Chapter-1

INTRODUCTION

___________________________________________________

Overview

The title of the thesis suggests that the present work is concerned with the hydrazone

derivatives of isoindole-1,3-dione. Hence, the review of the derivatives of isoindole-

1,3-dione (phthalimide) and hydrazones is included in this chapter.

1.1 ISOINDOLE-1,3-DIONE (PHTHALIMIDE) DERIVATIVES

Phthalimides are a group of compounds that can be described as the imides of phthalic

acids. They are aromatic compounds which contain two carbonyl groups bound to a

primary amine and their IUPAC nomenclature system describes them as “isoindolin-

1,3-diones”.

N

O

O

CH3

N-Methyl phthalimide

Solid, Molecular weight = 161.16 g/mol, Melting point = 137C

The most important synthesis of phthalimides is the dehydrative condensation of

phthalic anhydride at high temperatures with primary amines, when the amine is

available. When the amine is not readily accessible, the direct N-alkylation of

phthalimides with alcohols under Mitsunobu conditions and of potassium phthalimide

with alkyl halides (Gabriel Synthesis) is popular alternative approaches to

phthalimide-protected amines.

Chapter-1

2

O

O

O

N

O

O

R

O

O

NH

NH+ H2N-R

H2NNH2

+ H2N-R

R= Alkyl

In peptide synthesis, the exhaustive substitution of primary amines is desirable to

block both hydrogens and avoid racemization of the substrates. Phthalimides are

suitable protective groups for this purpose, but beyond the most frequently used

methods of hydrazinolysis and basic hydrolysis, there are only a few deprotection

methods that are gentle and near-neutral, and this is a main drawback.

1.1.1 Protection of amino groups

An economical and practical method for the synthesis of a wide range of imide

derivatives has been developed by using inexpensive and readily available reagents

under mild conditions [1].

O

O

O

R N

O

O

RR+ H2N-R

1 eq. ZnBr2

1.5 eq. HMDS

Benzene

rt, 1-4 h

reflux, 0.5-6.0 h

R=Alkyl

A Lewis acid catalyzed and solvent free procedure for the preparation of imides from

the corresponding anhydrides uses TaCl5-silica gel as Lewis acid under microwave

irradiation [2].

Chapter-1

3

O

O

O

R N

O

O

RR+ H2N-R

0.1 eq. TaCl5 / SiO2

neat

MW(450w) 5-7min

R=Alkyl

1.1.2 Reactions of phthalimide–protected amino groups

A convenient, efficient, and selective N-Alkylation of N-acidic heterocyclic

compounds with alkyl halides is accomplished in ionic solutions in the presence of

potassium hydroxide as a base. In this manner, phthalimide, indole, benzimidazole,

and succinimide can be successfully alkylated [3].

NH

O

O

N

O

O

R+ X-R

2 eq.

2.0 eq. KOH

[bmim]BF4

40-80°C, 2-5 h

R = Alkyl

An efficient and simple method enables the N-alkylation of aromatic cyclic imides

using caesium carbonate as the base in anhydrous N,N-dimethylformamide (DMF) at

low temperatures (20-70C). The employment of microwave irradiation presents

noteworthy advantages over conventional heating. The method is compatible with

base labile functional groups [4].

Chapter-1

4

NH

O

O

y'

Y

N

O

O

R+ X-R

0.2 eq. NaI

X = Cl, Br

R = Alkyl

1.1 eq. Cs2CO3

DMF, MS 4 A

MW (100-200 W)

55-60°c, 10-60 min

Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride enable a

selective and practical deprotection sequence. Treatment of these intermediates with

propylene glycol enables the rapid release of amine hydrochloride salts in good yields

without epimerization of the amino center. The hydrochloride salts can be isolated or

carried forward for subsequent chemistry [5].

RNH

O

RNH

Cl

OHOH

R N phthalimide

1.2 eq. pyridine

1.1 eq. [COCl]2

THF, 0 °c, 15 min

2 eq.

0oC rt

< 1 h

2 eq. phthalic anhydride

eq. pyridine, toluene reflux 12 h

[Dean stark for removal of THF and Water]

R = Alkyl

The synthesis of isomerically pure allylic amines, including farnesyl amine, is

achieved in excellent yields using a modified Gabriel synthesis [6].

R'

R

R"

OH NH

O

O

N

O

OR'

R

R"

+

1.3 eq

1.3 eq DIAD

1.3 eq PPh3

THF, r.t., 4 h

R,R',R'' =Alkyl/Aryl

Chapter-1

5

1.1.3 Deprotection of phthalimide derivatives

Phthalimides are converted to primary amines in an efficient, two-stage, one-flask

operation using NaBH4/2-propanol, then acetic acid. Phthalimides of α-amino acids

are smoothly deprotected with no measurable loss of optical activity [7].

N

O

O

R

O

OH

NHR

R

5 eq. NaBH4

2-PrOH / H2O [6:1]

r.t, 24 h

18 eq.

CH3COOH80oc, 2h

H2NR=alkyl

The synthesis of isomerically pure allylic amines, including farnesyl amine, is

achieved in excellent yields using a modified Gabriel synthesis [8].

NPhth

NH2

3.0 eq. MeNH2 (40%) EtOH, 70oC, 4 h

Chapter-1

6

NPhth NH2

H2NNH2. H20

MeOH, rt, 0.5 h

HCl (5%), rt, 12 h

While 3,4,5,6-di-O-isopropylidene-N-phthaloyl-D-glucosamine propane-1,3-diyl

dithioacetal underwent fast β-elimination, the corresponding N-acetyl derivative was

easily deprotonated with butyl lithium to form the dilithiated intermediate.

Stoichiometry and temperature were crucial factors for selective C-C coupling with

various electrophiles [10].

N

O

O

S

S

O

O

O

O

N

O

O

S

S

O

O

O

O

NO

OO

O

S

S

O

O

BuLi

_

_

Chapter-1

7

1.2 HYDRAZONE DERIVATIVES

Hydrazones have been demonstrated to possess, among other, antimicrobial,

anticonvulsant, analgesic, antiinflammatory, antiplatelet, antitubercular and

antitumoral activities.

Isonicotinic acid hydrazide (isoniazid, INZ) has very high in vivo inhibitory activity

towards M.tuberculosis. Sah and co-workers synthesized INZ hydrazide-hydrazones

(1) by reacting INZ with various aldehydes and ketones. These compounds were

reported to have inhibitory activity in mice infected with various strains of M.

tuberculosis [11]. They also showed less toxicity in these mice than INZ [12,13]

Buu-Hoi et al. synthesized some hydrazide-hydrazones that were reported to have

lower toxicity than hydrazides because of the blockage of amine group. These

findings further support the growing importance of the synthesis of hydrazide-

hydrazones compounds [13].

N

N

O

H

NR

H

R=Alkyl/Aryl

(1)

Hydrazones containing an azometine proton -NHN=CH- are synthesized by heating

the appropriate substituted hydrazines/hydrazides with aldehydes and ketones in

solvents like ethanol, methanol, tetrahydrofuran, butanol, glacial acetic acid, ethanol-

glacial acetic acid. Another synthetic route for the synthesis of hydrazones is the

coupling of aryldiazonium salts with active hydrogen compounds. In addition,

4-acetylphenazone isonicotinoyl hydrazones was prepared by Amal and Ergenc [14]

by exposing an alcohol solution of 4-acetylphenazone and INZ to sunlight or by

mixing them with a mortar in the absence of the solvent.

Chapter-1

8

The biological results revealed that in general, the acetyl hydrazones (2) provided

good protection against convulsions while the oxamoyl hydrazones (3) were

significantly less active [15].

R2

R1

H3C-C-N-N=C

O H R3

R2

R1

H3C-C-C-N-N=C

OH R3

O

(2) (3)

Fifteen new hydrazones of (2-oxobenzoxazoline-3-yl) acetohydrazide (4) were

synthesized and their antiepileptic activity was tested in scPTZ test. The 4-fluoro

derivative was found to be more active than the others [16].

N

O

O

CH2-C-NH-N=CH

O

R

(4)

4-Aminobutanoic acid (GABA) is the principal inhibitory neurotransmitter in the

mammalian brain. GABA hydrazones (5) were designed and synthesized and

evaluated for their anticonvulsant properties in different animal models of epilepsy.

Some of the compounds were effective in these models [17].

H2N CH2CH2CH2 CONHNH2

(5)

Ten new arylidenehydrazides (6) which were synthesized by reacting 3-phenyl-5-

sulfonamidoindole-2-carboxylic acid hydrazide with various aldehydes, evaluated for

their antidepressant activity. 3-Phenyl -5- sulfonamideindole -2- carboxylic acid

Chapter-1

9

3,4-methylenedioxy / 4- methyl / 4-nitrobenzylidene-hydrazide showed antidepressant

activity at 100 mg/kg .

H2NO

2S

N

C6H

5

C-N-N=C

H

O H HR

(6)

The most important anti-inflammatory derivative 2-(2-formylfuryl) pyridyl hydrazone

(7) presented a 79 % inhibition of pleurisy at a dose of 80.1 μmol/kg. The authors also

described the results concerning the mechanism of the action of these series of

N-heterocyclic derivatives in platelet aggregation that suggests a calcium ion

scavenger mechanism. Compound (7) was able to complex Ca2+ in in vitro experiment

at 100 μM concentration, indicating that these series of compounds can act as Ca2+

scavenger depending on the nature of the aryl moiety present at the imine subunit

[18].

N N

H

NO

H

(7)

A new series of antinociceptive compounds that belong to the N-acylarylhydrazone

class were synthesized from natural safrole. [(4′-N,N-Dimethylaminobenzylidene-3-

(3′,4′-methylenedioxyphenyl) propionylhydrazine] (8) was more potent than dipyrone

and indomethacine, are used as standard anti-inflammatory/antinociceptive drugs

[19].

O

ON

O

N

H

H

N

CH3

CH3

(8)

Chapter-1

10

The antiplatelet activity of novel tricyclic acylhydrazone derivatives (9) was evaluated

by theirability to inhibit platelet aggregation of rabbit platelet-rich plasma induced by

platelet-activating factor (PAF) at 50 nM. Benzylidene- / 4′-bromobenzylidene 3-

hydroxy-8-methyl-6-phenylpyrazolo [3,4-b] thieno-[2,3-d] pyridine-2-carbohydrazide

were evaluated at 10 μM, presenting, respectively, 10.4 and 13.6% of inhibition of the

PAF-induced platelet aggregation [20].

N

Ar

HNH

NN

CH3

N

S OH

H

O

(9)

The evaluation of platelet antiaggregating profile let to identification of a new potent

prototype of antiplatelet derivative, that is benzylidene 10H-phenothiazine-1-

carbohydrazide (IC50=2.3 μM) (10), which acts in the arachidonic acid pathway

probably by inhibition of platelet COX-1 enzyme. Additionally, the change in para-

substituent group of acylhydrazone framework permitted to identify a hydrophilic

carboxylate derivative and a hydrophobic bromo derivative as two new analgesics that

are more potent than dipyrone, which is the standard, possessing selective peripheral

or central mechanism of action [21].

S

N

N

O

H

H

N

H

Ar

(10)

Chapter-1

11

Gokhan-Kelekci et al. synthesized hydrazones containing 5-methyl-2-benzoxazoline.

The analgesic effects of 2-[2-(5-methyl-2-benzoxazoline-3-yl) acetyl]-4-chloro-/

4-methyl benzylidene hydrazine (11a) and (11b) were found to be higher than those

of morphine and aspirin. In addition, 2-[2-(5-methyl-2-benzoxazoline-3-yl) acetyl]-4-

methoxybenzylidene hydrazine at 200 mg/kg dose possessed the most anti-

inflammatory activity [22].

N

O

O

CH2-C-NH-N=CH

O

Cl

(11a)

N

O

O

CH2-C-NH-N=CH

O

CH3

(11b)

Duarte et al. have described N′-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-6-nitro-1,3-

benzodioxole-5-carbohydrazine (12a) as a novel anti-inflammatory compound [23].

O

O

C-NH-NH=CH

NO2

O

OH

(12a)

The aroylhydrazone chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone

(13) showed greater antimalarial activity than desferrioxamine against chloroquine-

resistant and sensitive parasites [24].

Chapter-1

12

N

N

O

H

NOH

(13)

A series of N1-arylidene-N2-quinolyl- (14) and N2-acrydinylhydrazones- (15) were

synthesized and tested for their antimalarial properties. The new synthesized

compounds, including (14a-14d) and (15a-15c) showed an antiplasmodial activity

against the chloroquine-sensitive D10 strain in the same range of chloroquine (CQ).

Similarly, (14c) and (14d) displayed the same activity as CQ against

chloroquinesensitive 3D-7 strain, while compound 15b was 10 times more potent than

CQ. Two analogues (15b) and (15c) were more active against W2 CQ-resistant than

D10 CQ-sensitive strains [25].

N

CONH-N=CH-Ar

R

N

X

Cl

CONH-N=CH-Ar

H3CO

(14a-14d) (15a-15c)

1-Substituted phenyl-N′-[(substitutedphenyl) methylene]-1H-pyrazole-4-carbohydrazides

(16) were synthesized and their leishmanicidal and cytotoxic effects were compared

to the prototype drugs (ketoconazole, benznidazole, allopurinol and pentamidine) in

vitro. The 1H-pyrazole-4- carbohydrazide derivatives with X = Br, Y = NO2 and X =

NO2, Y = Cl demonstrated the highest activity and they were more effective on

promastigotes forms of L. amazonensis than on L. chagasi and L. braziliensis species

[26].

Chapter-1

13

NN

N

H

O

Y

NC

H

X

(16)

N1-(4-methoxybenzamido)benzoyl]-N

2-[(5-nitro-2-furyl)methylene] hydrazine (17)

inhibited the growth of several bacteria and fungi [27].

C-NH

OO

C-N-NH=CHO NO

2

H3CO

(17)

Nifuroxazide and six analogs (18) were synthesized by varying the substituent at the

p-position of the benzene ring and the heteroatom of the heterocyclic ring. These

compounds were evaluated for their antimicrobial activity against S. aureus and found

to be active at concentration 0.16-63.00 μg/mL [28].

RN

H

O

N

XHNO

2

(18)

N2-Substituted alkylidene/arylidene-6-phenylimidazo [2,1-b] thiazole-3-acetic acid

hydrazides 19 were synthesized and evaluated for their in vitro antimicrobial activity

[29].

Chapter-1

14

S

N

N

H5C

6

CH2-C-N-N=CH-CH=CH

O H

O NO2

(19)

Turan-Zitouni et al. found 5-bromoimidazo[1,2-a]pyridine-2-carboxylic acid benzyli-

denehydrazide (20) and 5-bromoimidazo[1,2-a]pyridine-2-carboxylic acid 4-methoxy

benzylidenehydrazide (21) to possess antimicrobial activity at 3.9 μg/mL against

E. fecalis and S. epidermis [30].

NBr

NC-NH-N=CH

H

O

NBr

NC-NH-N=CH

H

O

OMe

(20) (21)

A series of hydrazones derived from 1,2-benzisothiazole hydrazides (R1=H) (22-26)

as well as the parent cyclic (22 and 25) and acyclic (23, 24 and 26)

1,2-benzisothiazole hydrazides, were synthesized and evaluated as antibacterial and

antifungal agents. All of the 2-amino-1,2-benzisothiazole-3(2H)-one derivatives,

belonging to series (22) and (25) showed good antibacterial activity against Gram

positive bacteria. Most of them were also active against yeasts, too [31].

N

S

R1

O

R

N

S

CONHR1

N

S

R

CH2CONHR

1

(22) (R=H), 25 (R=CH3) (23) (24) (R=H), (26) (R=CH3)

Rollas et al. synthesized a series of hydrazide hydrazones (27) and 1,3,4-

oxadiazolines of 4-fluorobenzoic acid hydrazide as potential antimicrobial agents and

tested these compounds for their antibacterial and antifungal activities against

S. aureus, E. coli, P. aeruginosa and C. albicans.

Chapter-1

15

F

N N

O

H OHNO

2

(27)

Kucukguzel et al. synthesized diflunisal hydrazide-hydrazone derivatives. 2′,4′-

Difluoro-4- hydroxybiphenyl-3-carboxylic acid [(5-nitro-2-furyl)methylene] hydrazid

(28) has shown activity against S. epidermis and S. aureus at 18.75 μg/mL and 37.5

μg/mL, respectively [32].

OH

NNO

H

F F

ONO

2

H

(28)

4-Substituted benzoic acid [(5-nitro-thiophene-2-yl) methylene] hydrazides (29) were

synthesized as potential bacteriostatic activity and some of them indeed showed

bactericidal activity [33].

R2

R1

C

O

NHN

CH S NO2

(29)

Tuberculosis is a serious health problem that causes the death of some three million

people everyyear worldwide [34]. In addition to this, the increase in M. tuberculosis

strains resistant to front-line antimycobacterial drugs such as rifampin and INZ has

further complicated the problem, which clearly indicates the need for more effective

drugs for the efficient management of tuberculosis. Meyer and Mally prepared new

hydrazones by reacting isoniazid (INZ) with benzaldehyde, o-chlorobenzaldehyde and

Chapter-1

16

vanilin. Shchukina et al. prepared INZ hydrazide-hydrazones 1 by reacting INZ with

various aldehydes and ketones; the compounds were reported to have activity in mice

which had been infected with various strains of M. tuberculosis, and also indicated

lower toxicity than INZ.

The reaction of 1-methyl-1H-2-imidazo[4,5-b]pyridinecarboxylic acid hydrazide with

substituted aldehydes yielded the corresponding hydrazide-hydrazones. Compound

(30) exhibited antimycobacterial activity against M.tuberculosis isolated from patients

and resistant against INZ, ethambutol, rifampicine at 31.2 μg/mL [35].

N N

N

C-NH-N=CH

O

CH3

OH

OMe

(30)

Various 2,3,4-pentanetrione-3-[4-[[(5-nitro-2-furyl/pyridyl/substituted-phenyl)-methy

lene] hydrazino] carbonyl]phenyl]hydrazones (31) were synthesized for their anti-

myco-bacterial activity.

OO2N

NN

H

O

N

HO

NCH

3

CH3

O

(31)

Isonicotinoylhydrazones have been further reacted with pyridinecarboxaldehydes to

give the corresponding pyridylmethyleneamino derivatives (32). The new synthesized

hydrazones and their pyridylmethyleneamino derivatives were tested for their activity

against mycobacteria, Gram-positive and Gram-negative bacteria. The cytotoxicity

was also tested. Several compounds showed a good activity against M. tuberculosis

H37Rv and some isonicotinoylhydrazones showed a moderate activity against

clinically isolated M. tuberculosis (6.25-50 μg/mL) which was INZ resistant [36].

Chapter-1

17

O

R N

N

N

N

O

Py

H

(32)

The reaction of 2-acetylimidazo [4,5-b] pyridine with INZ yielded the corresponding

hydrazidehydrazones 33. This compound exhibited activity against M. tuberculosis

isolated from patients and resistant against INZ, ethambutol, rifampicine at 3.13

μg/mL [37].

N N

N CH3

N-NH-C N

OH

(33)

N2-Substitutedalkylidene/arylidene-6-phenylimidazo[2,1-b]thiazole-3-acetic acid

hydrazides (34) were synthesized and evaluated for in vitro antimycobacterial

activity.

N S

NH

5C

6

CH2-C-N-N=CH

O H

ONO

2

(34)

[5-(Pyridine-2-yl)-1,3,4-thiadiazole-2-yl-thio] acetic acid arylidene-hydrazide deriva-

tives (35) were synthesized and tested for their in vitro antimycobacterial activity

[38].

S

NN

N

S N

O

H

N

R

(35)

Chapter-1

18

N-Alkylidene/arylidene-5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazides

(36) were synthesized and evaluated for in vitro antimycobacterial activity. The

compounds exhibited different degrees of inhibition (3-61%) against M. tuberculosis

at 6.25 μg/mL [39].

CH2-C-NH-N=CH-R

C2H

5O

O

NN

N S

(36)

A series of 4-quinolylhydrazones (37) were synthesized and tested against

M. tuberculosis. Preparation of the title compounds was achieved by reaction of

4-quinolylhydrazine and aryl- or heteroarylcarboxaldehydes. Most of the derivates

had antitubercular properties; two compounds were identified with the highest activity

and they were tested also against M. avium [40].

N

N-N=CH-Ar

R

R

H

(37)

Benzoic acid [(5-nitro-thiophene-2-yl) methylene] hydrazide series (38) were

synthesized and tested against M. tuberculosis. Rando and co-workwers have applied

Topliss methodolgy to a set of nitrogen analogues. 4-Methoxybenzoic acid [(5-

nitrothiophene-2-yl) methylene] hydrazide (38a) was demonstrated as being the most

active, with a MIC value of 2.0 μg/mL [41].

MeO

N

O

H

N

S NO2

38a

Chapter-1

19

Novel coupling products (39) were synthesized and evaluated for their

antimycobacterial activity against M. tuberculosis and M. avium Compound (39b)

was found to be the most potent derivatives of these series with the MIC value of 6.25

μg/mL against M. tuberculosis [42].

ON2O

NN

H

O

N

HO

NCH

3

O

(39b)

[5-(Pyridine-2-yl)-1,3,4-thidiazole-2-yl]acetic acid (3,4-diaryl-3H-thiazole-2-ylidene)

hydrazide derivatives (40) were synthesized and tested for their in vitro

antimycobacterial activity towards three strains [43].

NS

N N

S

S

N

CH3

NN

O

H

(40)

N'-{1-[2-hydroxy-3-(piperazine-1-yl-ethyl) phenyl] ethylidene}isonicotinohydrazide

(41) was found to be the most active compound with the MIC of 0.56 μM, and it was

more potent than INZ (MIC of 2.04 μM). After 10 days of treatment, same compound

decreased the bacterial load in murine lung tissue as compared to controls, which was

equipotent to INZ [44].

C=N-NH-C

OH

CH2-R

CH3 O

N

(41)

Chapter-1

20

As a part of an ongoing search for the new isoniazid-related isonicotinoylhydrazones

(ISNEs), 2'- monosubstituted isonicotinohydrazides and cyanoboranes (42-47) were

studied and evaluated in vitro advanced antimycobacterial screening. Some of tested

compounds displayed excellent (MICs ranging from 0.025 to 0.2 μg/mL) to moderate

(6.25 to 12.5 μg/mL) MICs against ethambutol and rifampin resistant strains [45].

NN

R

R1

N

O

H

(42-47)

Novel fluoroquinolones (48) containing a hydrazone structure were synthesized and

evaluated in vivo against M. tuberculosis in Swiss albino mice by Shindikar et al.

Results of the study indicate the potent antitubercular activity of the test compouds

[46].

N

C

O

NHN N

NCH

3

CH3

F

F

NH2

N

O

C

O

OH

CH3

(48)

N′- Arylidene -N-[ 2-oxo-2-(4-aryl-piperazin-1-yl ) ethyl ] hydrazide derivatives (49)

containing INZ hydrazide-hydrazones were synthesized and evaluated

antimycobacterial activity against M. tuberculosis and M. tuberculosis clinical isolates

[47].

Chapter-1

21

N

N

O

NN

R

C

C

H

N

O

(49)

Sriram et al. synthesized a new series of antimycobacterial agents (50) containing

INZ hydrazidehydrazones [48].

F NH-C-NH

S

C

N-NH-C

O

NCH

3

(50)

In 2006 Nayyar et al. found that the most active compounds of type (51),

N-(2-fluorophenyl)-N′-quinoline-2-yl-methylenehydrazine,N-(2-adamantan-1-yl)-N′-

quinoline-4-yl-methylene)-N′-4-fluorophenyl)hydrazine and N-(2-cyclohexyl)-N′-

quinoline-4-yl-methylene)-(2-fluorophenyl)hydrazine exhibited 99% inhibition at the

lowest tested concentration of 3.125 μg/mL against drug-sensitive M.tuberculosis

strain [49].

NN

NH

RN

NNH

R

NH

R

N

N

(51)

Chapter-1

22

Various diclofenac acid hydrazones (52) were synthesized and evaluated for their

antimycobacterial activities against M. tuberculosis in vitro and in vivo. Preliminary

results indicated that most of the compounds demonstrated better in vitro

antimycobacterial activity at concentrations ranging from 0.0383 to 7.53 μM [50].

NH

NH-N=C

R1

RCl

Cl

C

O

(52)

Hydrazide-hydrazones (53), based on series of 4-substituted benzoic acid were

synthesized and screened for antituberculosis activity.

F C-NH-N=CH

O

SNO

2

(53)

Sixteen new hydrazones (54) containing a pyrrole ring were synthesized as potential

tuberculostatics and nine showed 92-100% inhibition of M. tuberculosis at 6.25

μg/mL. Two leads exhibited low minimum inhibitory concentrations (MIC) and

excellent selectivity indices [51].

NN

O

H

NR

R'

N

CH3

HOOC

C6H

4Cl

NH

O N=C

R

R'

n

(54)

Following compounds (55) are also found as most bioactive agents:

Chapter-1

23

N

NN

S

N

H3COCHN

S

NH

C=O

NO2

CH2 C

O

NH-N=CH

(55)

N

NN

S

N

H5C

6OCHN

S

NH

C=O

NO2

CH2 C

O

NH-N=CH

(56)

A series of hydrazones (57) were synthesized from INZ, pyrazineamide, p-amino

salicylic acid, ethambutol and ciprofloxacin. 2-Hydroxy-4-{[(isonicotinoylhydrazono)

methyl] amino} benzoic acid (57a) showed the highest inhibition (96%) of M.

tuberculosis [52].

N

C

O NH

NCH

NH OH

COOH

(57a)

A variety of antitumoral drugs are currently in clinical use. The search for antitumoral

drugs led to the discovery of several hydrazones having antitumoral activity. Some of

diphenolic hydrazones showed maximum uterotrophic inhibition of 70%, whereas

Chapter-1

24

compound (58) exhibited cytotoxicity in therange of 50-70% against MCF-7 and ZR-

75-1 human malignant breast cell lines [53].

N

OH

N

H NO2

NO2

(58)

N′- (1-{1- [4- nitrophenyl -3 – phenyl -1H - pyrazole -4- yl} methylene) -2-

chlorobenzohydrazide (59) was found to be the most active, with full panel median

growth inhibition, total growth concentration and median lethal concentration mean

graph mid-point of 3.79, 12.5 and 51.5 μM, respectively [54].

NO2

N

H Cl

O

N

NN

(59)

Some novel 2,6-dimethyl-N′-substituted-phenylmethyleneimidazo[2,1-b][1,3,4]thia

diazole-5- carbohydrazides (60) were synthesized and showed the most favourable

cytotoxicity [55].

S

N

CH3

N

NCH

3

NH

O

N

OH

(60)

Chapter-1

25

3-[[(6-Chloro-3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl] hydrazono]-5-fluo

ro-1H-2- indolinone (61) showed the most favourable cytotoxicity against the renal

cancer cell [56].

N

NCl

O

S-CH2-C-N-N

O HN

F

O

H

(61)

Some recently synthesized compounds were found to possess antiproliferative

properties. The most active compound of the series was the 3- and 5-methy-

lthiophene-2-carboxaldehyde α-(N)-heterocyclichydrazones derivatives (62), which

exhibited tumor growth inhibition activity against all cell [57].

N

N

N

H

C

H

S

CH3 N

N

N

H

C

H

S

CH3

(62)

5-Chloro-3-methyl (phenyl) indole-2-carboxylic acid (benzylidene) hydrazide (63),

(64a-64b) were found to arrest T47D cells in G2/M phase of the cell cycle and to

induce apoptosis as measured by the flow cytometry analysis [58].

N

CH3

Cl

N

H

O

NNO

2

(63)

Chapter-1

26

N

C6H

5

CH3

N

H

O

NCH

3

(64a)

N

C6H

5

Cl

N

H

O

N

NO2

(64b)

The critical reviews have been published recently, and giving an outlook on the latest

research developments on antimycobacterial substances [59-61].

1.3 RESEARCH GAPS ABOUT THE HETEROCYCLIZATION OF

3-(ISOINDOL- 1,3-DIONE METHYL)-6-HYDROXY BENZOIC ACID

HYDRAZIDE(IHBH)

As per the review about the derivatization of isoindol-1,3-dione (phthalimide) and

hydrazone derivatives. It is a hydrazide of IHBH and it is one of the most intensively

investigated classes of aromatic compound. Hydrazone derivatives find now a variety

of application ranging from bacterostatics, antibiotics CNS regulants of high selling

diuretics. All these facts were driving force to develop novel IHBH derivatives with

wide structural variation. Thus hydrazone derivatives plays important role in

medicinal chemistry.

As a part of interest in heterocycles that have been explored for developing

pharmaceutically important molecules, 2-azetidinones [62-65], 4-thiazolidinones,

fused thiazolidinones, 2-pyrrole and 2-pyrolidinones [66-69] have played an

important role in medicinal chemistry. Moreover they have been studied extensively

Chapter-1

27

because of their ready accessibility, diverse chemical reactivity and broad spectrum of

biological activity. The area in which the heterocyclization of IHBH into above

mention heterocycles has not been reported so far. Hence, it was thought to undertake

such study.

1.4 OBJECTIVES

In view of above literature review, the prime objective of the present research work is

heterocyclization of the compounds based on 3-(isoindol-1,3-dione methyl)-6-

hydroxy benzoic acid hydrazide (IHBH) into heterocycles like azetidinones,

thiazolidinones, fused thiazolidinones, pyrrole and pyrrolidinones derivatives.

1.5 THE PRESENT WORK

With this aim, the research work was carried out and distributed into following

chapters of the present thesis.

Chapter-2 of the thesis comprises two sections. Section-A includes the details about

techniques used to characterize the compounds. While, Section-B deals with the

synthesis and characterization of arylidine derivatives of 3-(isoindol-1,3-dione

methyl)-6-hydroxy benzoic acid hydrazide (IHBH).

4-Thiazolidinone and fused thiazolidinone derivatives were derived from IHBH. Their

literature survey, synthesis and characterization are furnished in Chapter-3.

2-Azetidinone derivatives were derived from IHBH. Their review, synthesis and

characterization are included in Chapter-4.

Various 2-pyrrole and 2-pyrrolidinone derivatives were prepared by condensation of

IHBH with maleic anhydride and succinic anhydride respectively. Their review,

synthetic details and characterization are presented in Chapter-5.

Chapter-1

28

The antimicrobial activity studies of all the compounds mentioned in chapters 3 to 5

are furnished in Chapter-6.

The schematic route of the work is shown in Scheme 1.1.

N

O Cl

Ar

S

N

O

Ar

N

O

Ar

COOH

N

O

Ar

COOH

OH

OH

OMe OH

OMe

Cl

N

O

O

OH

OH

CONHNH2

N

O

OOH

CONHNH2

N

O

OOH

CONHN

N

O

OOH

CONH

N

O

OOH

CONH

N

O

OOH

CONH

N

O

OOH

CONH

N

O

OOH

CONH

N

N

S

N

Ar

O2N OH

Br

(1)

(i) ArCHO

(II) EtOH / Conc. H2SO4

(3a-h)

(7a-h)

2-Azetidinones

(4a-h)

pyrazolo[3,4-d]Thiazole

(8a-h)

(9a-h)

2-pyrroles

2-pyrrolidinones

Ar = , , ,

Where,

, ,

+

CH Ar

(6a-h)

4-Thiazolidinones

,

condensation

(2a-h)

Scheme 1.1

Chapter-1

29

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