Microwave Assisted Synthesis of Some Novel Series of 4-Thiazolidinone Derivatives as Potent Antimicrobial Analogs

Several substituted 4‐thiazolidinone derivatives 2a‐q have been synthesized from halogenohydroxy substituted Schiff bases 1a-q under microwave irradiation technique. The reactions were carried out using ethanol: 2-methoxyethanol mixture as efficient reaction solvent system to afford high yield of product. The structures of newly synthesized compounds have been established on the basis of elemental analysis, IR, H & C NMR and mass spectral data. Further, all newly synthesized compounds were screened for their in vitro antimicrobial activity. The antifungal and antibacterial effects of the tested compounds are due to their molecular structure and substituent present.

The use of microwave induced reactions in organic synthesis has increased dramatically in the last years, receiving widespread acceptance and becoming an indispensable tool [21].Microwave technology has become a powerful tool in organic synthesis, since by employing this technique it is generally possible to prepare organic compounds very fast, with high purity and better yields compared to other more conventional method [22][23][24].Additionally, in the search for economic and environmentally friendly synthetic methods, one-pot syntheses could offer a significant step ahead [25].Since, the aim of our research has concerned on achieving reasonable yields of the synthesized heterocyclic compounds which might have prospective biological and pharmaceutical activities, we have synthesized new 4-thiazolidinone derivatives that may be of value in development of new, potent, selective and less toxic antimicrobial agents.As a part of our research work towards some green synthetic strategy [26-28], herein we plan to explore the possibility of a greater route with the help of microwave technique for the synthesis of 4thiazolidinone derivatives (Figure 1).The reaction between imines (Schiff bases) [29] and mercaptoacetic acid were carried out using ethanol: 2-methoxyethanol combination as efficient reaction solvent system to afford high yield of product.Therefore, present communication describes, microwave synthesis, characterization and study in vitro antimicrobial activity of novel 4-thiazolidinone derivatives.

MATERIAL AND METHODS
Melting points were determined in an open capillary tube and are uncorrected.The chemicals and solvents used were of laboratory grade and were purified.Purification of the compound was indicated using TLC (ethyl acetate / hexane, 0.25 mL: 0.25 mL, v/v as the mobile phase).FT-IR spectra were recorded in KBr pellets on a Perkin-Elmer (8201) spectrometer.1 H NMR spectra were recorded on a Gemini 300-MHz instrument in DMSO-d6 as the solvent and TMS was used as an internal standard.The mass spectra were recorded on SHIMADZU (GCMS-QP 1000 EX) GC-EI-MS spectrometer.Elemental analyses were performed on a Perkin-Elmer 240 CHN elemental analyzer.The reactions were carried out in EtOH: 2methoxyethanol (10mL: 10mL, v/v) as reaction medium in QPro-M modified microwave oven, made in Canada at 200 watts and 2450 MHz frequency.

Microwave method
A mixture of halogenohydroxy substituted imines 1a-q (0.001 mole) in EtOH: 2-methoxyethanol (10mL: 10mL, v/v) containing anhydrous ZnCl2 (0.01 g) and thioglycolic acid (0.001 mole) was irradiated in QPro-M microwave oven for about intermittently at 30 sec.interval for 2-6 min.Then reaction mixture was diluted with ice-cold water.The solid product thus formed was filtered, dried and recrystallized from ethanol to yield pure 4-thiazolidinone derivatives 2a-q as reddish brown crystals.

Antimicrobial activity
The antibacterial activities of the synthesized compounds (2a-q) were determined by agar well diffusion method 32  were procured from Institute of Microbial Technology (IMTech), Chandigarh, India.The antibiotic streptomycin (12.5μ/mL & 10.5 μ/mL) and Nystatin (25 μ/mL) used as reference drug for antibacterial and antifungal activity, respectively.Dimethyl sulphoxide (1%, DMSO) in sterilized distilled water used a control for all sample treatment.The minimum inhibitory concentrations (MIC's) values were determined by comparison to streptomycin and Nystatin as the reference drugs for bacterial and fungal activity respectively, as shown in Table 2.

RESULTS AND DISCUSSION
In view of the importance of this class of heterocycles and in continuation of our earlier investigation, reported the synthesis of 4thiazolidinones from imines and some of the 4thiazolidinone derivatives found to have significant antibacterial activity [30].Therefore, in present paper, we have synthesized new class of 4-thiazolidinones (2a-q) by cyclocondensation reaction of imines (Figure 1).The starting iodo anilines required for the preparation of imines were prepared by iodination of substituted anilines using molecular iodine and iodic acid under refluxing technique [31].Obtained different substituted iodo anilines on condensation with halogeno substituted 1-(1-Hydroxy-naphthalen-2-yl)ethanone (ketones) under solvent-free grindstone technique to yield imines (Schiff bases) [29] 1a-q.
Microwave oven is used for syntheses of 4thiazolidinone derivatives as a convenient source of heat in laboratory.The microwave assisted reactions occur more rapidly, safely, easy isolation of products and with more chemical yields and better time economy thus, render microwave method superior to conventional method.The structures of newly synthesized compounds (2a-q) are well established on the basis of spectral data.

CONCLUSION
In summary, 4-thiazolidinone derivatives have been synthesized from halogenohydroxy substituted imines using EtOH:2-methoxyethanol solvent system in Q-Pro-M modified microwave oven.The method is efficient, convenient in terms of simple reaction procedure, short reaction time, increasing the purity of resulting products, and enhances the quantitative yield in comparison with classical procedure.Further preliminary in vitro antimicrobial study of newly synthesized compounds reveals that, presence of Cl, Br and I in basic nucleus of 4-thiazolidinones enhances the pharmacological activity.The electronic effect also plays an important role in pharmacological activity, as can be seen from compounds 2d, 2e, 2f, 2j, 2k and 2l which possess -NO2 group has more electronic withdrawing character shows sharp decrease in antimicrobial activity.Owing to these results, the synthesized compounds 2i and 2m have broader value than standard drug used for screening of bacterial and fungal strains.Therefore, the present study is useful for drugs in medicinal investigation against bacterial and fungal diseases.

Table 1 .
Physical data of newly synthesized 4-thiazolidinon derivatives (2a-q).Staphylococcus aureus (MTCC 6535), Candia crusei (MTCC 14264) and Candida albicans (MTCC 64558).The results of these studies in terms of zone of inhibition (ZOI) and minimum inhibitory concentrations (MICs) are summarized in a: Isolated yield of the product by microwave method.b: Isolated yield of the product by conventional method.