**2. Synthesis**

In the literature, a variety of techniques for creating 4-thiazolidinones have been extensively described. An amine, a carbonyl molecule, and a mercapto-acid are the three elements that are often used in the main synthesis pathways for 1,3-thiazolidin-4. The disclosed classical synthesis can be either a two-step method or a one-pot, three-component condensation (**Figure 1**). The first step in the reactions is the creation of an imine (the nitrogen of the amine attacks the carbonyl of the aldehyde or ketone). This is followed by intramolecular cyclization on the removal of water.

**Figure 1.** *Synthesis of thiazolidinone by condensation.*

*Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

The most common method for making 4-thiazolidinone derivatives is syntheic [15]. On being treated with mercaptoacetic acid while having silica chloride present as a heterogeneous catalyst to speed up the intramolecular cyclocondensation in a solvent-free environment, a variety of quinazolinyl azomethines produce 4 thiazolidinones (**Figure 2**).

By using benzylidene-anilines and mercaptoacetic acid in benzene at 30 C for 10 min, Bolognese et al. [16] produced a variety of 1,3-thiazolidin-4-one derivatives. Following chromatographic purification, the 1,3-thiazolidin-4-ones are extracted at a yield of 65–90% (**Figure 3**).

A solvent-free, nano-titania-supported sulfonic acid [nano-TiO2- SO3H (n-TSA)] catalysed method has been developed by Ruby Singh et al. [17]. for the synthesis of novel hybrids of isoxazolyl-spiro-thiazolidinones that are promising for use in pharmaceuticals (**Figure 4**).

To create a few thiazolidinone derivatives using the recommended techniques to look into their potential antiamoebic effect as described in a three step reaction process for obtaining target chemicals (**Figure 5**). In the first stage,

**Figure 2.** *Synthesis of thiazolidinone by intramolecular cyclocondensatio.*

**Figure 3.** *Synthesis of thiazolidinone by Bolognese et al.*

**Figure 4.** *Synthesis of thiazolidinone by Ruby Singh et al.*

**Figure 5.** *Synthesis of thiazolidinone by Knoevenagel condensation.*

2-methylpropan-1-amine and phenylisothiocyanate were combined with toluene to create 1-(2-methylpropyl)-3 phenylthiourea. The second stage was the cyclization of 3-(2-methylpropyl)-2-(phenylimino)- 1,3-thiazolidin-4-one with the use of sodium acetate and chloroacetic acid. In the third stage, 3-(2-methylpropyl)-2-(phenylimino)-1,3-thiazolidin-4-one was Knoevenagel condensation with various substituted aldehydes in ethanol to produce the target compounds [18].

Another method involves employing dialkyl substituted bromoacetic acid or bromacetyl chloride as the starting material to create 5-substituted dialkyl thiazolidinones. In order to produce the intermediate, which was then hydrolyzed to produce 5,5-dialkyl- thiazolidin-2,4-dione, the reaction begins with the refluxing of dialkyl substituted bromoacetic acid or bromoacetyl chloride with thiourea in the presence of sodium acetate in ethanol (**Figure 6**) [19].

**Figure 6.** *Synthesis of thiazolidinone by Knoevenagel condensation.*

*Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

By refluxing the mixture of substituted benzaldehyde **35** with L-cysteine **36** in the presence of ethanol for 1.5–48 hours, 2-substituted phenyl thiazolidine-4-carboxylic acid derivatives have been created (**Figure 7**) [20].

By reacting 4-hydrazinobenzenesulfonamide hydrochloride with 4-substituted aldehydes in the presence of sodium acetate in ethanol, followed by the reaction of the resulting phenyl hydrazones with excess thiolactic acid at 60°C for 3 h, Abdellatif et al. [21], were able to produce 2,4,5-trisubstituted thiazolidinone derivatives, as shown in (**Figure 8**).

Velmurugan. V et al. [22] have been synthesized Thiazolidinone derivatives from thiourea (**Figure 9**).

Novel oxazinyl thiazolidinone compounds have been created by Rajalakshmi et al. [23], as powerful antidiabetic agents (**Figure 10**).

Novel Thiazinyl-thiazolidinone compounds have been created by Rajalakshmi et al. [24], as potential in vitro anti-diabetic and antioxidant agents (**Figure 11**).

**Figure 7.** *Synthesis of thiazolidinone.*

**Figure 8.** *Synthesis of thiazolidinone by Abdellatif et al.*

#### **Figure 9.**

*Synthesis of thiazolidinone by Velmurugan. V et al.*

**Figure 10.** *Synthesis of thiazolidinone by Rajalakshmi et al.*

*Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

**Figure 11.**

*Synthesis of thiazolidinone by Rajalakshmi et al.*

Substituted benzaldehyde/acetophenone were reacted with thiosemicarbazide in HCl to get the intermediate schiffbase. Schiff base intermediate react with chloro acetic acid and sodium acetate in acetic acid to obtain 4-thiazolidinone analogs by Rahim et al. [25]. Saiz et al. [26] have been synthesized 2-hydrazolyl-4 thiazolidinones by the reaction involving aldehydes, thiosemicarbazides, and maleic anhydride, effectively assisted by microwave irradiation (**Figure 12**).

Benmohammed et al. [27] a series of reaction involving thiosemicarbazones react with ethyl 2-bromoacetate in anhydrous sodium acetate afforded to the thiazolidin-4 one derivatives (**Figure 13**).

Ottana et al. [28] has been reported the series of new thiazolidinone derivatives by reacting *N*-hydroxypropyl-*N*<sup>0</sup> –phenylthiourea of methyl bromoacetate in the presence of triethylamine (**Figure 14**).

One pot three component synthesis containing aldehyde, thiourea and chloroform to give 2-amino-4-thiazolidinone derivatives (**Figure 15**) reported. Various imino thiazolidinones were developed by using different reagents with different reaction conditions by Jieping et al. [29].

**Figure 12.** *Synthesis of thiazolidinone by Saiz et al.*

**Figure 13.** *Synthesis of thiazolidinone by Benmohammed et al.*

**Figure 14.**

*Synthesis of thiazolidinone by Ottana et al.*

**Figure 15.** *Synthesis of thiazolidinone by Jieping et al.*

*Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

Pang et al. [30] were synthesized by the Mesoporous MCM-41 supported Schiff base and CuSO4.5H2O mediated in the cyclocondensation of mercaptoacetic acid with imines (or aldehydes and amines) to afford thiazolidinone derivatives (**Figure 16**).

## **2.1 The Bioimplication of Thiazolidinones**

Thiazolidinones are the primary compounds with a diverse range of biological activity. This ring handles several pharmacological processes. Thiazolidinones are being studied biologically using a variety of mechanisms, including receptor-mediated mechanisms and enzymatic activity. The biological study of thiazolidinones has shown that substitution at positions 2, 3, and 5 imparts various activity. As seen in **Figure 17**, many commercial medications that contain the thiazolidinone scaffold exhibit a variety of biological actions.

**Figure 16.** *Synthesis of thiazolidinone by Pang et al.*

**Figure 17.** *Pharmacological action of thiazolidinones and its derivatives.*

#### **2.2 Antibacterial and antifungal activity**

Veerasamy et al. [31] have prepared a series of 1,3-thiazolidin-4-one derivatives **(50)**.These compounds were also evaluated for *in-vitro* antibacterial, antifungal and anti-viral activities. Preliminary results indicated that most of the compounds demonstrated moderate to good antimicrobial activity, comparable to standard drugs.

Different levels of inhibition against bacteria and fungus are present in thiazolidinones with substituted positions at C-2 and N-3. Multi-drug resistance microbial infections have rapidly increased in frequency during the past few decades, posing a serious health risk. Nearly every location of the 4-thiazolidinone has been investigated in an effort to increase its antibacterial and antifungal activities. Thiazolidinone derivatives' SAR analyses revealed that they are more efficient against gram-negative bacteria than gram-positive bacteria. Therefore, finding novel antimicrobial drugs will continue to be a difficult and vital work for medicinal chemists. According to Liesen et al., 4-thiazolidinone compounds made from ethyl (5-methyl-1-H-imidazole-4-carboxylate). The entire produced chemicals were tested for their antibacterial and antifungal activities against a variety of diseases. The findings demonstrated that, in comparison to common antibacterial and antifungal medications like *chloramphenicol*, *rifampicin*, and *ketoconazole*, the examined compounds had modest antibacterial and antifungal properties. Against *Bacillus subtilis*, compound (**51**) displayed a MIC of 270 lg mL1 [32].

The kind of the substituents at the thiazolidinone ring's C-2 and N-3 substantially influences antibacterial activity. Compound 51–3-(1,5-dimethyl-3-oxo-2-phenyl-2,3 dihydro-1H-pyrazol-4-yl) -2- \s(2-hydroxy-3,5-diiodophenyl) -thiazolidin-4-one (**52**) had a zone of inhibition of 27, 24, and 25 mm against *Escherichia coli, B. subtilis*, and *Salmonella typhi*, respectively, and had antipyrine at N-3 and a 3-iodo substituted phenyl ring at C-2.

Recently, a group of 2-thioxo-4-thiazolidinones and 4,40-bis(2-thioxo-4 thiazolidinone-3-yl)diphenylsulfone derivatives were synthesised by El-Gaby et al. The majority of the compounds were found to have moderate efficacy against the tested bacterial strain. *Bacillus cereus* was found to be the target of the highest antibacterial activity in thiazolidinones (**53**) with sulfamoyl and thioxo moieties, while *Staphylococcus* aureus was the target of the highest antibacterial activity in thiazolidinone derivative (**54**) with pyrimidine nucleus, sulfamoylphenyl, and thioxo moieties [33].

Bondock et al. [34]. created thirteen compounds and tested them against *B. subtilis, Bacillus megaterium,* and *E. coli* for antibacterial activity. By using *ampicillin* and *chloramphenicol* in a concentration of 25 mg/mL as a reference medicine, the majority of the produced thiazolidinone derivatives (**55, 56**) revealed comparable action against tested bacteria.

Bonde et al. [35] reported the synthesis of *N*- [(2Z)-3-(4- bromophenyl)-4- oxo-1,3-thiazolidin–2-ylidene]–2-(pyrazin-2-yloxy)acetohydrazide **(57)** exhibiting for antibacterial activity against two different strains of Gram-negative (E. coli and S. typhi), Gram-positive (S.aureus and B.subtilis) bacteria and the antimycobacterial activity against H37Rv strain of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) was determined for test compounds and for reference standards.

#### **2.3 Antitubercular activity**

Kucukguzel et al. [36]. reported substituted 4-thiazolidinones have antimycobacterial action, although only compounds (**58** and **59**) demonstrated 90 and 98% inhibitions at 6.25 lg mL1, respectively.

The synthesis of N-pyridyl-N0 -thiazolylhydrazine derivatives was described by Zitouni et al. [37]. High antituberculosis activity was demonstrated by compound **60** (IC50: 6.22 lg/mL and IC90: 6.78 lg/mL). Analysis of compound (60) structural details revealed that 2-pyridyl and 2-hydroxy-5-methoxyphenyl groups are necessary for antimycobacterial activity while 3-pyridyl and 4-pyridyl groups are unfavourable for activity.

## **2.4 Anticancer activity**

A series of 2-arylthiazolidine-4-carboxylic acid amides were examined by Gududuru et al. for potential cytotoxic action against prostate cancer. With an IC50 of 0.55 lM and a 38- fold selectivity in *PPC-1* cells, compound **61** was discovered to be the most powerful and selective cytotoxic agent. The SAR study demonstrated that as the chain length increased from C7 to C18, the potency also increased. However, continuing to lengthen the alkyl chain by one carbon unit resulted in a significant loss of activity, making the alkyl chain with a C18 unit the ideal length for the efficacy of thiazolidine analogues. The potency was decreased when the phenyl ring was replaced with an alkyl or cyclohexyl group, but the cytotoxicity was maintained when the furanyl ring derivative was used in its place. The same research team created a novel series of 2-aryl-4-oxo-thiazolidin-3-yl amides (**62**), and each chemical was tested against five different types of human prostate cancer cell lines. According to their findings, replacing the alkyl chain with an aryl group decreased biological activity while increasing the alkyl chain increased the antiproliferative activity.

*Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

The primary cytotoxic activity of several 5-bromo-3-[(3-substituted-5-methyl-4 thiazolidinone-2-ylidene)hydrazono]-1H-2-indolinones (**63**) against a panel of three cell lines, NCI-H460 (Lung), MCF7 (Breast), and SF-268, was examined (CNS). Thiosemicarbazone derivatives of indolinones were shown to have potential cytotoxic properties [38].

Moorkoth et al. [39] have synthesized thiazolidinone **(64)** derivatives and evaluated in vivo anti-cancer activity performed in albino mice bearing Dalton's ascites carcinoma showed that the new analogs enhanced life span and prevented increases in body weight owing to tumor volumes. Moreover, cell-cycle analysis and Hoechst staining analysis proved the apoptotic potential of these analogs. Preliminary pharmacokinetic evaluation was carried out on the synthesized compounds to determine the lipophilicity and pKa. Lipophilicity was determined usinghigh-performance liquid chromatography and the results showed a direct correlation between the observed anti- cancer activity and log P value, while pKa values indicated the ionizing range which is a prediction tool for solubility and permeability.

Kaminskyy et al. [40] have synthesized thiazolidinone derivatives these compounds were evaluated for their anticancer activity. Among the tested compounds, 3-(2,4-thiazolidinedione-5-ylidene)-carboxyimino]olean-12-en-28-oic acid methyl ester was superior to other related compounds with mean values of pGI50 = 5.51/5.57, pTGI = 5.09/5.13, and pLC50 = 4.62/4.64,low toxicity and moderate activity level in vivo hollowfiberassay. Zhou et al. have prepared a series of 2- thioxo-4-thiazolidinone derivatives **(65)** and evaluated them on *peroxisomeproliferator* activated receptor g (PPARg) binding activities. Through thebiological assays, compounds5-(2-(allyloxy)- 5-bromobenzylidene)-2 thioxothiazolidin-4-one and 5-(5-bromo-2-iodobenzylidene)-2 thioxothiazolidin-4- one were highlightedwith Ki values of 12.15 nmol/L and 14.46 nmol/L, respectively.

Sala et al. [41] have synthesized 2,3-thiazolidin-4-one **(66)** possessing strong inhibitory effects on breast cancer cell growth. Our results indicate that some of thiazolidin-based resveratrol derivatives may become a new potent alternative tool for the treatment of human breast cancer.

### **2.5 Anti-inflammtory and analgesic activity**

Inflammation is a biological reaction to damage stimuli that is complicated and associated with numerous pathophysiological diseases. The short-lived free radical nitric oxide is one of the pro-inflammatory chemicals that are released by macrophages in response to inflammatory stimuli (NO). The commonly used nonsteroidal anti-inflammatory medicines naproxen and ibuprofen, which inhibit the COX enzyme that catalyses the manufacture of prostaglandins and tromboxane from arachidonic acid, are derived from arylalkanoic acids. These medications' modes of action are linked to unpleasant side effects include renal and gastrointestinal toxicity. The anti-inflammatory and analgesic effectiveness of a new series of quinazolinone compounds with thiazolidinone at the second position was reported by Kumar et al. to combat the aforementioned side effects. Interestingly, compound **67**, which replaced the phenyl ring at the second position with a chloro group, shown nearly identical anti- inflammatory effect to phenylbutazone at 50 mg/kg. Another study found that 5- (arylidene)- 2-(aryl)-4-oxothiazolidin-3-yl amide derivatives of biphenyl-4-carboxylic acid were significantly anti-inflammatory. Bromine substitutions on both aromatic rings in compound 58 resulted in percentage inhibition values of 44.59 and 55.73 at 2 and 4 hours, respectively [42, 43].

**52**

### *Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

In their investigation of 3,30 -(1,2-ethanediyl)-bis[2-aryl-4- thiazolidinone] derivatives (**69**), Ottana et al. hypothesised that these derivatives would interact preferentially with inducible COX-2 isoform due to their remarkable stereo selective antiinflammatory/analgesic actions. The anti-inflammatory activity of 3-[2- (4 methylphenyl)-2- oxo-l-phenylethyl]-2,4-thiazolidinedione (70) was increased and the analgesic activity was lowered in its absence of the 5-arylmethylidene moiety. The 2,4-thiazolidinedione ring's bulkiness at the NH group either reduced or eliminated the anti-inflammatory action [44, 45].

The ability of 2-aryl-3-[([1, 3, 4] thiadiazino [6,5-b]indol-3-ylamino]methyl] to reduce inflammation In order to study 1,3,4-thiadiazol-2-yl, 1,3-thiazolidin-4-one (**71**), rats' paw edoema caused by carrageenan was used. Azetidinones were shown to have stronger anti- inflammatory and analgesic properties than their comparable thiazolidinone molecules, according to Bhati and Kumar [46].

Vigorita et al. [47] have synthesized 3,3<sup>0</sup> -(1,2-Ethanediyl)-bis[2-aryl-4 thiazolidinone]**(72)** exhibiting for Antiinflammatory activity was investigated by the carrageen in-inducedpawedema test and analgesic activity by acetic acid writhing and hot plate tests in rats.

### **2.6 Anticonvulsant and antidepressant activity**

Shiradkar et al. have created a brand-new series of clubbed thiazolidinonebarbituric acid (**73**) and thiazolidinone-triazole derivatives (**74**) in order to

research the effects of a hydrophobic unit, hydrogen bonding domain, and electron-donor group on the compounds' anticonvulsant action. They discovered that the -OH function at the 4-position of the phenyl ring is necessary for anticonvulsant activity and that its removal or substitution by the moieties -Cl, CH3, or - NO2 results in a loss of activity. The activity was eliminated when the hydroxyl group responsible for hydrogen bonding was replaced since there was no longer an HBD (hydrogen bonding domain). It was discovered that compounds with pmethoxyphenyl substitution at the C-2 of the thiazolidinone ring were more active than standard medication sodium phenytoin in a series of thiazolidinonyl 2-oxo/ thiobarbituric acid derivatives [48, 49].

#### **2.7 Antiviral/anti-HIV activity**

Different 2-(2,6-dihalophenyl)-3-(4,6-dimethyl-5-(un)substituted-pyrimidin-2 yl)- thiazolidin-4-ones were created by Chen et al. The analytical and spectral data of these newly synthesised chemicals supported their structures. The ability of these substances to inhibit HIV-RT was also tested. It was claimed that a high hydrophobicity value will have a significant impact on HIV-RT inhibitory efficacy. Compounds **75** and **76**, which had an ethyl group at the 5-position on the N-3 position of the pyrimidine ring, were found to be the most effective ones, with IC50 values of 0.26 and 0.23 lM, respectively. According to their research, the analogues' overall hydrophobicity as well as the steric and electronic properties of the 3-hetero-aryl moiety's meta- and parasubstituents on thiazolidin-4-one resulted in a significant increase in antiviral activity [50–52].

HIV-RT inhibitory action in a group of 2-aryl-3-(4,5,6-trimethylpyrimidin-2-yl) thiazolidin-4-ones was negatively influenced by substitution at C-5 and positively affected by the addition of a chlorine atom on the phenyl at C-2. The anti-HIV-RT activity of compound 66 was remarkably strong (IC50 = 2.95 lM) [53].

*Synthesis and Biological Applications of Thiazolidinone DOI: http://dx.doi.org/10.5772/intechopen.109102*

Ravichandran et al. [54] have synthesized 1,3,4-thiazolidinone derivatives. The present 3D-QSAR study attempts to explore the structural requirements of thiazolidinone derivatives for anti-HIV activity. Based on the structures and biodata of previous thiazolidinone analogs,3D-QSAR studies have been performed with a training set consisting of 96 molecules, which resulted in two reliable computational models, *CoMFA* and *CoMSIA* with r2 values of 0.931 and 0.972, standard error of estimation (SEE) of 0.173 and 0.089, andq2 values of 0.663 and 0.784, respectively, with the number of partial least-squares (PLS) components being six. Rao et al. [55] have synthesized 2,3-diaryl-1,3-thiazolidin-4-ones **(78**) bearing a methyl group at C- 5 position and tested as anti-HIV agents. The results of the *in vitro* tests showed that some of them proved to be effective inhibitors of HIV-1 replication.

#### **2.8 Antidiabetic activity**

Compound **79**, which had the benzylidene-2,4-thiazolidinedione ring at position C-5 replaced with 5-(2-(3,5-bis(trifluoromethyl) benzyloxy)-5bromobenzylidene), was the most effective at inhibiting PTP1B. The anti-hyperglycemic action of a number of thiazolidine-2,4- dione derivatives with carboxylic ester moieties at N-3 and benzyl and heteroaryl substituents at C-5 has also been investigated. The most promising anti-hyperglycemic activity was found to be compound **80** [56].

Liu et al. [57] studied a series of thiazolidinone-substituted biphenyl scaffold**(81)** as PTP1B inhibitors and reported that introduction of the 4- oxothiazolidine-2-thione moiety showed better inhibitory activity against PTP1B.

Bhosle et al. [58, 59] have synthesized 2-hydrazolyl-4-thiazolidinone-5- carboxylic acids with pyrazolyl pharmacophore and evaluated for the antihyperglycemic activity in sucrose loaded rat model. Maccari et al. [59] have synthesized 5-arylidene-2-thioxo-4- thiazolidinones **(82)** and evaluated as aldose reductase inhibitors (ARIs) and most of them exhibited good or excellent in vitro efficacy. Out of the tested compounds, most N-unsubstituted analogues were found to possess inhibitory effects at low micromolar doses and two of them exhibited higher potency than sorbinil, used as a reference drug. The insertion of an acetic chain on N-3 of the thiazolidinone scaffold led to analogues with submicromolar affinity for ALR2 and IC50values very similar to that of epalrestat, the only ARI currently used in therapy.
