Michael additions of

aldehydes and ketones to nitrostyrene. Organic Letters 4: 3611-14.

Ali, B.H., Bashir, A.K. and Tanira, M.O.M. (1995). Anti-inflammatory, antipyretic, and

analgesic effects of Lawsonia inermis L. (henna) in rats. Pharmacology 51: 356-63.

Anastas, P.T., Bartlett, L.B., Kirchhoff, M.M. and Williamson, T.C. (2000). The role of

catalysis in the design, development, and implementation of Green Chemistry. Catalysis

Today 55: 11-22.

Anastas, P.T. and Kirchhoff, M.M (2002). Origins, current status and future challenges of

Green Chemistry. Accounts of Chemical Research 35: 686-94.

Anastas, P.T., Kirchhoff, M.M. and Williamson, T.C. (2001). Catalysis as a foundational

pillar of Green Chemistry. Applied Catalysis A: General 221: 3-13.

Anastas, P.T. and Warner, J.C. (1998). Green Chemistry: Theory and practice. Oxford

University Press, New York.

Appukkuttan, P. and der Eycken, E.V. (2006). Microwave-assisted natural product

chemistry. Topics in Current Chemistry 266: 1-47.

Armstrong, R.W., Beau, J.M., Cheon, S.H., Christ, W.J., Fujioka, H., Ham, W.H., Hawkins,

L.D., Jin, H., Kang, S.H. (1989). Total synthesis of palytoxin carboxylic acid and

palytoxin amide. Journal of the American Chemical Society 111: 7530-33.


30

Araico, A., Terencio, M.C., Alcaraz, M.J., Dominguez, J.N., Leon, C. and Ferrandiz, M.L.

(2006). Phenylsulphonyl urenyl chalcone derivatives as dual inhibitors of cyclo-

oxygenase-2 and 5-lipoxygenase. Life Sciences 78: 2911-18.

Atsushi, M., Takeo, K. and Yoshinobu, I. (1998). Anionic polymerization of 3,5-(2,4-)

dimethoxystyrene and 2,4,6-trimethoxystyrene and functionalization of the resulting

polymers by lithiation. Reactive and Functional Polymers 37: 39-47.

Atwal, K.S., Rovnyak, G.C., Kimball, S.D., Floyd, D.M., Moreland, S., Swanson, B.N.,

Gougoutas, J.Z., Schwartz, J., Smillie, K.M. and Malley, M.F. (1990).

Dihydropyrimidine calcium channel blockers. II. 3-Substituted-4-aryl-1,4-dihydro-6-

methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.

Journal of Medicinal Chemistry 33: 2629-35.

Awasthi, S.K., Mishra, N., Dixit, S.K., Singh, A., Yadav, M., Yadav, S.S. and Rathaur, S.

(2009). Antifilarial activity of 1,3-diarylpropen-1-one: Effect on glutathione-S-

transferase, a phase-II detoxification enzyme. American Journal of Tropical Medicine

and Hygiene 80: 764-68.

Aziz, N.H., Farag, S.E., Mousa, L.A.A. and Abo-Zaid, M.A. (1998). Comparative

antibacterial and antifungal effects of some phenolic compounds. Microbios 93: 43-54.

Babula, P., Adam, V., Havel, L. and Kizek, R. (2007). Naphthoquinones and their

pharmacological properties. Ceska a Slovenska Farmacie 56: 114-20.

Babula, P., Mikelová, R., Adam, V., Kizek, R., Havel, L. and Sladký, Z.

(2006). Naphthoquinones - Biosynthesis, occurrence and metabolism in plants. Ceska a

Slovenska Farmacie 55: 151-59.

Beckman, C.H. (2000). Phenolic-storing cells: keys to programmed cell death and periderm

formation in wilt disease resistance and in general defence responses in plants?

Physiological and Molecular Plant Pathology 57: 101-10.

Begum, N.A., Roy, N., Laskar, R.A. and Roy, K. (2011). Mosquito larvicidal studies of

some chalcone analogues and their derived products: structure-activity relationship

analysis. Medicinal Chemistry Research 20: 184-91.

Beletskaya, I.P. and Cheprakov, A.V. (2000). The Heck reaction as a sharpening stone of

palladium catalysis. Chemical Reviews 100: 3009-66.

Benavente-García, O., Castillo, J., Marin, F.R., Ortuño, A. and Del Río, J.A. (1997). Uses

and properties of citrus flavonoids. Journal of Agricultural and Food Chemistry 45:

4505-15.


31

Benzoukian, P.Z. (1986). Perfumery and Flavoring Synthetics. Allured Publishing

Cooperation, IL, USA.

Bhatia, N.M., Mahadik, K.R. and Bhatia, M.S. (2009). QSAR analysis of 1,3-diaryl-2-

propen-1-ones and their indole analogs for designing potent antibacterial agents.

Chemical Papers 63: 456-63.

Bhuyan, R. and Saikia, C.N. (2005). Isolation of color components from native dye-bearing

plants in northeastern India. Bioresource Technology 96: 363-72.

Binder, R.G., Benson, M.E. and Flath, R.A. (1989). Eight 1,4-naphthoquinones from

Juglans. Phytochemistry 28: 2799-801.

Bisht, K.S., Tyagi, O.D., Prasad, A.K., Sharma, N.K., Gupta, S. and Parmar, V.S. (1994).

Biotransformations in the regioselective deacetylation of polyphenolic peracetates in

organic solvents. Bioorganic and Medicinal Chemistry 2: 1015-20.

Bisignano, G., Tomaino, A., Cascio, R.L., Crisafi, G., Uccella, N. and Saija, A. (1999). On

the in-vitro antimicrobial activity of oleuropein and hydroxytyrosol. Journal of

Pharmacy and Pharmacology 51: 971-74.

Bonnet, M.C., Monteiro, A.L. and Tkatchenko, I. (1999). Carbonylation reactions: 7.

Regioselective synthesis of 2-arylpropionic acids by catalytic carbonylation of styrene

derivatives in the presence of palladium compounds: the critical role of the counter

anion. Journal of Molecular Catalysis A Chemical 143: 131-36.

Bravo, L. (1998). Polyphenols: Chemistry, dietary sources, metabolism and nutritional

significance. Nutrition Reviews 56: 317-33.

Bruce, P.Y. (2004). Organic Chemistry. 4th edn. Pearson Education, Upper Saddle River,

NJ.

Bruggink, A., Roos, E.C. and de Vroom, E. (1998). Penicillin acylase in the industrial

production of β-lactam antibiotics. Organic Process Research and Development 2: 128-

33.

Bur. S.K. and Padwa, A. (2004). The Pummerer Reaction: Methodology and strategy for

the synthesis of heterocyclic compounds. Chemical Reviews 104: 2401-82.

Cadenas, E. and Packer, L. (1996). Hand Book of Antioxidants. Plenum, New York.

Campos, P.J., García, B. and Rodríguez, M.A. (2000). One-pot selective synthesis of β-

nitrostyrenes from styrenes, promoted by Cu(II). Tetrahedron Letters 41: 979-82.

Carando, S., Teissedre, P.L., Pascual-Martinez, L. and Cabanis, J.C. (1999). Levels of

flavan-3-ols in French wines. Journal of Agricultural and Food Chemistry 47: 4161-66.


32

Chan, M.M.Y. (2002). Antimicrobial effect of resveratrol on dermatophytes and bacterial

pathogens of the skin. Biochemical Pharmacology 63: 99-104.

Chen, M., Theander, T.G., Brøgger Christensen, S., Hviid, L. and Kharazmi, A. (1994).

Licochalcone A, a new antimalarial agent inhibits the in vitro growth of the human

parasite Plasmodium falciparum and protects mice from P. yoelii infection.

Antimicrobial Agents and Chemotherapy 38: 1470-75.

Chimenti, F., Fioravanti, R., Bolasco, A., Chimenti, P., Secci, D., Rossi, F., Yanez, M.,

Francisco, O.F., Ortuso, F. and Alcaro, S. (2009). Chalcones: A valid scaffold for

monoamine oxidases inhibitors. Journal of Medicinal Chemistry 10: 1-8.

Clardy, J. and Walsh, C. (2004). Lessons from natural molecules. Nature 432: 829-37.

Connon, S.J. (2006). Chiral phosphoric acids: Powerful organocatalysts for asymmetric

addition reactions to imines. Angewandte Chemie International Edition 45: 3909-12.

Connon, S.J. (2008). Asymmetric catalysis with bifunctional cinchona alkaloid-based urea

and thiourea organocatalysts. Chemical Communications 2008: 2499-510.

Còrdova, A. (2004). The direct catalytic asymmetric Mannich reaction. Accounts of

Chemical Research 37: 102-12.

Cos, P., Ying, L., Calomme, M., Hu, J.P., Cimanga, K., Poel, B.V., Pieters, L., Vlietnck,

A.J. and Berghe, D.V. (1998). Structure-activity relationship and classification of

flavonoids as inhibitors of xanthine oxidase and superoxide scavengers. Journal of

Natural Products 61: 71-76.

Crozier, A., Jaganath, I.B. and Clifford, M.N. (2009). Dietary phenolics: Chemistry,

bioavailability and effects on health. Natural Product Reports 26: 1001-43.

Dalko, P.I. and Moisan, L. (2004). In the golden age of organocatalysis. Angewandte

Chemie International Edition 43: 5138-75.

Draths, K.M. and Frost, J.W. (1998). In: Anastas, P.T. and Williamson, T.C. (eds). Green

Chemistry: Frontiers in Benign Chemical Syntheses and Processes. Ch. 9. p 150.

Oxford University Press, New York.

Daskiewicz, J.B., Comte, G., Barron, D., Pietro, A.D. and Thomasson, F. (1999).

Organolithium mediated synthesis of prenylchalcones as potential inhibitors of

chemoresistance. Tetrahedron Letters 40: 7095-98.

Dixon, R.A. (2001). Natural products and plant disease resistance. Nature: 411: 843-47.

Domínguez, J.N., Charris, J.E., Lobo, G., de Domínguez, N.G., Moreno, M.M., Riggione,

F., Sanchez, E., Olson, J. and Rosenthal, P.J. (2001). Synthesis of quinolinyl chalcones


33

and evaluation of their antimalarial activity. European Journal of Medicinal Chemistry

36: 555-60.

Dömling, A. (2005). Multicomponent reactions - Superior chemistry technology for the new

millennium. Organic Chemistry Highlights, April 5.

Dömling, A. (1998). Isocyanide based multi component reactions in combinatorial

chemistry. Combinatorial Chemistry High Throughput Screening 1: 1-22.

Duthaler, R.O. (2003). Proline-catalyzed asymmetric α-amination of aldehydes and ketones-

an astonishingly simple access to optically active α-hydrazino carbonyl compounds.

Angewandte Chemie International Edition 42: 975-78.

Eicher, T. and Hauptmann, S. (2003). The chemistry of heterocycles: Structure, reactions,

syntheses and applications. 2nd edn. Wiley-VCH, Weinheim.

Erkkila, A. Majander, I. and Pihko, P.M. (2007). Iminium catalysis. Chemical Reviews 107:

5416-70.

Elangovan, V., Ramamoorthy, N., Balasubramanian, S., Sekar, N. and Govindasamy, S.

(1994). Studies on the antiproliferative effect of some naturally occurring bioflavonoidal

compounds against human carcinoma of larynx and sarcoma-180 cell lines. Indian

Journal of Pharmacology 26: 266-69.

Elliott, A.J., Scheiber, S.A., Thomas, C. and Pardini, R.S. (1992). Inhibition of glutathione

reductase by flavonoids. Biochemistry and Pharmacology 44: 1603-08.

Enders, D., Hüttl, M.R.M., Grondal, C. and Raabe, G. (2006). Control of four stereocentres

in a triple cascade organocatalytic reaction. Nature 441: 861-63.

Faber, K. (1997). Biotransformations in organic chemistry: A textbook. pp 8-10. Springer,

Berlin.

Ferrali, M., Signorini, C., Caciotti, B., Sugherini, L., Ciccoli, L., Giachetti, D. and

Comporti, M. (1997). Protection against oxidative damage of erythrocyte membranes by

the flavonoid quercetin and its relation to iron chelating activity. FEBS Letters 416: 123-

29.

Floreani, M., Forlin, A., Pandolfo, L., Petrone, M., Bellin, S. (1996). Mechanisms of

plumbagin action on guinea pig isolated atria. Journal of Pharmacology and

Experimental Therapeutics 278: 763-70.

Freemantle, M. (1998). Designer solvents- ionic liquids may boost clean technology

development. Chemical and Engineering News 76: 32-37.


34

Freire, R.S., Morais, S.M., Catunda-Junior, F.E.A. and Pinheiro, D.C.S.N. (2005). Synthesis

and antioxidant, anti-inflammatory and gastroprotector activities of anethole and related

compounds. Bioorganic and Medicinal Chemistry 13: 4353-58.

Frölich, S., Schubert, C., Bienzle, U. and Jenett-Siems, K. (2005). In vitro antiplasmodial

activity of prenylated chalcone derivatives of hops (Humulus lupulus) and their

interaction with haemin. Journal of Antimicrobial Chemotherapy 55: 883-87.

Fujii, N., Yamashita, Y., Arima, Y., Nagashima, M. and Nakano, H. (1992). Induction of

topoisomerase II-mediated DNA cleavage by the plant naphthoquinones plumbagin and

shikonin. Antimicrobial Agents and Chemotherapy 36: 2589-94.

Gang, D.R., Wang, J., Dudareva, N., Nam, K.H., Simon, J.E., Lewinsohn, E. and Pichersky,

E. (2001). An investigation of the storage and biosynthesis of phenylpropenes in sweet

basil. Plant Physiology 125: 539-55.

Garuti, L., Roberti, M. and Pizzirani, D. (2007). Nitrogen-containing heterocyclic quinones:

A class of potential selective antitumor agents. Mini Reviews in Medicinal Chemistry 7:

481-89.

Gartner, S., Kullmer, J. and Schlottmann, U. (2003). Chemical safety in a vulnerable world.


Gedye, R., Smith, F., Westaway, K., Ali, H., Baldisera, L., Laberge, L. and Rousell, J.

(1986). The use of microwave ovens for rapid organic synthesis. Tetrahedron Letters

27: 279-82.

Giguere, R.J., Bray, T.L., Duncan, S.M. and Majetich, G. (1986). Application of

commercial microwave ovens to organic synthesis. Tetrahedron Letters 27: 4945-48.

Geissman, T.A. (1963). Flavonoid compounds, tannins, lignins and related compounds. In:

Florkin, M. and Stotz, E.H. (eds). Pyrrole pigments, isoprenoid compounds and

phenolic plant constituents. Vol 9. pp 265. Elsevier, New York.

Gil, C. and Braese, S. (2009). Solid-phase synthesis of biologically active benzoannelated

nitrogen heterocycles: An update. Journal of Combinatorial Chemistry 11: 175-97.

Go, M.L., Wu, X. and Liu, X.L. (2005). Chalcones: an update on cytotoxic and

chemoprotective properties. Current Medicinal Chemistry 12: 481-99.

Gupta, M., Paul, S. and Gupta, R. (2010). General aspects of 12 basic principles of green

chemistry with applications. Current Science 99: 1341-60.

Gutowski K.E., Broker, G.A., Willauer, H.D., Huddleston, J.G., Swatloski, R.P., Holbrey,

J.D. and Rogers R.D. (2003). Controlling the aqueous miscibility of ionic liquids:

Aqueous biphasic systems of water-miscible ionic liquids and water-structuring salts for


35

recycle, metathesis, and separations. Journal of the American Chemical Society 125:

6632-33.

Harborne, J.B. (1982). Introduction to ecological biochemistry. 2nd edn. Academic Press,

New York.

Harborne, J.B., Baxter, H. and Moss, G.P. (1999). Phytochemical dictionary- A handbook of

bioactive compounds from plants. Taylor and Francis, London.

Harborne, J.B. and Turner, B.L. (1984). Plant chemosystematics. Academic Press, London.

Harborne, J.B. and Williams, C.A. (2000). Advances in flavonoid research since 1992.

Phytochemistry 55: 481-504.

Hayes, B.L. (2002). Microwave synthesis: Chemistry at the speed of light. CEM Publishing,

NC, USA.

Heys, L., Moore, C.G. and Murphy, P.J. (2000). The guanidine metabolites of Ptilocaulis

Spiculifer and related compounds; Isolation and synthesis. Chemical Society Reviews

29: 57-67.

Higa, M., Ogihara, K. and Yogi, S. (1998). Bioactive naphthoquinone derivatives from

Diospyros maritime Blume. Chemical and Pharmaceutical Bulletin 46: 1189-93.

Hirano, R., Sasamoto, W., Matsumoto, A., Itakura, H., Igarashi, O. and Kondo, K. (2001).

Antioxidant ability of various flavonoids against DPPH radicals and LDL oxidation.

Journal of Nutritional Science and Vitaminology 47: 357-62.

Horváth, I.T. and Anastas, P.T. (2007). Innovations and Green chemistry. Chemical

Reviews 107: 2169-73.

Hoegberg, T., Bengtsson, S., De Paulis, T., Johansson, L., Stroem, P., Hall, H. and Oegren

S.O. (1990). Potential antipsychotic agents. 5. Synthesis and antidopaminergic

properties of substituted 5,6-dimethoxysalicylamides and related compounds. Journal

of Medicinal Chemistry 33: 1155-63.

Hoelderich, W.F. (2000). One-pot reactions: a contribution to environmental protection.

Applied Catalysis A: General 194-195: 487-96.

Hulme, C., Zhu, J. and Bienayme, H. (2005). Multicomponent Reactions. Wiley, Weinheim.

Hult, K. and Berglund, P. (2007). Enzyme promiscuity: mechanism and applications.

Trends in Biotechnology 25: 231-38.

Indrayan, A.K. and Sharma, V. (1999). Isolation and extraction of medicinally useful dye

from the heartwood of Acacia catechu using different solvents. Oriental Journal of

Chemistry 15: 191-92.


36

Joshi, B.P., Sharma, A. and Sinha, A.K. (2005). Ultrasound-assisted convenient synthesis of

hypolipidemic active natural methoxylated (E)-arylalkenes and arylalkanones.

Tetrahedron 61: 3075-80.

Kalia, S. and Kaith, B.S. (2008). Microwave enhanced synthesis of flax-g-poly(MMA) for

use in phenolic composites as reinforcement. E-Journal of Chemistry 5: 163-68.

Kamal, A., Kumar, M.S., Kumar, C.G. and Shaik, T.B. (2011). Bioconversion of

acrylonitrile to acrylic acid by Rhodococcus ruber strain AKSH-84. Journal of

Microbiology Biotechnology 21: 37-42.

Kamal, A., Reddy, J.S., Ramaiah, M.J., Dastagiri, D., Bharathi, E.V., Sagar, M.V.P.,

Pushpavalli, S.N.C.V.L., Ray, P. and Pal-Bhadra, M. (2010). Design, synthesis and

biological evaluation of imidazopyridine/pyrimidine-chalcone derivatives as potential

anticancer agents. MedChemCommun 1: 355-60.

Kapadia, G.J., Balasubramanian, V., Tokuda, H., Konoshima, T., Takasaki, M., Koyama,

J., Tagahaya, K. and Nishino, H. (1997). Anti-tumor promoting effects of

naphthoquinone derivatives on short term Epstein-Barr early antigen activation assay

and in mouse skin carcinogenesis. Cancer Letters 113: 47-53.

Kappe, C.O. (1993). 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron

49: 6937-63.

Kappe, C.O. (2000). Recent advances in the Biginelli dihydropyrimidine synthesis. New

tricks from an old dog. Accounts of Chemical Research 33: 879-88.

Kappe, C.O. (2004). Controlled microwave heating in modern organic synthesis.


Kappe, C.O. (2008). Microwave dielectric heating in synthetic organic chemistry.

Chemical Society Reviews 37: 1127-39.

Kappe, C.O. and der Eycken, E.V. (2010). Click chemistry under non-classical reaction

conditions. Chemical Society Reviews 39: 1280-90.

Kasana, R.C., Sharma, U.K., Sharma, N. and Sinha, A.K. (2007). Isolation and

identification of a novel strain of Pseudomonas chlororaphis capable of transforming

isoeugenol to vanillin. Current Microbiology 54: 457-61.

Kaushik, S., Kumar, N. and Drabu, S. (2010). Synthesis and anticonvulsant activities of

phenoxychalcones. The Pharma Research 3: 257-62.

Kayser, O., Kiderlen, A.F., Laatsch, H. and Croft, S.L. (2000). In vitro leishmanicidal

activity of monomeric and dimeric naphthoquinones. Acta Tropica 77: 307-14.


37

King, F.D. and Oxford, A.W. (1999). Progress in medicinal chemistry. Elsevier Science

BV, Amsterdam.

Klibanov, A.M. (1986). Enzymes that work in organic solvents. ChemTech 16: 354-59.

Kohlpaintner, C.W. and Frohning, C.D. (1996). In: Cornils, B. and Herrmann, W.A. (eds).

Applied homogeneous catalysis with organometallic compounds. Vol 1. pp 1-39. Wiley-

VCH Weinheim.

Kokate, C.K. and Purohit, A.P. (2004). Text book of pharmacognosy. Vol 29. pp 317-37.

Nirali Prakashan, Pune, India.

Kondratyuk, T. and Pezzuto, J. (2004). Natural product polyphenols of relevance to human

health. Pharmaceutical Biology 42: 46-63.

Krause, M., Ligneau, X., Stark, H., Garbarg, M., Schwartz, J.C. and Schunack, W. (1998).

4-Alkynylphenyl imidazolylpropyl ethers as selective histamine h3-receptor

antagonists with high oral central nervous system activity. Journal of Medicinal


Kroon, P. and Williamson, G. (2005). Polyphenols: Dietary components with established

benefits to health. Journal of the Science of Food and Agriculture 85: 1239-40.

Kumar, M., Shah, B.A. and Taneja, S.C. (2011). Tandem catalysis by lipase in a vinyl

acetate-mediated cross-Aldol reaction. 353: 1207-12.

Kumar, R., Mohanakrishnan, D., Sharma, A., Kaushik, N.K., Kalia, K., Sinha, A.K. and

Sahal, D. (2010). Reinvestigation of structure-activity relationship of methoxylated

chalcones as antimalarials: Synthesis and evaluation of 2,4,5-trimethoxy substituted

patterns as lead candidates derived from abundantly available natural β-asarone.

European Journal of Medicinal Chemistry 45: 5292-301.

Kumar, V., Sharma, A., Sharma, A., Sinha, A.K. (2007). Remarkable synergism in

methylimidazole-promoted decarboxylation of substituted cinnamic acid derivatives in

basic water medium under microwave irradiation: a clean synthesis of hydroxylated (E)-

stilbenes. Tetrahedron 63: 7640-46.

Kuwahara, H., Kanazawa, A., Wakamatu, D., Morimura, S., Kida. K., Akaike, T. and

Maeda, H. (2004). Antioxidative and antimutagenic activities of 4-vinyl-2,6-

dimethoxyphenol (canolol) isolated from canola oil. Journal of Agricultural and Food

Chemistry 52: 4380- 87.

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

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

European Journal of Medicinal Chemistry 43: 2220-28.


38

Lampe, J.W. (1999). Health effects of vegetables and fruit: assessing mechanisms of action

in human experimental studies. American Journal of Clinical Nutrition 70: 475S-90S.

Lattanzio, V., Lattanzio, V.M.T. and Cardinali, A. (2006). Role of phenolics in the

resistance mechanisms of plants against fungal pathogens and insects. Phytochemistry:

Advances in Research 2006: 23-67.

Lee, J.Y., Lee, J.Y., Yun, B.S. and Hwang, B.K. (2004). Antifungal activity of β-asarone

from rhizomes of Acorus gramineus. Journal of Agricultural and Food Chemistry 52:

776-80.

Leite, A.C.L., da Silva, K.P., de Souza, I.A., de Araújo, J.M. and Brondani, D.J. (2004).

Synthesis, antitumour and antimicrobial activities of new peptidyl derivatives containing

the 1,3- benzodioxole system. European Journal of Medicinal Chemistry 39: 1059-65.

Lerner, R.A., Benkovic, S.J. and Schultz, P.G. (1991). At the crossroads of chemistry and

immunology–Catalytic antibodies. Science 252: 659-67.

Lévêque, J.M. and Cravotto, G. (2006). Microwaves, power ultrasound and ionic liquids. A

new synergy in green organic synthesis. Chimia International Journal of chemistry 60:

313-20.

Li, C., Feng, X.W., Wang, N., Zhou, Y.J. and Yu, X.Q. (2008). Biocatalytic promiscuity:

the first lipase-catalyzed asymmetric aldol reaction. Green Chemistry 10: 616-18.

Li, C.J. (2005). Organic reactions in aqueous media with a focus on C-C bond formations:

A decade update. Chemical Reviews 105: 3095-165.

Li, C.J. and Chan, T.H. (2007). Comprehensive organic reactions in aqueous media. Wiley,

New York.

Li, C.J. and Trost, B.M. (2008). Green chemistry for chemical synthesis. Proceedings of

National Academy of Science USA 105: 13197-202.

Likhitwitayawuid, K., Kaewamatawong, R., Ruangrungsi, N. and Krungkrai, J.

(1998). Antimalarial naphthoquinones from Nepenthes thorelii. Planta Medica 64: 237-

41.

Lim, S.S., Kim, H.S. and Lee, D.U. (2007). In vitro antimalarial activity of flavonoids and

chalcones. Bulletin of the Korean Chemical Society 28: 2495-97.

Lindstrom, U.M. (2007). Organic reactions in water. Blackwell, Oxford.

List, B. (2004). Enamine catalysis is a powerful strategy for the catalytic generation and use

of carbanion equivalents. Accounts of Chemical Research 37: 548-57.


39

Liu, M., Wilairat, P. and Go, M.L. (2001). Antimalarial alkoxylated and hydroxylated

chalones: structure-activity relationship analysis. Journal of Medicinal Chemistry 44:

4443-52.

Lunardi, F., Guzela, M., Rodrigues, A.T., Corre, R., Eger-Mangrich, I., Steindel, M.,

Grisard, E.C., Assreuy, J., Calixto, J.B. and Santos, A.R.S. (2003). Trypanocidal and

leishmanicidal properties of substitution-containing chalcones. Antimicrobial Agents

and Chemotherapy 47: 1449-51.

Malik, S., Nadir, U.K. and Pandey, P.S. (2008). Microwave-assisted efficient methylation of

alkyl and arenesulfonamides with trimethylsulfoxonium iodide and KOH. Synthetic

Communications 38: 3074-81.

Manach, C., Williamson, G., Morand, C., Scalbert, A. and Remesy, C. (2005).

Bioavailability and bioefficacy of polyphenols in humans. Review of 97 bioavailability

studies. American Journal of Clinical Nutrition 81: 230S-42S.

Mann, J., Davidson, R.S., Hobbs, J.B., Banthorpe, D.V. and Harborne, J.B. (1994). Natural

products their chemistry and biological significance. pp 361-388. Longman Scientific

and Technical, UK.

Manzer, L.E. (1994). Chemistry and catalysis: Keys to environmentally safer processes. In

Anastas, P.T. and Farris, C.A. (eds). Benign by design: Alternative synthetic design for

pollution prevention. American Chemical Society, Washington DC.

Mason, T.L. and Wasserman, B.P. (1987). Inactivation of red beet betaglucan synthase by

native and oxidized phenolic compounds. Phytochemistry 26: 2197-202.

Matthew S. (1995). Taxol, science and applications. CRC Press, New York.

Mayer, T.U., Kapoor, T.M., Haggarty, S.J., King, R.W., Schreiber, S.L. and Mitchison, T.J.

(1999). Small-molecule inhibitor of mitotic spindle bipolarity indentified in a

phenotype-based screen. Science 286: 971-74.

Medentsev, A.G. and Akimenko, V.K. (1998). Naphthoquinone metabolites of the fungi

Phytochemistry 47: 935-59.

Middleton, E., Kandaswami, C. and Theoharides, T.C. (2000). The effects of plant

flavonoids on mammalian cells: Implications for inflammation, heart disease, and

cancer. Pharmacological Reviews 52: 673-751.

Moore, S.B. and Hopke, N.J. (2001). Discovery of new bacterial polyketide biosynthetic

pathway. Chemistry and Biochemistry 2: 35-38.

Motta, L.F., Gaudio, A.C. and Takahata, Y. (2006). Quantitative structure-activity

relationships of a series of chalcone derivatives (1,3-diphenyl-2-propen-1-one) as anti-


40

Plasmodium falciparum agents (antimalaria agents). Internet Electronic Journal of

Molecular Design 5: 555-69.

Naczk, M. and Shahidi, F. (2004). Extraction and analysis of phenolics in food. Journal of

Chromatography A 1054: 95-111.

Najafian, M., Ebrahim-Habibi, A., Hezareh, N., Yaghmaei, P., Parivar, K. and Larijani, B.

(2010). Trans-chalcone: a novel small molecule inhibitor of mammalian alpha-amylase.

Molecular Biology Reports 10: 271-74.

Nicholson, R. and Hammerschmidt, R. (1992). Phenolic compounds and their role in

disease resistance. Annual Review of Phytopathology 30: 369-89.

Nicolaou, K.C. and Snyder S.A. (2004). The essence of total synthesis. Proceedings of the

National Academy of Sciences USA 101: 11929-36.

Nicolaou, K.C. and Sorensen, E.J. (1996). Classics in total synthesis. VCH, New York.

Nishida, K. and Kobayashi, K. (1992a). Dyeing properties of natural dyes under after

treatment using metallic mordants. American Dyestuff Reporter 81: 61-62.

Nishida, K. and Kobayashi, K. (1992b). Dyeing properties of natural dyes from natural

sources: Part I. American Dyestuff Reporter 81: 44-45.

Noyori, R. (2005). Pursuing practical elegance in chemical synthesis. Chemical

Communications 14: 1807-11.

Ohno, H. (2003). Ionic Liquids: The Front and Future of Material Developments. CMC,

Tokyo.

Ohno, H. and Fukumoto, K. (2007). Amino acid ionic liquids. Accounts of Chemical

Research 40: 1122-29.

Onal, A., Yildiz, A. and Tutar, A. (1999). Extraction of dyestuff from Valonia oak (Quercus

cerris): Dyeing of woolen strips, cotton and feathered-leather. Bulletin of Pure and

Applied Science 18C: 77-87.

Patil, A.D., Kumar, N.V., Kokke, W.C., Bean, M.F., Freyer, A.J., De Brosse, C., Mai, S.,

Truneh, A., Faulkner, D.J., Carte, B., Breen, A.L., Hertzberg, R.P., Johnson, R.K.,

Westley, J.W. and Potts, B.C.M. (1995). Novel alkaloids from the sponge Batzella sp.:

Inhibitors of HIV gp120-human CD4 binding. The Journal of Organic Chemistry 60:

1182-88.

Paul, M.D. (1997). Medicinal natural products: A biosynthetic approach. John Wiley and

Sons, New York.

Perry, C.W. (1973). Method for making 2,3-dimethyl-1,4-bis(3,4-hydrocarbonyloxy

phenyl)-1,4-butandione. US Patent 3769350.


41

Pfruender, H., Amidjojo, M., Kragl, U. And Weuster-Botz, D. (2004). Efficient whole-cell

biotransformation in a biphasic ionic liquid/water system. Angewandte Chemie

International Edition 43: 4529-31.

Pfruender, H., Jones, R. and Weuster-Botz, D. (2006). Water immiscible ionic liquids as

solvents for whole cell biocatalysis. Journal of Biotechnology 124: 182-90.

Plunkett, M. and Ellman, J.A. (1997). Combinatorial chemistry and new drugs. Scientific

American 276: 68-73.

Plechkova, N.V. and Seddon, K.R. (2008). Applications of ionic liquids in the chemical

industry. Chemical Society Reviews 37: 123-50.

Polshettiwar, V. and Varma, R.S. (2008). Greener and expeditious synthesis of bioactive

heterocycles using microwave irradiation. Pure and Applied Chemistry 80: 777-90.

Prasad, A.K., Trikha. S. and Parmar, V.S. (1999). Nucleoside synthesis mediated by

glycosyl transferring enzymes. Bioorganic Chemistry 27: 135-54.

Pridham, J.B. (1960). Phenolics in plants in health and disease. Pergamon Press, New

York.

Prior, R.L. and Cao, G. (1999). Antioxidant capacity and polyphenolic components of teas:

implications for altering in vivo antioxidant status. Proceedings of the Society for

Experimental Biology and Medicine 220: 255-61.

Puupponen-Pimiä, R., Nohynek, L., Meier, C., Kähkönen, M., Heinonen, M., Hopia, A. and

Oksman-Caldentey, K.M. (2001). Antimicrobial properties of phenolic compounds from

berries. Journal of Applied Microbiology 90: 494-507.

Rahman, M.A. (2011). Chalcone: A valuable insight into the recent advances and potential

pharmacological activities. Chemical Sciences Journal 2011: CSJ-29 (1-16).

Ramachary, D.B. and Barbas, C.F. (2004). Towards organo-click chemistry: Development

of multicomponent reactions through combination of aldol, Wittig, Knoevenagel,

Michael, Diels-Alder and Huisgen cycloaddition reactions. Chemistry- A European

Journal 10: 5323-31.

Rawat, P., Kumar M., Rahuja, N., Srivastava, S.D.L., Srivastava, A.K. and Maurya R.

(2011). Synthesis and antihyperglycemic activity of phenolic C-glycosides. Bioorganic

and Medicinal Chemistry Letters 21: 228-33.

Rice-Evans, C.A., Miller, N.J. and Paganga, G. (1996). Structure–antioxidant activity

relationships of flavonoids and phenolic acids. Free Radical Biology and Medicine 20:

933-56.


42

Rideout, D.C. and Breslow, R. (1980). Hydrophobic acceleration of Diels-Alder reactions.

Journal of the American Chemical Society 102: 7816-17.

Rogers, R.D. and Seddon, K.R. (2003). Ionic Liquids-Solvents of the Future? Science 302:

792-93.

Rogers, R.D. and Voth, G.A. (2007). Ionic Liquids. Accounts of Chemical Research 40:

1077-78.

Romagnoli, R., Baraldi, P.G., Carrion, M.D., Cara, C.L., Cruz-Lopez, O. and Preti, D.

(2008). Design, synthesis and biological evaluation of thiophene analogues of

chalcones. Bioorganic and Medicinal Chemistry 16: 5367-76.

Rovnyak, G.C., Atwal, K.S., Hedberg, A., Kimball, S.D., Moreland, S., Gougoutas, J.Z.,

O’Reilly, B.C., Schwartz, J. and Malley, M.F. (1992). Basic 3-Substituted-4-aryl-1,4-

dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. Journal of

Medicinal Chemistry 35: 3254-63.

Saito, S. and Yamamoto, H. (2004). Design of acid-base catalysis for the asymmetric direct

aldol reaction. Accounts of Chemical Research 37: 570-79.

Samman. (1998). Flavonoids and coronary heart disease: Dietary perspectives. In: Rice-

Evans, C.A. and Packer, L. (eds). Flavonoids in health and disease. pp 469-82. Marcel

Dekker, New York.

Samy, R.P. and Gopalakrishnakone, P. (2010). Therapeutic potential of plants as anti-

microbials for drug discovery. eCAM 7: 283-94.

Sasaki, K., Abe, H. and Yoshizaki, F. (2002). In vitro antifungal activity of naphthoquinone

derivatives. Biological and Pharmaceutical Bulletin 25: 669-70.

Saxena, S., Pant, N., Jain, D.C. and Bhakuni, R.S. (2003). Antimalarial agents from plant

sources. Current Science 85: 1314-29.

Schmid, A., Dordick, J.S., Hauer, B., Kiener, A., Wubbolts, M. and Witholt, B. (2001).

Industrial biocatalysis today and tomorrow. Nature 409: 258-68.

Schreiber, S.L. (2000). Target-oriented and diversity-oriented organic synthesis in drug

discovery. Science 287: 1964-69.

Seddon, K.R. (1999). In: The International George Papatheodorou Symposium:

Proceedings. Boghosian, S., Dracopoulos, V., Kontoyannis, C.G. and Voyiatzis, G.A.

(eds). pp 131-35. Institute of Chemical Engineering and High Temperature Chemical

Processes. Patras, Greece.

Seddon, K.R. (2003). Ionic liquids: A taste of the future. Nature Materials 2: 363-65.

Sheldon, R.A. (1994). Consider the environmental quotient. ChemTech 24: 38-47.


43

Sheldon, R.A. (2005). Green solvents for sustainable organic synthesis: state of the art.

Green Chemistry 7: 267-78.

Sies, H. (1996). Antioxidants in disease: Mechanisms and therapy. Academic Press, New

York.

Sidler, D.R., Larsen, R.D., Chartrain, M., Ikemote, N., Roerber, C.M., Taylor, C.S., Li, W.

and Bills, G.F. (1999). Alpha-1a adrenergic receptor antagonists. WO 99/07695.

Singh, S.K. and Singh, K.N. (2011), Eco-Friendly and facile one-pot multicomponent

synthesis of acridinediones in water under microwave. Journal of Heterocyclic


Sinha, A.K., Sharma, N., Shard, A., Sharma, A., Kumar, R. and Sharma, U.K. (2010).

Green methodologies in synthesis and natural product chemistry of phenolic

compounds. Indian Journal of Chemistry B 48: 1771-79.

Sivakumar, P.M., Prabhakar, P.K. and Doble, M. (2011). Synthesis, antioxidant evaluation

and quantitative structure activity relationship studies of chalcones. Medicinal

Chemistry Research 20: 482-92.

Shahidi, F. (2002). Interface friction and energy dissipation in soft solid processing

applications. In: Morello, M.J., Shahidi, F. and Ho C.T. (eds). Vol 807. pp 162-75. ACS

Symposium Series, American Chemical Society, Washington DC.

Shahidi, F. and Naczk, M. (2004). Phenolics in food and nutraceuticals: Sources,

applications and health effects. CRC Press, Boca Raton, FL.

Sheldon, R.A. (2007). The E Factor: fifteen years on. Green Chemistry 9: 1273-83.

Song, G.Y., Zheng, X.G., Kim, Y., You, Y.J., Sok, D.E. and Ahn, B.Z.

(1999). Naphthazarin derivatives (II): Formation of glutathione conjugate, inhibition of

DNA topoisomerase-I and cytotoxicity. Bioorganic and Medicinal Chemistry Letters 9:

2407-12.

Springob, K. and Kutchan, T.M. (2009). Introduction to the different classes of natural

products. In: Osbourn, A.E. and Lanzotti, V. (eds). Plant-derived natural products:

Synthesis, function and application. pp 3-50. Springer, New York.

Srinivas, K.V., Rao, K.Y., Mahender, I., Das, B., Rama Krishna, K.V., Hara Kishore, K.

and Murty, U.S. (2003). Flavanoids from Caesalpinia pulcherrima. Phytochemistry 63:

789-93.

Srinivas, P., Gopinath, G., Banerji, A., Dinakar, A. and Srinivas, G. (2004). Plumbagin

induces reactive oxygen species, which mediate apoptosis in human cervical cancer

cells. Molecular Carcinogenesis 40: 201-11.


44

Steffen, A. (1994). Perfume and flavor chemicals. Aroma chemicals. Vols 1 and 2. Allured,

USA.

Stewart, A.J., Bozonnet, S., Mullen, W., Jenkins, G.I., Lean, M.E. and Crozier, A. (2000).

Occurrence of flavonols in tomatoes and tomato-based products. Journal of Agricultural

and Food Chemistry 48: 2663-69.

Stuart, R.R., Colette, S.M. and David, J.L. (1994). Epoxidation of styrene and substituted

styrenes by whole cells of Mycobacterium sp. M156. Bioorganic and Medicinal


Suri, O.P., Bindra, R.S., Satti, N.K. and Khajuria, R.K. (1987). Synthesis of apocynin, a

choleretic constituent of Picrorhiza kurroa & its homologues. Indian Journal of

Chemistry B 26: 587-88.

Tabakova, S., Manolov, I., Kantardjiev, T., Mateev, G., Stoichkov, K., Braykova, A.,

Vakhan, V. and Golovinsky, E. (1999). Anticandidial effect of phenylbutene derivatives

and their interaction with ergosterol. Z Naturforsch 54c: 61-64.

Tao, G.H., He, L., Liu, W.S., Xu, L., Xiong, W., Wang, T. and Kou, Y. (2006). Preparation,

characterization and application of amino acid-based green ionic liquids. Green


Tao, G.H., He, L., Sun, N. and Kou, Y. (2005). New generation ionic liquids: cations

derived from amino acids. Chemical Communications 2005: 3562-64.

Tietze, L.F. and Rackelmann, N. (2004). Domino reactions in the synthesis of heterocyclic

natural products and analogs. Pure and Applied Chemistry 76: 1967-83.

Tilay, A., Bule, M. and Annapure, U. (2010). Production of biovanillin by one-step

biotransformation using fungus Pycnoporous cinnabarinus. Journal of Agricultural and

Food Chemistry 58: 4401-05.

Trivedi, J.C., Bariwal, J.B., Upadhyay, K.D., Naliapara, Y.T., Soshi, S.K., Pannecouque,

C.C., De Clercq, E. and Shah, A.K. (2007). Improved and rapid synthesis of new

coumarinyl chalcone derivatives and their antiviral activity. Tetrahedron Letters 48:

8472-74.

Trost, B.M. (1991). The atom economy: A search for synthetic efficiency. Science 254:

1471-77.

Trost, B.M. (2002). On inventing reactions for atom economy. Accounts of Chemical

Research 35: 695-705.

Tsuchiya, H., Sato, M., Miyazaki, T., Fujiwara, S., Tanigaki, S., Ohyama, M., Tanaka, T.

and Iinuma, M. (1996). Comparative study on the antibacterial activity of


45

phytochemical flavanones against methicillin-resistant Staphylococcus aureus. Journal

of Ethnopharmacology 50: 27-34.

van Rantwijk, F., Lau, R.M. and Sheldon, R.A. (2003). Biocatalytic transformations in ionic

liquids. Trends in Biotechnology 21: 131-38.

Varma. R.S. (1999). Solvent-free synthesis of heterocyclic compounds using microwaves.

Journal of Heterocyclic Chemistry 36: 1565-71.

Varma, R.S. (2001). Solvent-free accelerated organic syntheses using microwaves. Pure

and Applied Chemistry 73: 193-98.

Vogel, S., Ohmayer, S., Brunner, G. and Heilmann, J. (2008). Natural and non-natural

prenylated chalcones: Synthesis, cytotoxicity and anti-oxidative activity. Bioorganic

and Medicinal Chemistry 16: 4286-93.

Vuorela, S., Meyer, A.S. and Heinonen, M. (2004). Impact of isolation method on the

antioxidant activity of rapeseed meal phenolics. Journal of Agricultural and Food


Wang, J., Li, H., Zu, L., Jiang, W., Xie, H., Duan, W. and Wang, W. (2006).

Organocatalytic enantioselective conjugate additions to enones. Journal of the American

Chemical Society 128: 12652-53.

Walden, P. (1914). Über die Molekulargroße und elektrische Leitfähigkeit einiger

geschmolzener Salze. Bulletin of the Academy of Imperial Science (St. Petersburg) 8:

405-22.

Walton, N.J. and Brown, D.E. (1999). Chemicals from plants: Perspectives on plant

secondary products. Imperial College Press, London.

Warner, J.C., Cannon, A.S. and Dye, K.M. (2004). Green chemistry. Environmental Impact

Assessment Review 24: 775-99.

Wasserscheid, P. and Welton, T. (2003). Ionic liquids in synthesis. Wiley-VCH, Weinheim,

Germany.

Weber, L., Illgen, K. and Almstetter, M. (1999). Discovery of new multicomponent

reactions with combinatorial methods. Synlett 3: 366-74.

Weber, W.M., Hunsaker, L.A., Abcouwer, S.F., Decka, L.M. and Jagt, D.L.V. (2005). Anti-

oxidant activities of curcumin and related enones. Bioorganic and Medicinal Chemistry

13: 3811-20.

Wegman, M.A., Janssen, M.H.A., van Rantwijk, F. and Sheldon, R.A. (2001). Towards

biocatalytic synthesis of β-Lactam antibiotics. Advanced Synthesis and Catalysis 343:

559-76.


46

Wen, A.M., Delaquis, P., Stanich, K. and Toivonen, P. (2003). Antilisterial activity of

selected phenolic acids. Food Microbiology 20: 305-11.

Westermann, B. (2003a). Asymmetrische katalytische Aza-Henry-reaktionen zu 1,2-

diaminen und 1,2-diaminocarbonsäuren. Angewandte Chemie 115: 161-63.

Westermann, B. (2003b). Asymmetric catalytic Aza-Henry reactions leading to 1,2-

diamines and 1,2-diaminocarboxylic acids. Angewandte Chemie International Edition

42: 151-53.

William, A.A., David, J.M. and Priyotosh, C. (1996). Phenolic and other metabolites of

Phellinus pini, a fungus pathogenic to pine. Phytochemistry 42: 1321-24.

Wong, C.H. and Whitesides, G.M. (1994). Enzymes in Organic Chemistry. Elsevier,

Oxford.

Wu, X., Wilairat, P. and Go, M.L. (2002). Antimalarial activity of ferrocenyl chalcones.

Bioorganic and Medicinal Chemistry Letters 12: 2299-302.

Yadav, G.D. and Lathi, P.S. (2004). Synergism between microwave and enzyme catalysis in

intensification of reactions and selectivities: transesterification of methyl acetoacetate

with alcohols. Journal of Molecular Catalysis A: Chemical 223: 51-56.

Yadav, H.L., Gupta, P., Pawar, P.S., Singour, P.K. and Patil, U.K. (2011). Synthesis and

biological evaluation of anti-inflammatory activity of 1,3-diphenyl propenone

derivatives. Medicinal Chemistry Research 20: 461-65.

Yang, Z. and Pan, W. (2005). Ionic liquids: Green solvents for non-aqueous biocatalysis.

Enzyme Microbial Technology 37: 19-28.

Yenesew, A., Induli, M., Derese, S., Midiwo, J.O., Heydenreich, M., Peter, M.G., Akala,

H., Wangui, J., Liyala, P. and Waters, N.C. (2004). Anti-plasmodial flavonoids from the

stem bark of Erythrina abyssinica. Phytochemistry 65: 3029-32.

You-Ping, Z. (1998). Chinese materia medica: Chemistry, pharmacology and applications.

Harwood Academic Publishers, Autralia.

Zacchino, S.A., López, S.N., Pezzenati, G.D., Furlán, R.L., Santecchia, C.B., Muñoz, L.,

Giannini, F.A., Rodríguez, A.M. and Enriz, R.D. (1999). In vitro evaluation of

antifungal properties of phenylpropanoids and related compounds acting against

dermatophytes. Journal of Natural Product 62: 1353-57.

Zaks, A. and Klibanov, A.M. (1985). Enzyme-catalyzed processes in organic solvents.

Proceedings of the National Academy of Science USA 82: 3192-96.

Zarghi, A., Zebardast, T., Hakimion, F., Shirazi, F.H., Rao, P.N.P. and Knaus, E.E. (2006).

Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a


47

methanesulfonamido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors.

Bioorganic and Medicinal Chemistry 14: 7044-50.

Zhang, X.W., Zhao, D.H., Quan, Y.C., Sun, L.P., Yin, X.M. and Guan, L.P. (2010).

Synthesis and evaluation of anti-inflammatory activity of substituted chalcone

derivatives. Medicinal Chemistry Research 19: 403-12.

Zhong, S.M., Waterman, P.G. and Jeffreys, J.A.D. (1984). Naphthoquinones and triterpenes

from african Diospyros species. Phytochemistry 23: 1067-72.

Zhu, J. and Bienayme, H. (2005). Multicomponent reactions. Wiley-VCH, Weinheim,

Germany.

Documents

Chemical and Biotransformation studies of Some Bioactive ...shodhganga.inflibnet.ac.in/bitstream/10603/10457/5/... · (1998 ); Walton and Brown (1999 )]. For instance, several bioactive