Potential Antibacterial Agents : 4 - Thiazolidinone

Anjani N. Solankee and Riki P. Tailor

Department of Chemistry, B. K. M. Science College, Valsad - 396001

(Affilated to TheVeer Narmad South Gujarat University, Surat). India

E - mail: dranjani_solankee@yahoo.com

INTRODUCTION

Heterocyclic compounds represent one of the most active classes of compounds possessing a

wide spectrum of biological activities, including antibacterial, antifungal and other biological

activities1-6. Further, the treatment of infectious diseases still remains an important and

challenging problem because of a combination of factors including emerging infectious

diseases and the increasing number of multi-drug resistant microbial pathogens. The cases of

microbial resistance create a major distress to the scientific society and have become a hazard

for human life because microbial infections caused by multi-drug-resistant Grampositive

bacteria and microbes which are difficult to diagnose and treat7. Grampositive bacteria and

microbes are the major origin of morbidity and mortality especially in immunosuppressed

and hospital acquired patients8. So, to prevail over these problems, the development of new

antimicrobial agents with better efficiency is required. One of the best way to design new

antimicrobial agents is to generate hybrid molecules by combining two bioactive heterocyclic

moieties in a single molecular scaffold. Among various pharmacologically important

heterocyclic compounds, 4 - Thiazolidinone and its derivatives have been known to possess a

wide range of biological properties include good antimicrobial agents.

4 - Thiazolidinone is the first parent compound in which thiazole ring was recognized by

pattan et al 2004. 4 - Thiazolidinone is derivatives of thiazolidine, which belong to an

important group of heterocyclic compounds containing sulfur and nitrogen in a five member

1
ring. 4 - Thiazolidinone, with a carbonyl group at position 2 - [I], 4 - [II] and 5 -[III] have

been subject of extensive study in the recent past. Numerous reports have appeared in the

literature, which highlight their chemistry and use. 4 - Thiazolidinone, a saturated form of

thiazole with carbonyl group on fourth carbon, has been considered as a magic moiety

(wonder nucleus) [II].

O
NH NH NH
4 3 4 3 4 3

5 2 5 2 5 2
1 1 1
S O S O S

[I] [ II ] [ III ]

Substituents in the 2, 3 and 5-positions may be varied but the greatest difference in the

structure and properties is exerted by the group attached to the carbon atom in the 2-position

and nitrogen atom at the 3- position. The chemistry of 4 - Thiazolidinone was reviewed in

depth by Brown F. C9, Danila G10, Newkome G. R and Nayak A11. 4 - Thiazolidinones play a

vital role due to their wide range of biological activities and industrial importance. 4 -

Thiazolidinones are always being an attraction point for researchers because of its efficiency

towards various pharmacological usages. The introduction of antimicrobial agents into

general clinical use represents one of the landmark medical advances of modern medicine12.

Investigations of new antimicrobial substances are very useful because there are no medicinal

for which bacteria will not become resistant13. Sulfonamide drugs were the first antimicrobial

drugs, which lead to the antibiotic revolution in medicine14 but use of sulfonamides becomes

rarer because of resistant bacteria and side effects. Thiazoles being an integral part of many

potent biologically active molecules such as sulfathiazole (antimicrobial drug), ritonavir

2
(antiretroviral drug), abafungin (antifungal drug) and bleomycin (antineoplastic drugs) have

been explored previously. They have interesting activity profiles mainly cox-1 inhibitors,

inhibitors of bacterial enzyme, non nucleoside inhibitors of HIV Type 1 Reverse

Transcriptase (HIVRT) and antihistaminic agents15. Instead of these microbial agents, 4 -

Thiazolidinones also shows different types of biological activities such as anti-

inflammatory16, anti-HIV 17
, antihistaminic 18
, anti protozoan19, analgesic20 etc... . So the

derivatives of 4-thiazolidinone nucleus have occupied a unique place in the field of medicinal

chemistry.

PREPRATION OF 4 - THIAZOLIDINONE

Thiazolidinones, in the presence of various reagents, undergo different types of reactions to

yield other heterocyclic compounds such as thiazole, benzimidazole, thiopyranothiazolone,

benzodiazepine, triazoles, benzothiophenes, triazinones etc… . The most widely used

procedure for the preparation of 4 - thiazolidinones describes the formation of the 3, 4 - bond

via cyclisation of an appropriately substituted acyclic compound. Generally 4-

thiazolidinones prepared from either thiourea or mercaptoacetic acid derivatives.

Other different methods for the preparation of 4-thiazolidinones are as follows :

1. By the reaction of α - haloalkanoic acid with dithiocarbamates :

The dithiocarbamates, formed by the reaction of primary amines with carbon disulfide in the

presence of a base, react with α - haloalkanoic acid in presence of NaHCO3 to give 2 - thiono

- 4 - thiazolidinones 21, 22.

R-NH-CS-S-R1 + X-CH-COOH
-R1X
R2
O C N-R
R-NH-CS-S-CH-COOH
R2 C C S
R2 S

3
2. By the reaction of α - bromosuccinic acid with dithio carbaminates :

α - Bromosuccinic acid react with dithiocarbaminates yields 2 - thiono - 4 - oxo - 5 -

thiazolidine acetic acid 23.

O C NR
HOOC-CH2-CH-COOH + KS-CS-NHR HOOC-H2C C C S
S
Br

3. By the reaction between carbodiimides and α - mercapto propionic acid :

Monforte et al 24
have synthesized 4 - thiazolidinones by reacting carbodiimides with α -

mercaptopropionic acid.

SH-CH-COOH NR O C NR
+
C NR1 H C C NR1
CH3
S
CH3
R = R1 = Alkyl or Aryl.

4. Nucleophilic addition of ethyl bromoacetate to thiosemi carbazides :

Acylthiosemicarbazide obtained from the reaction of hydrazide and isothiocynates were

reacted with ethyl bromoacetate in absolute C2H5OH in the presence of sodium acetate to

furnish 2 - hydrazono - 4 - tiazolidinone derivatives.

5. Reaction of α-halogenated amide with NH4SCN :

Halogenated amide reacted with NH4SCN in C2H5OH in the presence of sodium acetate to

furnish 2 - imino - 4 - thiazolidinone via rearrangement reaction.

In recent years, several new methods for the preparation of thiazolidinone derivatives and

their reactions have been reported in the literature. Mane R. A25 and co-workers have

synthesised 4 - thiazolidinone bearing 2 - mercapto - 4 - methylimidazoles moiety.

4
Mogilaiah26 et al have synthesized 2 - aryl - 3 - (2 - trifluromethyl - 1, 8 - naphthyridine - 3 -

carbonylamino) - 4 - thiazolidinones.

ANTIBACTERIAL ACTIVITY

4 - Thiazolidinones with C - 2 and N - 3 substituted positions show various degrees of

inhibition against bacteria. In the past, the significantly growing prevalence of multi - drug

resistant microbial infections has become a serious health problem. Approximately all the

positions of 4-thiazolidinone have been explored to improve the antibacterial. The SAR

studies of thiazolidinone derivatives showed that they are more effective on gram - negative

bacteria as compared to gram - positive bacteria. The search for new antimicrobial agents will

subsequently remain as an important and challenging task for medicinal chemists. There are

several reports in the literature describing the 4 - Thiazolidinones derivatives for their

antibacterial activity and some of them are covered in this chapter.

Solankee A.27 Synthesised 2- (Aryl / Substitutedaryl / Heterocyclic) - 3 - ( 2', 3' - Dimethyl -

1'- Phenyl - 3'- Pyrazoline - 5' - one - 4' yl ) - 4 - Oxo - Thiazolidines and screened for their

antibacterial activity by disc plate method against S. Aureus, E. Coli, S. Paratyphi A., S.

Paratyphi B., P. Ulgarius , S. Mercoseens, P. Aerusenosa and E. Acerogens. She found that,

Compounds 2a, 2b, 2c, 2d, 2f, 2j, 2k and 2l showed good activity against S. Aureus, E. coli,

S. Paratyphi A.

H
R C N C C CH3

O C N CH3
N
O C C O
C
H2

5
Solankee A.28 Synthesised 2- ( Substitutedphenyl / Cinnnamyl) - 3 - ( 6' - methyl pyridine -

3'- carboxamido ) - 4 - Thiazolidinones and evaluated for their antibacterial test and they

found that, In case of Gram +Ve bacterial substitution of diethyl group at 4th position

increase antibacterial activity of compounds in both series. While in case of Gram -Ve

bacterial substitution of nitro group at 4th position increase antibacterial activity against E.

coli. (MTCC - 443).

O O
C N N C
H
N CH3
H2C CH R
C
H2

Solankee et al29 Synthesised 2- phenyl - 3 - Substituted phenyl 4 - Thiazolidinones and

screened for their antibacterial activity. They found that, Compound 5 has shown maximum

activity towards S. aureus, E. coli, S. typhi and E. aerusenes. Compound 8 shown good

activity against S. aureus and S. typhi. Similarly Compound 2, 3, 4, 5, 6, 7 and 9 shown good

activity against S. aureus . All the compounds were compared with ampicilin and penicillin G

as standard drugs.

O R
C N
MeO

MeO C C CH
H
S
MeO

Solankee et al30 Synthesised 2 - (3' - phenoxyphenyl) - 3 - Aryl - 5- methyl - 4 -

Thiazolidinones and evaluated for their antibacterial activity. They found that, Compounds

6
II b, II s and II v exhibited quite good activity aginast all microbes while compound II f

exhibited good activity against Bacillus sybtillis and serratia marcesscens.

O C N AR

H3C C CH
H
S
OC6 H5

Solankee et al31 Synthesised 2 - (Phenyl / Substitutedphenyl / 2'- thienyl ) - 3 - ( 4' -

TrifluorormethylPhenyl ) – 5[( 3', 4', 5' - Trimethoxy )Benzylidine ] - 4 -Thiazolidinones and

screened for their antibacterial test and reported that, compound 7d and 7h showed good

activity against S. Aureus , compound 7j showed good activity against S. Paratyphi A.

H3C N C O
OMe

R C C C OMe
H H
S
OMe

Paola Vicini et al32 synthesized 2 - Heteroarylimino - 5 - benzylidene - 4 - thiazolidinones

analogues of 2 – thiazolylimino -5 – benzylidene - 4 - thiazolidinones and evaluated their anti

- microbial activity.

H O
S N
N C
N S

7
Ranjana Sharma et al33 synthesized phthalimido [ 2 - aryl - 3 - (5'- (4''- pyridyl) -1', 3', 4' -

thiadiazol - 2' - yl ) - 4 - oxothiazolidin - 5 - yl] ethanoates and screened for their anti-

microbial activity using Escherichia coli, Proteus vulgaris, Klebsiella pneumoniae,

Pseudomonas auregenosa, Salmonella typhi and Bacillussubtilis bacterial strain by cup or

well method . In their studies they found that all synthsized compounds have shown very

little activity against B. subtilus, P. vulgaris and S. Typhi, moderate activity against E. coli

and very strong activity against K. pneumoniae and P. auregenosa as compared to standards

used i.e. Ciprofloxacin and Gentamicin. In their Comparative study of the substitution pattern

of the aryl group towards antibacterial activity they found that electron withdrawing group

causes more activity and donating group causes less activity.

O C C O
RA
N N S
N
S
N

Handan Altintas et al34 synthesized Various 5 - substituted 5 - (N, N - disubstituted

aminomethyl) - 2- [( 4 - carbethoxymethylthiazo l - 2 - yl) imino] - 4 - thiazolidinones and

screened for their in vitro antibacterial activity against Staphylococcus aureus ATCC 6538,

Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella

pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella

flexneri and Proteus mirabilis ATCC 14153 using disk diffusion.

8
 H O
N N
C2H5OOCH2C
N C
R
S S
C R'
H2

El - Gaby et al35 recently synthesized a series of 2- thioxo - 4 - thiazolidinones and 4, 4 -bis (

2 - thioxo - 4 - thiazolidinone - 3 - yl) diphenylsulfone derivatives. Most of the compounds

were found moderate in activity against tested strain of bacteria. Thiazolidinones with

sulfamoyl and thioxo moieties were found to possess highest antibacterial activity towards

Bacillus cereus whereas thiazolidinone derivative bearing pyrimidine nucleus,

sulfamoylphenyl and thioxo moieties revealed high activity against S. aureus.

S
O S
H2N S N
O
O

S
N O S
N S N
H
N O
O
B

Prasad D. et al36 synthesised 2 - arylthiazolidin - 4 - ones and the in vitro antibacterial

activities of compounds were carried out against a Gram - positive bacterial strain viz.

Staphylococcus aureus (Sa) and three Gram - negative bacteria viz. Escherichia coli (Ec),

Klebsiella pneumoniae (Kp) and Pseudomonas aeruginosa (Pa). They found out of Out of 18

newly synthesized compounds, only 7 compounds (8a-f and q) were found to be active

9
against the tested bacterial strains. 4 - Thiazolidinones (8a - f) bearing 4 - (1H -

imidazolylmethyl) phenyl - substituent at position 3 were found significantly active (

minimum inhibitory concentration - MIC 12. 5 - 50 μg / mL ) against Gram - negative strain

Kp. In addition, compounds (8a - c) have also shown moderate activity against Sa. In

contrast, thiazolidinone 8q with 3 - (4 - morpholinophenyl) - substituent exhibited activity (50

μg/mL) specifically against a Gram-negative bacterial strain Ec, which was found to be

comparable with the standard drug ampicillin. Surprisingly, 4 - thiazolidinone derivatives

containing 4 - (1,2,4 - triazolylmethyl)phenyl and 4 - (morpholinomethyl) phenyl

functionalities at position 3 were found inactive against all the tested bacterial strains.

R4 R5
S
R3 C O
N

R2 R1

Where R = O N

10
CONCLUSION

Over the last 150 years, bacterial infections were quite easily diagnosed and cured but the

need for new antibacterial drugs were low. The death ratio due to bacterial infections takes

second place in the world even though, at present many and various cures are used for the

infections more effective but safe preparations are still missing. The choice of antibacterial

preparations method is less and limited range of action proves the need of new effective

medicines for bacterial diseases. So, it is necessary to develop new and less toxic antibacterial

compounds. Now a day, there has been growing concern of rapidly increasing bacteria

resistance to the antibacterial preparations in the markets but the search for new antibacterial

drugs with high -effective is issue of the day because of the appearance of a large group of

antibiotic resistant strains.

The potency of 4-thiazolidinone nucleus as Antibacterial is mainly dependent on the nature

of the substituents at C - 2 and N - 3 position of 4 - thiazolidinone ring . The presences of

electron-withdrawing group on aromatic ring on C - 2 position of 4 - thiazolinone showing

various degrees of inhibition against Gram - positive and Gram - negative bacteria and work

good on bacterial strain as compare to the standard drugs. The activity of the compounds also

depends upon the nature and position of the substituents at the aryl moiety attached with

thiazolidinone ring. So further investigation in this direction may yield fruitful results and

quite rewarding. From these observations, the importance of the nucleus is highlighted but

there is much scope in this promising moiety as a number of different molecular targets is

available for 4 - thiazolidinone. The literature given away that 4 - thiazolidinone has diverse

biological potential and the easy synthetic routes for synthesis. So 4 - thiazolidinone draw

attention for the researchers to work on it in the future with increase antibacterial activity.

11
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