Microwave Mediated Synthesis and Antifungal Activity of Some 5-Benzylidene-2, 4-thiazolidinediones

 

M. Srinivas1, K. Satyanarayana1*, S. Kiran Kumar2, N. Sravan Kumar2, V. Ajay2 and N. Kishore2

1Department of Medicinal Chemistry, Mother Teresa College of Pharmacy, Ghatkesar, R.R.Dist., A.P, India.

2Department of Medicinal Chemistry, Nagarjuna University, Guntur, A.P, India.

*Corresponding Author E-mail: rajshaz@gmail.com; srinu_629@yahoo.co.in

 

ABSTRACT:

A series of 5-benzylidene-2,4-thiazolidinedione derivatives were synthesized by employing microwave irradiation. The synthesis involves microwave irradiation of an aromatic aldehyde with 2,4-thiazolidinedione in sodium acetate/acetic acid in ethanol. The reaction was completed in 15-30 min with 68-82% yields and was environmentally friendly with easy workup. The synthesized compounds were evaluated for antifungal activity.

 

 

 


INTRODUCTION:

Search for new antifungal compounds is one of the most challenging tasks of current medicinal chemistry. As a matter of concern in the treatment of fungal infections is the limited number of efficacious antifungal drugs. Many of the currently available drugs are toxic, produce recurrence because they are fungistatic and not fungicides or lead to the development of resistance due in part to the prolonged periods of administration of the available antifungal drugs. Therefore, there is a clear need for the discovery of new structures with antifungal properties, which could lead to the development of new drugs for the management of fungal infections.

 

Thiazolidinedione derivatives have been proven to be attractive compounds because of their outstanding biological activities including antibacterial1-2, antifungal3, anticonvulsant4-5 and anticancer activities6.

 

In view of the above observations, the synthesis of these compounds are of considerable interest. In the present paper, we wish to report a simple, one step microwave mediated synthesis of some 5-benzylidene-2,4-thiazolidinediones and their antifungal activity.

 

RESULTS AND DISCUSSION:

In the 5-position of 2,4-thiazolidinedione, the methylene group is active. Conventional approaches for the synthesis of these compounds often involves long reaction times harsh reaction conditions, unsatisfactory yields and environmentally unfavorable solvents7. Therefore, 5- benzylidene -2,4-thiazolidinediones were rapidly synthesized by the condensation according to Knoevenagel, of commercially available 2,4-thiazolidinedione with various aromatic aldehydes in the presence of sodium acetate in acetic acid and ethanol as solvent. The reaction mixture was subjected to microwave irradiation (MWI). The results as summarized in Table-1 clearly reveal the scope and generality of the reaction with respect to various substituted aromatic aldehydes and that reasonable yields (68-82%) of the products were achieved after 15-30 min of microwave irradiation (Scheme-1).

 

Antifungal activity:

All the synthesized compounds were screened for invitro antifungal activity against Candida albicans, Saccharomyces cerevisiae and Aspergillus fumigatus and Aspergillus niger. The minimal inhibitory concentration (MIC) was measured using the two-fold serial dilution method using ketoconazole as a reference drug. The MIC of these compounds is listed in table 2. The tested compounds showed antifungal activity with a range of MICs between 32 and 250 mg/mL (Table-2). The results showed that the synthesized compounds possessed moderate antifungal activity.

 

Experimental:

Melting points were determined in open capillaries and are uncorrected. IR spectra (KBr) were recorded on a Perkin-Elmer 1800 (FTIR) spectrometer.

 


Table-1

Compound

R1

R2

R3

Mol.Form

Mol.Wt

1a

H

H

H

C10H7NO2S

205

1b

F

H

H

C10H6 FNO2S

223

1c

CH3

H

H

C11H9NO2S

219

1d

OCH3

H

H

C11H9NO3S

235

1e

CF3

H

H

C11H6F3NO3S

273

1f

H

F

H

C10H6FNO2S

223

1g

H

CH3

H

C11H9NO2S

219

1h

H

OCH3

H

C11H9NO3S

235

1i

H

CF3

H

C11H6F3NO3S

273

1j

H

H

CH3

C11H9NO2S

219

1k

H

Cl

CH3

C11H8ClNO2S

253

All compounds gave correct elemental data

 

Table-2

Compound

C albicansMIC

S cerevisiae MIC

A niger MIC

A fumigates MIC

1a

>250

>250

>250

>250

1b

62.5

62.5

125

125

1c

>250

>250

>250

>250

1d

125

125

125

125

1e

32

32

62.5

62.5

1f

>250

>250

>250

>250

1g

>250

>250

>250

>250

1h

62.5

62.5

62.5

62.5

1i

>250

>250

>250

>250

1j

>250

>250

>250

>250

1k

>250

>250

>250

>250

Ketoconazole

0.5

0.5

0.125

0.125

 

1H NMR spectra (DMSO-d6) were taken on a Bruker spectrometer (300 MHz) using TMS as internal standard and chemical shift are expressed in d ppm. The purity of the compounds determined by using Schimadzu RP HPLC system.

 

General procedure for preparation of compound 1a:

A mixture of 2,4-thiazolidinone 1 (1.17 g, 0.01mol), benzaldehyde (0.012mol), Sodium acetate (1.5 g), glacial acetic acid (1ml) were mixed in ethanol (50ml) and irradiated in monomode microwave system for 15 to 30 minutes by monitoring TLC using Ethylacetate: Hexane with different ratios as mobile phase. After completion of reaction the reaction mixture was poured into ice water and acidified with acetic acid to give compound 1a as solid which were recrystallized from methanol.

 

A similar method was adopted for the synthesis of compounds 1b-1k.

 

Spectral data of the compounds:

1a: m.p. 232-235C, Yield 70%. IR: 1655 (C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.65 (s, 1H, =CH), 7.30-7.45 (m, 5H), 12.6 (NH).

1b: m.p. 169-172, Yield 68%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.78 (s, 1H, =CH), 7.35-7.50 (m, 4H), 12.6 (NH).

1c: m.p. 176-179, Yield 78%. IR: 1650(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.72 (s, 1H, =CH), 7.27-7.44 (m, 4H), 12.6 (NH), 2.35 (s, 3H, CH3).

1d: m.p. 188-191, Yield 68%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.78 (s, 1H, =CH), 7.35-7.50 (m, 4H), 3.83 (s, 3H, OCH3), 12.64 (NH).

1e: m.p. 181-183, Yield 77%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.96 (s, 1H, =CH), 7.74-7.91 (m, 4H), 12.36 (NH).

1f: m.p. 210-212, Yield 79%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.50 (s, 1H, =CH), 7.39-7.68 (dd, 4H), 12.63 (NH).

1g: m.p. 176-179, Yield 78%. IR: 1650(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.72 (s, 1H, =CH), 7.27-7.44 (m, 4H), 12.6 (NH), 2.35 (s, 3H, CH3).

1h: m.p. 216-218, Yield 80%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.75 (s, 1H, =CH), 7.43-7.61 (m, 4H), 3.83 (s, 3H, OCH3), 12.63 (NH).

1i: m.p. 206-208, Yield 82%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.86 (s, 1H, =CH), 7.70-7.88 (m, 4H), 12.68 (NH).

1j: m.p. 165-167, Yield 77%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.30-7.45 (m, 5H), 2.30 (s, 3H, CH3), 12.6 (NH).

1k: m.p. 204-206, Yield 79%. IR: 1655(C=O); 3350 (NH). 1H NMR (DMSO-d6): 7.40-7.55 (dd, 4H), 2.35 (s, 3H, CH3), 12.6 (NH).

 

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Received on 09.02.2010 Modified on 23.02.2010

Accepted on 19.03.2010 RJPT All right reserved

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 619-621