1. INTRODUCTION:

Microwave Induced Organic Reaction Enhancement (MORE) Chemistry¹ is gaining importance as a simple, non-conventional technique for organic synthesis. Important features of MORE technique are requirement of simple, inexpensive instrument, rapid synthesis of organic compounds, easy access to very high temperatures in sealed containers, good control over the energy input in a reaction and eco-friendly technology. It can be termed as “e-chemistry” because it is easy, effective, economic and eco-friendly.²

MORE chemistry is just more than a decade concept used by many biochemists and chemists for hydrolytic reaction and organic synthesis. It is gaining popularity as a non-classical approach due to its utility in highly accelerated synthesis of divergent types of organic molecules. Traditionally, commercial microwave ovens are used as a convenient source of energy in chemical laboratories for efficient heating of water, for moisture analysis and wet ashing procedures of biological and geological materials. Their computerized versions are commercially available for acid digestion of ores and minerals in explosion proof vessels and for rapid determination of thermodynamic functions of chemical reactions. Application of microwave technology to catalytic hydrogenations of alkenes, hydro cracking of bitumen obtained from tar/sand, degradation of polychlorinated hydrocarbons, waste material management, polymer and ceramic technology are well known. Short ‘response time’ and highly accelerated reaction rate are the main advantages of MORE chemistry.³

MORE chemistry offers a simple, non-conventional technique for the synthesis of a large variety of compounds having medicinal, pharmaceutical and commercial importance. Highly accelerated rate of reaction is the main advantage, which enables the chemists to carry out the synthesis in much lesser time with reasonably good yields. For eg: esterification of benzoic acid with methanol proceeds one hundred times faster in microwave oven in sealed vessel than the conventional method. It provides a rapid and relatively inexpensive access to very high temperatures and pressure in sealed containers like Teflon bomb. Recent simplifications of this technique have increased safety profile and practical utility of microwave ovens for their use in the organic laboratories without any modification. Furthermore, there is no need for sealed vessels, reflux condensers, stirrers water separators etc. The currently available classical methods require much more elaborate apparatus, longer heating times, large volumes of organic solvents and it allow virtually no control over energy inputs.^4,5

The solvents used for organic synthesis conventionally, are of major concern as environment pollutants, many among which are proved carcinogenic, mutagenic and allergens. An eco-friendly method of organic synthesis is an important, distinct and salient feature of MORE chemistry. It does not require use of solvent (dry media synthesis) or requires very little solvent as energy transfer medium. Thus it offers a clean eco-friendly method.⁶

Heterocyclic synthesis has emerged as powerful technique for generating new molecules useful for drug discovery⁷. Heterocyclic compounds provide scaffolds on which pharmacophores can arrange to yield potent and selective drugs⁸.

The presence of thiazolidinone moiety in the structure of several naturally occurring molecules with important antibiotic, immunosuppressive and antitumor activities has been known for several year^9-12. Small ring heterocycles containing nitrogen and sulfur have been under investigation for a long time because of their important medicinal properties. Among the wide range of heterocycles explored to develop pharmaceutically important molecules, thiazoles have played an important role in medicinal chemistry. A survey of literature has shown that compounds having thiazolidinone nucleus possess a broad range of biological activities such as antibacterial¹³, antifungal¹⁴, antihyperglycemic¹⁵, anti-inflammatory¹⁶, antitubercular¹⁷, antioxidant¹⁸, antitumor¹⁹, anti-HIV²⁰, anesthetic²¹, anti-viral²², anticonvulsant²³, diuretics²⁴, nematicidal²⁵, and antihistaminic activity²⁶. Recently reported some of work on the synthesis, transformations and wide rang biological properties of various 4-thiazolidinones molecules^27-33.

In the view of the facts mentioned above, we have resynthesized some earlier reported thiazolidinone derivatives,³⁴ 4A-G, by microwave irradiation. These derivatives were characterized by spectral data and these compounds were tested for their antimicrobial activity.

2. MATERIALS AND METHODS:

2.1. Experimental section

Reactions and purity of compounds were monitored by TLC (silica gel G60) using Chloroform: Methanol (9:1) solvent system and the spots were identified by iodine vapor chamber. Melting points were determined in open capillary using paraffin bath and are uncorrected. The IR spectra of the compounds were recorded on NICOLET380 FT-IR spectrophotometer using KBr pellets. ¹H NMR spectra were recorded in DMSO on a 300 MHz Shimadzu FT-NMR (δ in ppm) relative to TMS as internal standard. The mass spectra were recorded on Triple Quadruple LC-MS with ESI source. Mfg. SCIEX at 70eV.

2.2. Preparation of p-acetamido acetophenone (1), 2-Amino-4-(4'-acetanilido)-thiazole (2) and 2-[(Substituted-benzylidene)amino]-4-(4'-acetanilido)-thiazole (3 A-G)

The compounds p-acetamido acetophenone (1), 2-Amino-4-(4'-acetanilido)-thiazole (2) and 2-[(Substituted-benzylidene)amino]-4-(4'-acetanilido)-thiazole (3 A-G) were prepared according to method used by Sharma et al³².

2.3. Preparation of N-{4-[2-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)-1,3-thiazol-yl] phenyl} acetamide (4A-G)

An equimolar amounts of Schiff’s base (0.01 mole) and thioglycolic acid (0.01 mole) and catalytic amount of anhydrous zinc chloride in to a 100 ml round bottom flask containing 10 ml of DMF were taken. The reaction mixture was subjected for microwave irradiation until completion of the reaction at 160 watts. Then the reaction mixture was poured into crushed ice. The solid obtained was filtered, washed with ethanol, dried and recrystallized from suitable solvents. The Schematic representation has been given in Scheme 1. The physical data and spectral data of the synthesized compound were given in Table 1 and Table 2, respectively.

a- Acetic anhydride, b- Thiourea, Iodine, c- Aromatic aldehyde, Glacial acetic acid, d- Thioglycolic acid, N,N-Dimethyl formamide, Zinc chloride, MW.

Scheme 1: Synthesis of thiazolidinone derivatives

Table 1. Physical data of synthesized compound: 4(A-G)

Code	Chemical name	Mol. formula	Mol. weight	Reaction time (min)	Recry. Solvent	M.P. ^oC	% Yield
Code	Chemical name	Mol. formula	Mol. weight	Reaction time (min)	Recry. Solvent	M.P. ^oC	Conv.*	MW
4A	N-(4-{2-[2-(4-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₀H₁₇N₃O₃S₂	411.49	4	Chloroform	240	42	63
4B	N-(4-{2-[2-(4-chlorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₀H₁₆ClN₃O₂S₂	429.94	3	Chloroform	230	68	76
4C	N-(4-{2-[2-(4-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₀H₁₆N₄O₄S₂	440.49	4	Ethanol	237	44	62
4D	N-(4-{2-[2-(3,4,6-trimethoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₃H₂₃N₃O₅S₂	485.57	4	Methanol	310	46	70
4E	N-(4-{2-[2-(4-hydroxy-3-methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₁H₁₉N₃O₄S₂	441.52	5	Methanol	235	51	73
4F	N-(4-{2-[2-(3-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₀H₁₆N₄O₄S₂	440.49	3	Chloroform	210	67	77
4G	N-(4-{2-[2-(4-hydroxy-3-ethoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C₂₂H₂₁N₃O₄S₂	455.54	3	Chloroform	307	53	69

Conven. = conventional, MW = microwave, * = as per reference no. 34

2.4. Antimicrobial activity

2.4.1. In vitro antibacterial activity

The antibacterial activity of the synthesized compounds was determined against Gram-positive bacteria (Klebsiella Pnemonia and Staphylococcus aureus) and Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli) in DMF by disc diffusion method using nutrient agar as media.³⁵ The sterile media (Nutrient Agar Media, 15 ml) in each petri plates was uniformly smeared with cultures of Gram-positive and Gram-negative bacteria. Sterile discs of 6 mm diameter were placed in the petri plates, to which 100 µl solution of synthesized compounds in DMF at different concentrations such as 100, 50, 25 and 12.5 µg/ml (10, 5, 2.5, 1.25 µg/disc) was added. The treatment also included 100 µl of DMF as negative control and ciprofloxacin as positive control³⁶ for comparison. The plates were incubated at 37 ± 2 ^oC for 24-48 h and the zone of inhibition was determined.

2.4.2. In vitro antifungal activity

All the synthesized compounds were screened for their antifungal activity against Aspergillus flavus and Candida albicans in DMF by the disc diffusion method.³⁷ The sterile media (Potato Dextrose Agar Media, 15 ml) in each petri plates was uniformly smeared with cultures of fungi. Sterile discs of 6 mm diameter were placed in the petri plates, to which 100 µl solution of synthesized compounds in DMF at different concentrations such as 100, 50 and 25 µg/ml (10, 5, 2.5 µg/disc) was added. The treatment also included 100 µl of DMF as negative control and griseofulvin and nystatin as positive control^37,38 for comparison. The plates were incubated at 26 ± 2 ^oC for 48-72 h and the zone of inhibition was determined.

3. RESULTS AND DISCUSSION:

All the compounds synthesized by microwave irradiation have taken very short time to synthesis along with higher yield than conventional reflux technique. Additionally, it is also found that quantity of solvent utilized for microwave technique is very less (Table 1).

The antibacterial property of thiazolidinone derivatives were screened in disc diffusion method using various concentration and microorganisms as shown in Table 2. The compound 4A, 4D, 4E and 4G has shown average antibacterial activity against E. coli and S. aureas. All other compounds showed low antibacterial activity against all the bacteria’s.

The antifungal property of thiazolidinone derivatives were screened in disc diffusion method using various concentration and microorganisms as shown in Table 3. The compound 4B, 4D, 4E and 4G has showed moderate antifungal activity against A. flavus and C. albicans, all other compounds showed low antifungal activity against both microorganisms.

Table 2. Spectral data of synthesized compound:

Compound Code	IR (KBr cm^-1)	¹H NMR (DMSO δ ppm)	Mass M+ m/z
4A	1159 (C-S), 1655 (C=O), 3304 (NH), 1637 (C=N), 2927 (C-H), 1536 (C=C), 3416 (OH).	2.49 (s, 3H, C-CH₃), 3.31 (s, 2H, CH₂), 4.48 (s, 1H, OH), 5.53 (s, 1H, CH), 6.52-6.95 (m, 9H, Ar-H), 9.94 (s, 1H, NH)	411
4B	1180 (C-S), 1671 (C=O), 3303 (NH), 1637 (C=N), 1491 (C=C), 2878 (C-H), 1258 (C-N), 839 (C-Cl)	2.38 (s, 3H, C-CH₃), 3.29 (s, 2H, CH₂), 5.48 (s, 1H, CH), 7.14-7.43 (m, 9H, Ar-H), 9.87 (s, 1H, NH)	429
4C	1180 (C-S), 1675 (C=O), 3307(NH), 1597 (C=N), 1518 (C=C), 2915 (C-H), 1370 (NO), 1180(C-N)	2.14 (s, 3H, C-CH₃), 3.12 (s, 2H, CH₂), 5.67 (s, 1H, CH), 6.72-6.98 (m, 9H, Ar-H), 8.62 (s, 1H, NH)	440
4D	1121 (C-S), 1654 (C=O), 3399 (NH), 1595 (C=N), 1459 (C=C), 2855 (C-H), 1234 (C-N)	2.04 (s, 3H, C-CH₃), 2.93 (s, 2H, CH₂), 3.86 (s, 9H, [OCH₃]₃), 5.53 (s, 1H, CH), 6.34-6.88 (m, 7H, Ar-H), 8.83 (s, 1H, NH)	485
4E	1086 (C-S), 1654 (C=O), 3423 (NH), 1635 (C=N), 1459 (C=C), 2927 (C-H), 1086 (C-N), 3512 (OH)	1.96 (s, 3H, C-CH₃), 3.17 (s, 2H, CH₂), 3.72 (s, 3H, OCH₃), 4.67 (s, 1H, OH), 5.49 (s, 1H, CH), 6.73-7.15 (m, 8H, Ar-H), 9.13 (s, 1H, NH)	441
4F	1179 (C-S), 1673 (C=O), 3303 (NH), 1597 (C=N), 1527 (C=C), 1404 (C-H), 1179 (C-N), 1349 (NO)	2.14 (s, 3H, C-CH₃), 3.28 (s, 2H, CH₂), 5.68 (s, 1H, CH), 6.98-7.55 (m, 9H, Ar-H), 9.06 (s, 1H, NH)	440
4G	1095 (C-S), 1637 (C=O), 1597 (C=N), 1560 (C=C), 3393 (NH), 2833 (C-H), 1226 (C-N), 3465 (OH)	1.27 (t, 3H, CH₃ of ethoxy), 2.49 (s, 3H, CO-CH₃), 3.19 (s, 2H, CH₂ of thiazolidinone), 3.76 (s, 2H, CH₂ of ethoxy), 4.06 (s, 1H, OH), 5.53 (s, 1H, CH), 6.45-7.67 (m, 8H, Ar-H), 9.19 (s, 1H, NH)	455

Table 3. Screening of compounds 4 (A-G) at different concentration by disc diffusion method (values are in mm)*

Compound	*E. Coli*				*Ps. Aurginosa*
Compound	100 μg/ml	50 μg/ml	25 μg/ml	12.5 μg/ml	100 μg/ml	50 μg/ml	25 μg/ml	12.5 μg/ml
Ciprofloxcin	28	26	25	19	22	20	18	17
4A	19	13	11	8	03	02	01	00
4B	12	11	11	05	05	04	02	01
4C	14	11	08	06	04	03	03	01
4D	25	23	18	13	03	02	01	00
4E	21	16	14	12	04	03	01	01
4F	14	14	11	09	02	02	00	00
4G	19	15	10	09	03	02	01	01

Table 3. Cont....

Compound	*S. Aureus*				*K. Pnemonia*
Compound	100 μg/ml	50 μg/ml	25 μg/ml	12.5 μg/ml	100 μg/ml	50 μg/ml	25 μg/ml	12.5 μg/ml
Ciprofloxcin	25	24	22	19	21	20	19	16
4A	17	14	11	08	07	05	04	02
4B	10	09	08	05	05	03	01	00
4C	12	10	08	08	06	05	03	01
4D	18	18	13	09	10	08	04	02
4E	19	17	16	15	09	07	04	02
4F	10	09	09	07	05	04	03	00
4G	13	10	08	08	09	07	03	02

*Average of three determinations

4. CONCLUSION:

In conclusion, we have described simple and more efficient microwave assisted protocol for the synthesis of thiazolidinone derivatives with good yields. All the derivatives which are synthesized by microwave irradiation used less quantity of solvent. In comparison to conventional methods microwave heating offered advantages such as reduced reaction time, better yields, selectivity and reproducibility. Selected synthesized compounds have been investigated for their in vitro antimicrobial activities. To summarize with, we found that the class of thiazolidinone have emerged as a valuable lead. Few of synthesized compounds might be useful as antimicrobial agents in future. These thiazolidinone derivatives have proved to be promising candidates for further efficacy evaluation.

5. ACKNOWLEDGEMENTS:

The authors are thankful to administration of SAC College of pharmacy, B.G. Nagara for providing research facilities and encouragement. The authors are also thankful to Dept. of USIC Karnatak University, Dharwad for providing Spectra.

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Received on 23.03.2016 Modified on 08.04.2016

Asian J. Research Chem. 9(4): April, 2016; Page 153-158

DOI: 10.5958/0974-4150.2016.00025.0