PART -B

Chapter - 7 Introduction

Part- B Introduction

7.1 Introduction

Heterocyclic compounds have been an important and major class of organic

compounds. Heterocycies play vital role in the human life as basic moieties in dyes,

drugs, polymers, food flavours etc. Some of the heterocycies such as pyridine,

pyrimidine, purine, indole etc. are known to play an important role in biological process

in the form of vitamins, nucleic acid, proteins, enzymes and so on. Several heterocyclic

compounds are widely distributed in nature particularly in plant kingdom. Alkaloids,

which have been used in the form of crude extract in earlier systems of medicine are

nitrogen heterocycies. Plant preparations used since ancient times for the treatment of

several diseases are known to contain oxygen heterocycies such as flavones, coumarins,

chromones, benzofurans. Most of these medicinally useful heterocyclic natural products

have served as lead compounds for many of the drugs currently in use.

The synthetic approach based on structural analogy with the existing drugs is a

most common approach for the drug discovery in most of the laboratories all over the

world. The structural modifications of existing drug molecules have often yielded

fruitful results. The present investigation is a similar effort.

Among a variety of heterocycies that have been explored for developing

pharmaceutically important molecules, benzoxazoles have played an important role in

medicinal chemistry. Benzoxazole derivatives have acquired a special place in the

heterocyclic field because of their broad spectrum biological activities. Most of the

natural products containing benzoxazole moiety are endowed with useful medicinal

properties.

127

Part- B Introduction

Benzoxazoles are important heterocyclic systems with varied biological

activities'. It exhibit antimicrobial, antiviral^, antiallergic'', hypoglycemic^ and

antiinflammatory^ activities. Benzoxazoles are also used as fluorescent probes, which

show high stokes shift and show thermal and photophysical stability due to an excited

state intramolecular proton transfer mechanism^. It interfere with the biosynthesis of

coloured carotenoids by inhibiting the enzyme phytoene desaturase, which are studied as

potential bleaching herbicides^. Benzoxazoles can be considered as structural isosters of

the naturally occurring nucleic bases adenine and guanine, which allow them to interact

easily with polymers of living systems. They have shown low toxicity in warm-blooded

animals^.

7.2 Naturally occurring benzoxazoles:

Benzoxazoles represents a rare category of heterocyclic natural compounds

having a veriety of pharmacological proprties, including antitubercular activity " . One

very interesting subclass of this category is the marine benzoxazoles''*''^. The carribben

sea whip Pseudopterogorgia elisabethae is a known source of the aforementioned

subcless of benzoxazoles and it contains several analogs that have been described as

strongly antimucobacterial'^''^. Having as target the investigation of the extensive

chemodiversity of P. elisabethae and the assessment of its secondary metabolites as

potential antitubercular agents. Recently Ileana et al.,'* reported the hexane extract of P.

elisabethae from natural habitat near the Island of Providencia, Colombia. They isolated

ilebethoxazole 1, from P. elisabethae and the structure of 1 was confirmed by ' H - ' H cosy

NMR study. The isolated compound was studied for Mycobacterium tuberculosis

128

Part- B Introduction

(H37Rv) (ATCC 27294) assay. The compound 1 was found to have potent inhibitory

activity (92%) against M. tuberculosis.

H g C ^

CH3

CH3

Structure of ilebethoxazole 1

The bis(benzoxazole) natural products are a structurally unique class of

Strptomyces secondary metabolites that have been recently been reported in literature''"^'.

In the course of a screening program for new biactive compounds, Taniguchi and co­

workers isolated benoxazole derivative 2 (UK-1) from the acetone extracts of

Streptomyces sp. Subsequently, Tsuji and co-workers isolated 3 from Streptomyces sp.

Both 2 and 3 were reported to possess growth inhibitory actrivity against the murune

cancer cell line P388, with IC50 values in the 0.3-1.6 range. Despite its cancer cell

cytotoxic properties, 2 does not inhibit the growth of Gram-positive or Gram-nigative

bacteria, yeast, or fungi at concentrations as high as 250 \xM, however, the semisynthetic

derivatives of 2 and dimethyl derivative have shown activity against Gram-positive and

Gram-negative bacteria. The compound 2 is also active against yeast and filamentous

fungi was reported by Devinder Kumar et al.'̂ ^

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Part- B Introduction

7.3 Synthetic Benzoxazole derivatives:

The benzoxazole skeleton is present in many natural products with biological

importance and its synthetic derivatives display diverse physical and biological

activities. The wide pharmacological potential of these bioactive molecules has attracted

many organic and medicinal chemists to develop efficient routes for their synthesis.

These synthesized compounds have been found to be associated with wide spectrum of

biological and pharmacological activities such as antibacterial, antifungal, anthelmintic,

analgesic, anti-inflammatory and antioxidant activities.

Excited state proton transfer plays an important role in a large variety of

photoinduced chemical and bilogical processess. The photoreaction in DNA may also

involve rate tautomers that may be difficult to detect by conventional methods due to the

fast time scale if the reactions and minimal heavy atom motion, as well as the

reversibility inherent to the proton-transfer reactions^ '̂̂ ''.

Recently efforts in detecting anion binding by "colorimetric anion sensors" which

alow the so-called "naked-eye" detection may provide important results. Jin Koo Lee

et al.,̂ ^ reported a new conjugted polymer-bases chemosensor for fluride anion

containing 2-(2'-hydroxy-phenyl)benoxazole unit in the main chain. 2-(2'-Hydroxy-

130

Part- B Introduction

phenyl)benoxazole has been widely studied from the view point of photophysics due to

its two emissions through the excited state intramolecular proton trasfer (ESIPT).̂ '̂̂ *̂

Recently, organic electroluminescence (EL) diode have been studied by many research

workers in order to realize various types of emission characteristics. The novel meterial,

biphenyl derivative with benzoxazole and alkoxy, was synthesized as an emittging layer

of OLED by Sung-Hee Son et al^'.

Won Sam Kim et al., in 2007 reported the electroluminescent properties of Zinc

(II)[2-(2-hydroxyphenyl)benzoxazole]^^, Zn(HPB)2 as a hole blocking layer in Organic

Light Emitting Diodes (OLEDs). The luminescence efficiencies and the turn-on voltage

are significantly affected by the presence of hole-blocking layer in Zn(HPB)2, 4.

Tania Costa, et al.^\ produced silica-gel compacts doped with 2,5-

Bis(benzoxazol-2'-yl)-4-methoxyphenol dye 5 using high pressure processing of powders

synthesized by sol-gel technique. The optical and mechanical properties of obtained

compact revealed that, they were transparent, dense and hard, allowing their use as

optical elements in different systems. Moreover, the dye entrapped in these compacts

still present its fluorescent properties in a similar way as the dye in ethanol.

131

Part- B Introduction

HO

OCH.

^

Yalcin et.al., compared the microbial activity of 5-methyl-2-[p-substituted

phenyljbenzoxazoles, 6 with 5-substituted-2-(p-substitutedphenyl)benzoxazole, 7

derivatives bearing nitro, chloro and amino groups which possess electronegative

properties on position^'*.

Hr,C >0-«̂

R=H, CI, NO2, NH2

6 7

Benzoxazoles have been extensively studied for new non-nucleside topoisomerase

I poisons^^ and HIV-1 reverse trascriptase inhibitors^^'^^.

In the last few years various 2-substituted benzoxazole derivatives were studied

extensively for their antitumor^^'^'*, antiviral'*^"^° and antimicrobial activities^' and as non-

nucleoside topoisomerase I posion HIV-1 reverse transcriptase and/or DNA gyrase

inhibitors'^^"^°. For example, the antibiotic Calcimycin that includes a 2-substituted

benoxazole ring in its molecular structure is very active against Bacillus cereus, Bacilus

megaterium and Micrococcus lutes^\ The benzoxazole derivative 3-(4,7-

dichlorobenzoxazol-2-ylmethylamino)-5-ethyl-6-methyI-pyridin-2-( 1 H)-one 8 was

132

Part- B Introduction

synthesised by Samia M. Rida et al., in 2005 and^^ found to be an effective non-

nucleoside selective HIV-1 reverse transcriptase inhibitor.

CI

>

Ozan Gulcan et al., have been reported the synthesis and pharmacological activity

of 2-oxo-3//-benzoxazoles. In the synthesized compounds (2-oxo-3//-benzoxazol-3-

yOpropanamides exhibited potent analgesic and anti-inflammatory activity ' . It was

also found that, the 6-acyl function attached to the benzene ring of 2-oxo-3//-

benzoxazole ring was favorable for analgesic activity in these derivatives. The (6-acyl-2-

oxo-3//-benzoxazol)alkanoic acids possessed potent analgesic and anti-inflammatory

activity with reduced gastric toxicity^'. In general, most of the research on this class of

compounds included substitutions on positions 3 and 6 of the 2-oxo-3//-benzoxazole

nucleus. As a result 2-oxo-3//-benzoxazoles bearing N-alkyl, N-acyl, N-diaminoalkyl

and 6-acyl substitutes were reported to have higher analgesic and anti-inflammatory

activity^^" '̂. From these observations, the amide derivatives of (5-chloro-2-oxo-3^-

benzoxazole-3-yl)butanoic acid, 9, was synthesized as potential analgesic and anti­

inflammatory compounds.

133

Part- B Introduction

An essential conmponent of the search for new leads in a drug designing program

is the synthesis of molecules, which are novel yet resemble known biologically active

molecules by virtue of the presence of some critical structural features. Certain small

heterocyclic molecules act as higly funtionalized scaffolds and are known

pharmacophores of a number of biologically active and medinicinally useful molecules.

Benoxazole nucleus is marked for its biological activity. 2-Substituted benzoxazoles were

shown to exhibit analgesic , fungicidal, insecticidal nematocidal , potent protease

. . . . . 64 • •

mhibitory activity.

Using a furanylthiazole acetic acid as a starting point, a novel series of

benzoxazol-5-yl-acetic acid derivatives^^ have been identified as heparanase inhibitors.

Heparanase, an endo-P-glucuronidase that cleaves heparan sulfate, is implicated in

several physiological and pathological processes^ '̂̂ .̂ Several compounds such as trans 2-

[4-[3-(3,4-dichlorophenylamino)-3-oxo-l-propenyl]-2-fluorophenyl]benzoxazole-5-yl-

acetic acid 10, which possess an IC50 of 200 nM against heparanase. CI

HOOC

0

CI

10

134

Part- B Introduction

A very interesting pliarmacological research article was reported in Acta

Biologica Hungarica, in 2006^*, the in vitro antioxidant properties of some new

benzoxazole derivatives were determined by their effects on the rat liver microsomal

NADPH-dependent lipid peroxidation (LP) level, the scavenging of superoxide anion and

the stable radical 2,2-diphenyl-l-picrylhydrazyl (DPPH). Compound 1,2 showed potent

scavenging effect on superoxide radical at 10'̂ M.

X = H 1,

Wang et al., reported femtosecond fluorescence upconversion studies of excited

state proton-transfer dynamics in 2-(2'-hydroxyphenyl)benzoxazole (HBO)^ ,̂ in liquid

solution and DNA. They have determined the typical time for the excited state

intramolecular proton-transfer reaction of the syn-enol tautomer in solution and in DNA

and also 'solvated enol' tautomer forms were determined in protic solvents, aprotic

solvents and DNA.

Chalcones are an interesting class of compounds containing an a,p-unsaturated

ketonic group. A few chalcones are known to occur in nature, for example Butelin

(2,4,3,4-tetrhydroxy chalcone) occurs in the flowers of Butea frondesa. Fedicin (2,5-

dihydroxy-3,5,6-trimethoxy chalcones) and pedicellin (2,3,4,5,6-pentamethoxy chalcone)

are the active constituents of the Himalayan drug Didymocarpus pediellata'^'^^.

Inspired by these observations several researchers prepared a number of

substituted chalcones to investigate their antibacterial activity. Some of the chloro

135

Part- B Introduction

substituted chalcones'^"'^ were shown to possess antibacterial activity equivalent to that

off powerful antibacterial, DADS (p-p'-Diamino Diphenyl Sulfone). A few bromo-

hydroxy substituted chalcones were found to be active against S. aureus at as a low

concentration. It was observed that the antibacterial activity of chalcone was due to its

unsaturation'^. Hydrogenation of the double bond destroyed the activity partially or

completely. This established that the a,p-unsaturated carbonyl group, is a pharmacopic

group.

Hydroxy and methoxy chalcones were studied for insecticidal properties against

fresh water fish. In case of hydroxy chalcones the symptoms of toxicity developed more

slowly but lasted longer. The methoxy chalcones were comparatively less toxic^'. The

reputed anthelmintic property of Kamala is attributed to its active constituent Rottlerin

12, which has the chalcone structure.

0=C-CH=CH—<^

H3C-C. OH i ^ o ^ ru

O The a,P-unsaturated carbonyl group (- CH = CH - C - ) which is responsible for

bacteriocidal activity of chalcones and also of great use in further chemical modifications

into various heterocyclic moieties such as pyrazole, isoxazole, thiazine, oxopyrimidine,

thiopyrimdine, aminopyrimidine, benzothiazipine, flavone and flavonol etc. Therefore

chalcones are considered as most potential synthons in the synthesis of various

136

Part- B Introduction

heterocyclic systems. 2-Hydroxy chalcones have been most widely investigated,

particularly because of their synthetic potential and biological activity. However, 2-

aminochalcones have not received considerable attention. Recently Donelly and Farell'^

reported the synthesis and some reactions of 2-aminochalcones. The fact that 2-

aminocholcones undergo intramolecular Michael addition to give l,2,3,4-tetrahydro-4-

quinolones Ujjina Matada Ravi et al., synthesized benzofuran analogues of 2-

aminochalcones and convert them in to benzofuro-[3,2-f/]pyridones''.

The wide spectrum of activities exhibited by various substituted chalcones and

their great synthetic potential has created enormous interest in the synthesis of various

heterocyclic analogues of chalcones for investigation of their pharmacological properties

and also for further chemical modification into biheterocyclic systems.

137

Part- B Introduction

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