Recent advances in synthetic strategies and SAR of thiazolidin-4-one containing molecules in cancer therapeutics

Cancer is one of the life-threatening diseases accountable for millions of demises globally. The inadequate effectiveness of the existing chemotherapy and its harmful effects has resulted in the necessity of developing innovative anticancer agents. Thiazolidin-4-one scaffold is among the most important chemical skeletons that illustrate anticancer activity. Thiazolidin-4-one derivatives have been the subject of extensive research and current scientific literature reveals that these compounds have shown significant anticancer activities. This manuscript is an earnest attempt to review novel thiazolidin-4-one derivatives demonstrating considerable potential as anticancer agents along with a brief discussion of medicinal chemistry-related aspects of these compounds and structural activity relationship studies in order to develop possible multi-target enzyme inhibitors. Most recently, various synthetic strategies have been developed by researchers to get various thiazolidin-4-one derivatives. In this review, the authors highlight the various synthetic, green, and nanomaterial-based synthesis routes of thiazolidin-4-ones as well as their role in anticancer activity by inhibition of various enzymes and cell lines. The detailed description of the existing modern standards in the field presented in this article may be interesting and beneficial to the scientists for further exploration of these heterocyclic compounds as possible anticancer agents.


Overview of cancer
Cancer is still a global health concern, and it is the second leading cause of death in developed countries [1]. Cancer is a markedly multigenic, complex, multi-factorial, and distinct pathway ailment. A very common characteristic associated with cancer is the fast generation of a group of cells that grow at a rapid rate beyond their limit, invading into adjacent body parts and spreading to the other surrounding organs leading to their destruction and sometimes metastasis [2,3]. The majority of the cancers result in a tumor, except some such as leukemia, which does not form a tumor. Cancer can occur at any age, including even the fetuses, but the danger for furthermost types of cancer surges with age [4]. On the other hand, benign tumors do not display malignant properties and are generally self-limited and do not show invasion or metastasis of adjacent tissues and organs [5,6]. It is particular to note that, although the rate of total incidences of cancer observed in the developed countries is double to that of reported in the developing world, the overall death rates 1 3 in both sexes related to cancer are almost similar. The most frequently spotted and the prime cause for cancer demises in females is breast cancer that accounts for 23% of the entire cancer cases as well as the death of 14% patients annually, whereas the lung is the most likely cancer spot between males responsible for 17% of the entire new cases. From the literature survey, it was estimated that in 2030 the new cases of cancer diagnosis are anticipated to be 21 million around the globe with per year deaths of 17 million people and estimation of people breathing with cancer would be 75 million [7]. Cancer is a leading cause of death worldwide, accounting for nearly 1,958,310 new cancer cases, and 609,820 cancer deaths are anticipated in the USA in 2023 (https:// cancerstatisticscenter.cancer.org/module/BmVYeqHT) . The progression of cytotoxicity begins from normal cells of the body. According to researchers, it may develop due to changes in control mechanism by activation of oncogenes and the inconsiderable role of cancer suppressor genes, and may be due to factors responsible for mutagenesis, i.e., due to mutations of genes [8]. As one of the cytoskeleton's main components, microtubules play a noteworthy role in a number of biological processes, namely the protection of cell shape, molecular signaling pathway, contributing to the movement of cell organelles, and more importing the antly, producing the mitotic spindle to ensure the cell cycle progression [9]. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor in adults and described by its extremely invasive potential and heterogeneity, which results in chemical resistance and rapid tumor reoccurrence [10]. Many tumor-related deaths in patients under 35 years of age have been regarded as caused by brain cancer. The numerous forms of brain tumors include meningeal, tumors of the cellular region, neuroepithelial, metastatic, and primary CNS lymphomas [11]. Tumor microenvironment has a crucial role in cancer development and metastasis. Macrophages are well-defined inflammation and host defense elements of the effector cells against tumors. Based on the tumor microenvironment, tumor-associated macrophages differentiate into either cytotoxic (M1) or tumor-promoting (M2) phenotypes [12]. Various efforts have been made by scientists for the treatment of malignancy; to fulfill this purpose, different treatment strategies (Fig. 1) like surgery, radiotherapy, hormone therapy, and chemotherapy were used [5]. Among all the treatment options, chemotherapy is the vital and chief treatment option involving natural and synthetic agents that are potent and widely used as anticancer agents [13,14]. Chemotherapy also has some limitations like severe side effects, toxicity, resistance, and shortage of chemotherapeutic agents. This problem can be solved by continuous research and the growth of innovative chemotherapeutic mediators. For the development of new drugs, DNA is an effective target among all the targets because drugs easily bind to the DNA and unnaturally alter or prevent its functions. The action of enzymes that metabolize DNA like topoisomerase can be repressed by the introduction of apoptosis when drugs bind to DNA and protein structure [13,15]. Even though ongoing research projects have led to considerable improvements in cancer treatments over the past few decades, numerous research projects are still needed for the efficient management of cancer and its associated symptoms. Moreover, the occurrence of adverse events associated with cancer treatment is imposing another challenge to the medicinal researchers. The major methodology that is primarily used to treat cancer patients depends upon the explicit stage, type, and location [16].

Physicochemical parameters and applications of nanotechnology for enhancing anticancer activity
The low water solubility of anticancer drugs was a prominent and serious problem that prevented their production and clinical application; many extremely active and effective chemotherapeutic agents were removed due to their low water solubility. A major challenge for the development of pharmaceutical drugs is to eradicate or at least minimize the negative, harmful effects of highly active drugs, especially those antitumor agents that show general toxicity in the body, which significantly limits their use [17]. Nanoparticles (NPs) can maximize the cellular penetration of chemotherapeutic drugs in malignant cells to reduce toxicity by the usage of active and passive target-specific approaches of cells [18]. Nanocarriers found use in separation, enrichment, cancer diagnosis, and cancer therapy [19]. Nanocarriers are encouraging alternatives used extensively in the field of oncology. Furthermore, these drug-charged nanomaterials display several important advantages such as passive targeting of malignant cells by increased permeability and retention effect, enhanced bioavailability, extended diffusion period, and decreased adverse reactions [20]. Nanotechnology being used in different biomedical applications, including the distribution of medications, has drawn growing concern owing to their capacity to change the pharmacokinetics of medicines. Nanomedicines enhance solubility of poorly soluble medications and decrease its metabolism by degradation of their hydrophilic or hydrophobic sections. Nanomedicines have extended half-life in plasma and varying biodistribution levels as compared to modern chemotherapy [21]. Physicochemical properties of nanoparticles such as size, shape, size distribution, crystallinity, porosity, concentration, and dissolution rate are predominantly relevant to establish their biological interactions and impacts [22,23]. Nanoparticles used as drug delivery systems are submicronsized particles (3-200 nm), structures, or systems that can be made from a range of materials like polymers (polymeric nanoparticles, micelles, or dendrimers), lipids (liposomes), viruses (viral nanoparticles), metallic (gold nanoparticles), oxides (iron oxide nanoparticles), and even organometallic compounds (nanotubes) [24]. Depending on the type of nanoparticles, drugs are released from nanoparticles at a particular concentration via internal or external stimuli. The nanoparticles utilized for the transportation of other substances at a particular site are called nanocarriers. Conventional nanoparticles do not have the ability to transport and release drugs at the right concentration at a specific site. Therefore, they requisite to be altered and functionalized to make them smart [25]. Diverse applications, properties, and types of nanoparticles for cancer treatment are outlined in Fig. 2.
Thiazolidin-4-one ring systems are also found in the natural products for the treatment of cancer [63][64][65][66]. Anticancer agents are classified as DNA-interacting agents, agents of molecular targeting, agents of anti-tubulin, antimetabolites, monoclonal antibodies, hormones, and other biological agents, which proved to be a valuable core to explore newer anticancer medications [67,68]. The majority of the currently available chemotherapeutic anticancer drugs act either by direct interaction with DNA or by inhibiting the relaxation process of DNA [69,70]. The quantitative 1 3 structure-activity relationships based protocols have been developed for thiazolidin-4-ones with objectives to develop more structurally diverse compounds of this class having the desired biological actions [71][72][73].
In several literatures, the noncyclic chemical structures for pseudo-thiohydantoin and rhodanine were first proposed because there was considerable confusion regarding the structure of thiazolidin-4-ones [59]. The carbon atom of methylene at site 5 of thiazolidin-4-one analogues depicts nucleophilic action and the Knoevenagel reaction of this (methylene group) has been widely attempted [77]. The carbonyl group of thiazolidin-4-one analogues has been observed to be highly unreactive. However, in some cases, it has been observed that the reaction of thiazolidine-4-ones with Lawesson's reagent produces the analogous 4-thione analogues [59].
The structural and conformational features of thiazolidin-4-ones are very important to establish a correlation between their biological actions and basicity. Several optical, geometrical, and regioselective isomers of thiazolidin-4-one derivatives have been described and different configurations with the envelope or half-chair conformation have also been observed [73,78].

Physico-chemical characteristics
Thiazolidin-4-one substituted at position 3 is a generally solid compound that often melts with decomposition. Their melting point is lowered with the alkyl substitution at the nitrogen atom. Thiazolidinones are slightly soluble in water but when there is no substitution of aryl or a higher alkyl group, they show solubility somewhat [56,59].

Synthetic approach
New synthetic strategies reported for development of novel thiazolidin-4-one containing compounds with special emphasis of synthesis using different reagents, click chemistry/green chemistry, and usage of nanocarrier-based catalysts have also been discussed in the following sections.

Synthetic aspects of thiazolidin-4-one
Thiazolidin-4-one heterocycles are also used for the designing of various novel drugs that act at various targets. Some important synthetic schemes (synthetic routes [1][2][3][4][5][6][7][8][9][10][11][12][13][14] are summarized in Fig. 5 [79]. In synthetic route 1, Foroughifar et al. designed a one-pot synthesis of 1, 3-thiazolidin-4-ones. In this path, the reaction of aromatic amine, aromatic aldehyde, mercaptoacetic acid, and Bi(SCH 2 COOH) 3 as a catalyst was done underneath solvent-free conditions. Thin-layer chromatography (TLC) was used to test the completion of reaction and purity of the chemicals. It was also reported that the yield of the product was enhanced by raising the temperature up to 70ºC [80]. In synthetic route 2, Kaboudin et al. recognized a sequence of thiazolidine-4-ones and 3H-thiazole analogues by means of one-pot four-component condensation-cyclization reaction. In this path, synthesis of thiazolidin-4-one analogues was performed using refluxing hydrazine carbothiomide derivatives and DMAD (dimethyl acetylenedicarboxylate) in 40 ml absolute ethanol with elimination of MeOH [81]. In synthetic route 3, Apostolidis et al. synthesized an innovative sequence of 5-arylidene-2-(1, 3-thiazol2-ylimino)-1, 3-thiazolidin-4-ones. In this path, substituted thiazole-2-amine was reacted with α-chloro acetyl chloride, dry benzene, and ammonium thiocyanate to create intermediates. Furthermore, this intermediate is reacted with substituted benzaldehyde, acetic acid, and sodium acetate to obtain thiazolidin-4-ones [82]. In synthetic route 4, Prasad et al. prepared an innovative sequence of 2-aryl-thiazolidin-4-one derivatives. In this pathway, aniline, benzaldehyde, and thioglycolic acid were reacted at 110ºC in PPG (polypropylene glycol) and the product was obtained in good yield (83%). Furthermore, all the derivatives synthesized by this route were decontaminated by column chromatography using silica gel of 60-120 mesh. It was reported that even after 24 h no product formation was detected when PEG (polyethylene glycol) is used as a catalyst. This problem was solved by using PPG in place of PEG [83]. In synthetic route 5, Prasad et al. prepared an innovative sequence of 2-aryl-thiazolidin-4-one analogues. In this path, the compounds containing the thiazolidin-4-one nucleus were synthesized similarly as synthesized in route 4. All the reactants are similar except the aniline derivative. As already shown thiazolidin-4-one analogues were synthesized in good yield by reacting aniline, aldehyde, and thioglycolic acid at 110ºC in PPG [83]. In synthetic route 6, Taherkhorsand et al. planned a sequence of 2-pyrazolo-3-phenyl-1, 3-thiazolidine-4-ones. In this pathway, pyrazole carbaldehyde, anilines, and thioglycolic acid DSDABCOC were reacted to obtain thiazolidin-4-one derivatives. It was found that the reaction gave the product in good yield (82-92%) when DSDABCOC was used as a catalyst. It was also found that the rate of reaction could be raised by using ultrasound and the consumption of energy could be reduced [84]. In synthetic route 7, Khillare et al. testified a novel sequence of thiazole-substituted pyrazolyl-4-thiazolidinones. In this path, a reaction between aromatic carbaldehyde, aromatic amines, and mercapto acetic acid in DTPEAC (diisopropyl ethyl ammonium acetate) at room temperature gives a product containing thiazolidin-4-one nucleus [85]. In synthetic route 8, Unsal-Tan et al. investigated a novel sequence of 2-aryl-3-(4-sulfamoyl/ methylsulfonylphenylamino)-4-thiazolidinones. In this pathway, phenylhydrazine was dissolved with benzaldehyde in methanol and then acetic acid has been incorporated as a catalytic medium in the mixture of reaction and then heated with Dean-stark separator to form an intermediate. Furthermore, the intermediate was refluxed with acid, i.e., mercaptoacetic acid to obtain the urged product [86]. In synthetic route 9, Zarghi et al. developed a new sequence of 2, 3-diaryl-1, 3-thiazolidine-4-one analogues. In this path, a reaction of aromatic amine, 4-methyl thiobenzaldehyde, and thioglycolic acid in dry toluene gives an intermediate. Furthermore, oxidation of intermediate with 30% H 2 O 2 (hydrogen peroxide) in the presence of WO 3 (tungsten trioxide) gives derivatives of thiazolidin-4-one [87]. In synthetic In this pathway, N′-ethyl-N′-(P-tolyl/thiourea) was reacted with the solution of chloroacetyl chloride and chloroform to obtain the product. The solution of chloroacetyl chloride and chloroform was added dropwise [88]. In synthetic route 11, Ranga et al. introduced a novel sequence of pyridine analogues of 4-thiazolidinone. In this path, a reaction of "2-chloro-N-arylacetamide" (obtained by aromatic amine, DMF, chloroacetyl chloride reaction) and ammonium thoicyanate in ethanol yields an intermediate. Furthermore, the intermediate was reacted with pyridine aldehyde and piperidine to obtain the product with thiazolidin-4-one nucleus [89]. In synthetic route 12, Sadou et al. reconnoitered innovative analogues of 4-thiazolidinone. In this pathway, the reaction of thiosemicarbazide with dehydroacetic acid gives thiosemicarbazenes which further reacted with (ethyl 2-bromo propionate), phenyl bromoacetate, or maleimide to obtain compounds with thiazolidin-4-one moiety [90]. In synthetic route 13, Küçükgüzel et al. described a novel sequence of 2-heteroarylimino-5-arylidene-4-thiazolidinone analogues. In this path, thiosemicarbazide was reacted with substituted benzoyl chloride, sodium bicarbonate, aldehyde, and ethanol to obtain thiazolidine-4-one derivatives [91]. In synthetic route 14, Apotrosoaei et al. testified a new series of analogues of 4-thiazolidinone. In this path, substituted aromatic aldehyde, ethyl 3-aminopropionate hydrochloride, mercaptoacetic acid, DIPEA (N, N-disopropyl ethylamine), toluene, ethanol, tetrahydrofuran, and dichloromethane were reacted to yield thiazolidine-4-one derivatives [92].

Click chemistry/green synthesis
The title role of chemistry is vital to ensure that our upcoming materials, energy production, and chemicals are more sustainable as compared to the present generation. The demand of eco-friendly chemical processes and products around the world needs progress of new and cost-effective methods for the prevention of pollution. Moreover, due to the pervasive use of heterocyclic molecules, numerous classical named reactions have been developed in the past to create heterocyclic derivatives. These reactions require thermal heating, harmful or expensive catalysts, high boiling solvents, and prolonged reaction times. When it comes to environmental safety protocols, these strategies are no longer a force to be reckoned in terms of safety. The most effective idea in chemistry to maintain sustainability is green chemistry with an approach towards the use of effective, safe, and efficient chemical methodologies for the synthesis of biologically active compounds. These sustainable methods continue to be in high demand and reduce or eliminate the use of hazardous materials in the context of environmental safety [93,94]. Several green chemistry-oriented methods include the usage of sonochemistry, ionic liquids, microwave-assisted technology, phase transfer catalysis, and numerous other techniques [95,96]. The sustainable techniques for synthesis have incredible feature such as lower energy consumption, increase selectivity, proper utilization of raw material and catalyst in the reaction, and less use of harmful solvents. Some green synthesis pathways of thiazolidin-4-ones are detailed in Fig. 6.
In synthesis 1, Angapelly et al. described a novel sequence of thiazolidin-4-one derivatives by using the green chemistry protocol. In this pathway, aldehydes, amines, and thioglycolic acid were reacted in the presence of VOSO 4 (vanadyl sulfate) in acetonitrile under ultrasonic irradiation [97]. In synthesis 2, Bhosle et al. arranged a novel sequence of 2, 3-disubstituted-4-thiazolidinones. In this path, the reaction of 4-(p-toulysulfonoxy) benzaldehyde, aryl/heteryl amines along with mercaptoacetic acid in PEG-400 gives thiazolidin-4-one derivatives [98]. In synthesis 3, Tiwari et al. presented a novel sequence of 2-(2-chloroquinoline-3-yl)-3-substituted phenyl thiazolidin-4-ones. In this path, 2-chloroquinoline-3-carbaldehyde and aromatic aniline condensed under microwave irradiation at 200 W give intermediate N-aryl-2-chloroquinolin-3-yl-azomethine. Furthermore, the intermediate formed was reacted with thioacetic acid (HSCH 2 COOH) and zeolite 5A under microwave irradiation to obtain the desired product [99]. In synthesis 4, Nikpassand et al. prepared a novel sequence of 2-pyrazolyl-1, 3-thiazolidine-4-ones using 2-oxoimidazolidine-1, 3-disulfonic acid. In this path, by the reaction of pyrazolcarbaldehyde, aniline and thioglycolic acid were reacted in the presence of mMWCNT nanocomposite and thiazolidin-4-one derivatives were obtained [100]. In synthesis 5, Mirzaei-Mosbat et al. introduced an innovative sequence of 1, 3-thiazolidin-4-ones. In this pathway, benzaldehyde, substituted aniline, and thioglycolic acid were reacted in the presence of LDHs@PpPDA catalyst and thiazolidin-4-one derivatives were obtained [101]. In synthesis 6, Prasad et al. developed a novel sequence of 2, 3-disubstituted 4-thiazolidinones. In this path, a solution of DBSA (4-dodecylbenzenesulfonic acid) is prepared in water and then aromatic/aliphatic primary amine, thioglycolic acid, and aromatic aldehyde were combined to obtain the desired product [102]. In synthesis 7, Thomas et al. used ultrasound to promote Schiff's base formation of isoniazid with aromatic aldehydes in water, which were converted to corresponding thiazolidinones using thioglycolic acid and zincchloride in THF (tetrahydrofuran) [96]. In synthesis 8, in this path, Nazeef et al. explored a new sequence of 1, 3-thiazolidin-4-ones. On a magnetic stirrer, a solution of aniline, thioglycolic acid, and aromatic aldehyde was stirred in a round bottom flask. At room temperature under the exposure of 22-W CFL, the reaction mixture was irradiated. In the round bottom flask, the reaction blend was kept 9 cm away from the compact fluorescent lamp and the reaction growth was observed by TLC [103]. Some green synthetic pathways of thiazolidin-4-ones are detailed in Fig. 6.

Synthesis of thiazolidinone-based nanomaterials
To overcome difficulties and to speed up the synthesis of nanoparticles, various scientists focused on the development of thiazolidinone-based nanocarriers [104]. Currently, nanoparticles particularly magnetic nanoparticles have fascinated growing attention due to their specific physical properties involving super paramagnetism, high surface area, toxicity, and possible uses in different fields [105]. Scientists have concentrated on the production of nanoparticles over the past decades. Nanotechnology advancement has encouraged scientists to develop and exemplify materials with remarkable properties and nanometric measurements [106]. Here, we discussed some thiazolidinonebased nanomaterials (Fig. 7).

Anticancer activity profile of thiazolidin-4-one derivatives
More than 90% of deaths due to cancer occur by metastasis. For understanding the pathogenesis of cancer, apoptotic ways and directing cell proliferation are the standard methodologies [116][117][118]. The biological route involves the conversion of normal cells into cancerous cells which is a major approach used by researchers [119,120]. During the treatment, drug resistance is the main obstacle, as resistance is developed against most of the chemotherapeutic mediators by means of diverse mechanisms like increase in drug export, restoration of drug-induced DNA damage, promotion of apoptosis, alteration of drug targets, and signaling transduction molecules [121]. Hence, there is an imperative necessity to grow new chemotherapeutic mediator to control the cancer because of augmented drug resistance. The possible mechanism of anticancer activity displayed by thiazolidinones involves inhibition of particular enzymes (Fig. 8). Among these, microtubules are polymers of tubulin that give structure and shape to eukaryotic cells. Therefore, inhibition of tubulin polymerization leads to mitotic arrest and cell death to prevent cancer progression. Carbonic anhydrases, protein tyrosine kinases, and protein tyrosine phosphatases are the enzymes responsible for various kinds of cancers. Inhibition of these enzymes regulates growth of cell and differentiation. Histone deacetylase inhibitors are the agents which lead to cell cycle arrest by regulating and altering gene expression. VEGFR are the receptors involved in angiogenesis and movement of monocytes and macrophages. EGFR and VEGFR are the members of tyrosine kinase family. Inhibition of EGFR and VEGFR regulates tumor progression by inducing apoptosis and by inhibiting angiogenesis. COX and BCl-2 are the proteins whose inhibition induces apoptosis.

Anticancer activity by enzyme inhibition
Enzyme inhibition was recognized as a substitute and important objective for the management of tumors. Compounds containing thiazolidin-4-one were found effective in inhibition of a large number of enzymes or various enzymatic routes [7]. Protein/tyrosine kinases, (c-Met, CDK2, PIM kinases, AKt, Src, Ron, KDR, c-Kit and IGF-IR), carbonic anhydrases, HDAC, EGFR, HER-2, VEGFR2, CDC25A, BCl-2 protein, tubulin polymerization, and HSP90 are inhibited by thiazolidinone.
Histone deacetylases (HDACs) are identified as an important target for cancer management and are inhibited by histone deacetylase inhibitors (HDACi) [122]. HDACi are innovative chemotherapeutic agents that increase acetylation of histones by regulation of gene expression, alteration of gene expression, and also inducement of chromatin relaxation [123]. HDAC has revolutionized the production of a new class of pharmacological agents, HDAC inhibitors (HDACi), which are cytostatic agents that inhibit tumor cell proliferation in culture and persuaded cell cycle arrest, differentiation, and apoptosis in vivo [124]. Studies indicated that HDACi regulate cell proliferation and cell cycle progress by convincing growth arrest, apoptosis in tumor cells, and differentiation [123]. Histone tail's lysine side chains were acetylated by histone acetyltransferases enzyme. In 2006, the first HDACi was "Zolinza" (SAHA, vorinostat) that acquired FDA (Food and Drug Administration) approval and is normally used in the management of T-cell lymphoma [125]. Several groups of HDACi were reported including benzamides, cyclic tetrapeptides, fatty acids (short-chain), benzofuranone, hydroxamic acid, boronic acid-based analogues, and sulfonamides comprising compounds and electrophilic ketones. Among these classes, HDACi based on hydroxamic acid was one of the foremost groups to which several studies have been described and it remains a dynamic research area [126]. Thus, HDACi has been depicted as an innovative class of chemotherapeutic drugs that control the expression of genes [124]. Angiogenesis is facilitated by vascular endothelial growth factor (VEGF) and its receptors. In a variety of cancers like renal cell, glioma, hepatocellular, and breast, VEGF is overexpressed [127]. Human protein kinases are the enzymes involved in cancer progression; therefore, protein kinases are the main objectives in the management of tumors [128]. Carbonic anhydrases catalyse the interconversion of H 2 O and CO 2 into bicarbonate; this process is essential in mammals in various biological processes such as transporting carbon dioxide and maintaining the acid-base balance. Generally, carbonic anhydrases are overexpressed in various forms of cancer [129]. Protein tyrosine kinases are involved in various cellular functions like proliferation and differentiation both in normal cells and cancer cells. Studies revealed that ATP binding protein kinases are the attractive targets for the development of new chemotherapeutic agents [130]. The following text involves the description of various enzymes involved in cancer progression and the role of thiazolidin-4-one derivatives to inhibit these enzymes by interacting with them and their receptors. The various enzymes involved in cancer therapy are presented in Fig. 9 and discussed briefly in the following section:

Protein tyrosine kinase inhibitors
In normal and neoplastic cells, a large number of mitotic signaling ways were identified, in which protein kinases also present and play a crucial part in cell proliferation, cell growth, and metastasis and also induce anti-apoptotic effects in cancer cells. Stimulation of protein kinases was a common mechanism of cancer beginning. Tyrosine kinases are the enzymes which play a role in the transfer of phosphate group to the target proteins from adenosine triphosphate. There are two types of protein kinases-receptor protein kinases and non-receptor protein kinases. The receptor tyrosine kinases play a key role in the transfer of extracellular signals to the cytoplasm of cells. The blockage of the signaling pathways involved in cancer progression was a major approach for the development of drugs used as protein kinase inhibitors [139,140].
In 2020, Nissan et al. have described an innovative sequence of various compounds in which compounds containing the 4-thiazolidinone nucleus also present. Anticancer action of such compounds was judged in response toMCF-7 (breast cancer cell line), HepG2 (liver cancer cell line), HCT-116 (colo-rectal cancer cell line), and A549 (lung cancer cell lines). Cytotoxic activity of all the prepared analogues was compared toward doxorubicin and 5-fluorouracil. Among the most potent analogues, compound 2 displayed CDK2 inhibitory activity (IC 50 = 56.97 ± 2 µM) as well as potent cytotoxic activity in response to MCF-7 and HepG2 tumor cell lines, possessing IC 50 value of 0.54 µM and 0.24 µM, respectively. Compounds 1 and 2 displayed potent activity in response to MCF-7 with (IC 50 0.37 and 0.54 µM). Compounds 1, 2, and 3 ( Fig. 10) exhibited good cytotoxic action towards the HepG2 cancer cell line having an IC 50 value of 1.58, Fig. 9 Various enzymatic pathways involved in cancer progression [131][132][133][134][135][136][137][138] 1 3 0.24, and 2.28 µM, respectively. As analogue 2 displayed the most potent activity, it could be used by researchers in the future for the progression of promising anticancer mediators [141].
In In 2018, Qi et al. in another study reported a novel sequence of N 1 -(2-aryl-1, 3-thiazolidin-4-one)-N 3 -aryl ureas and assessed for multi-tyrosine kinase inhibition activity. Among them, compound 6 ( Fig. 11) acquires potent inhibitory activity toward multi-tyrosine kinases comprising c-Met, Src, Ron, KDR, c-Kit, and IGF-IR, etc., possessing IC 50 = 0.021 µmol L −1 . Compound 6 was assessed for cytotoxic activity towards (lung carcinoma cell line) A549 at 0.041 µM concentration. Molecular modeling study revealed that compound 6 binds completely with binding sites of c-Met kinase enzyme and formed one weak hydrogen bond and two strong hydrogen bonds with ATP binding site [143].
In 2017, a new sequence of thiazolidin-4-one analogues was investigated and assayed by Bataille et al. for their PIM kinase inhibition. The synthesized sequence was found to be excellent PIM pan-inhibitors. Compound 7 (Fig. 11) showed potent PIM kinase inhibition (IC 50 = 2.2 ± 1.8 µM). Compound 7 also displayed anti-proliferative activity with regard to two leukemia cell lines (MV4-11 and K562) having IC 50 values of 3.4 µM and 0.75 µM [144].
In 2007, Richardson et al. explored a newer series of thiazolidin-4-one comprising CDK2 inhibitors and assayed for CDK2 and GSK-3β inhibitory activity. Compound 11 (Fig. 12) was found to express CDK2 (IC 50 = 0.03 µM), and compound 12 (Fig. 12) showed GSK-3β inhibitory activity (IC 50 = 0.002 µM). Molecular docking study was performed in two stages using rDock and rCat to bind the compounds against CDK ATP binding site. The molecular modeling study concluded that compounds form H-bond with the protein [146].

Carbonic anhydrase inhibitors
In prokaryotes and eukaryotes, carbonic anhydrases are the abundant zinc enzymes having four distant gene families: αCAs, βCAs, γCAs, and δCAs. CA IX was the first carbonic anhydrase reported to be linked with cancer. The second carbonic anhydrase co-expressed with CA IX in various tumor cells is CA XII. In cancer therapy, targeting cancer-linked enzymes is an encouraging strategy [147].
In  In 2017, Ansari et al. introduced an innovative class of pyridine-thiazolidinone analogues as powerful carbonic anhydrase IX inhibitors. Results indicated that among all tested analogues, compounds 22 and 23 inhibited the activity of carbonic anhydrase IX enzyme. The prepared analogues were also tested for cytotoxic activity in response to breast cancer cell line MCF-7 and liver cancer cell line HepG-2. Out of the most potent compounds, compounds 22, 23, and 24 were found to show powerful inhibitory activity toward MCF-7 cell line (IC 50 = 18.9 ± 2.19 µM, 13.0 ± 2.28 µM, and 12.4 ± 1.39 µM) and compounds 22, 23, 24, and 25 showed superior activity against HepG-2 cell line (IC 50 = 11.8 ± 1.95 µM, 18.9 ± 1.34 µM, 16.2 ± 1.34 µM, and 17.6 ± 2.12 µM). A molecular modelling study of the compounds 22 and 23 revealed that in compound 22, nitrobenzylidene ring created 6 hydrogen bonds with amino acid residues of enzymes like His94, His96, Thr199, and Thr200 while the thiazolidin-4-one ring created one hydrogen bond with active site residue Thr200 of enzyme. Similarly, with the dynamic site residues, compound 23 created seven hydrogen bond interactions and hydrophobic interactions [149] (Fig. 13). . Molecular modeling study demonstrated that compound 26 strongly interacts with the active site of the CA IX. Sulfonamide pharmacophore interacted with amino acid residues or residues of targeted proteins, e.g., Asn-62, His-64, Gln-67, Gln-92, and Thr-199 [150].

CDC25A phosphatase inhibitors
CDC25 (cell division cycle phosphatase) is a member of protein tyrosine phosphatases involved in the activation of cyclin-dependent kinases. For cell proliferation, proper regulation and activity of CDC25 are essential. Generally, three analogues of CDC25 are present in humans which are CDC25A, CDC25B, and CDC25C. As CDC25 involves tumor growth, consequently, it is an interesting target for expansion of anticancer drugs [151].

HDAC inhibitors
Histone deacetylase (HDAC) is an essential enzyme for removing the acetyl group from residues of lysine to the ends of histone proteins and generates positive charge which ultimately triggers the DNA's negatively charged phosphate backbone to strongly coil and control chromatin arrangements [153]. HDACi (histone deacetylase inhibitors) are found to be active curative mediators that kill melanoma cells by preventing the functions of histone deacetylase (HDAC) or by varying chromatin arrangements [126]. HDACs bind with DNA via multi-protein complexes but not directly. HDAC inhibitors are compounds that induce cell growth arrest and cell death, and therefore are widely used as anticancer agents. HDAC inhibitors generally involve three common structural components, i.e., zinc-binding moiety, a straight-chain alkyl, aryl or vinyl linker, an opposite capping group. A large range of HDAC inhibitors was used in combination with other anticancer agents for the management of malignancy [154]. Recent discoveries show that HDACi specifically induces differentiation, apoptosis, and growth arrest in melanoma cells through transcriptional stimulation of genes (a small set) that regulate cell proliferation as well as the production of cell cycles such as p21 [123].
In 2016, Yang et al. designed a sequence of thiazolidinones and verified for their histone deacetylase (HDAC) inhibitory activity. Major findings indicated that only compound 28 (Fig. 15) displayed HDACi with an IC 50 value of 73 ± 14. Vorinostat was employed as a reference and the outcomes specified that HDAC1 inhibition depends on linker-length. Synthesized compounds also assayed towards four tumor cell lines, HeLa (cervical carcinoma cell line), MCF-7 (breast cancer cell line), LNCaP (prostate carcinoma cell line), and A549 (lung cancer cell line). Compound 28 showed the most powerful response to all cancer cell lines (IC 50 = 3.2 ± 0.5, 2.1 ± 0.5, 2.9 ± 0.3, and 4.6 ± 0.8 µM, respectively). Results concluded that compound 28 not only showed anti-proliferative activity and impeded colony formation of tumor cell lines but also appeared to be superior inhibitors of metastasis of cancer cell lines [155].

Bcl-2 inhibitors
Apoptosis is a main type of PCD (programmed cell death). PCD is essential for mature organisms to sustain cell homeostasis. Bcl-2, a component of protein, is essential for the control of apoptosis. The elevated level of Bcl-2 proteins is liable for the cancer induction in cells; therefore, inhibition of Bcl-2 is vital to suppress cancer.
In the year 2015, Wan et al. arranged a new sequence of new 2-thioxo-4-thiazolidinone analogues and screened for their cytotoxic potential as Bcl-2 inhibitors. Among compounds, compound 29 inhibited Bcl-2 protein as well  showed better anti-proliferative action contrary to all cancer cell lines [156]. Graphical representation of the structures is reflected in Fig. 16.

Tubulin polymerization and HSP90 inhibitors
Microtubules are the proteins and components of mitotic  [157]. Microtubules involve cell growth, and cell proliferation, invasion, and migration. Microtubule-inhibiting agents are the major agents used to develop chemotherapeutic agents to combat the above cellular processes. There are two categories of microtubuleinhibiting agents: agents that inhibit the polymerization of microtubules and agents that promote or stabilize microtubules [158]. Tubulin protein has continuously been a significant, critical, and practical goal for the expansion of cytotoxic drugs [159].
In 2018, a novel series of 4-phenylcoumarin derivatives containing thiazolidinone nucleus was designed by Batran et al. Each prepared analogue has been assayed for tubulin polymerization inhibition action. Thiazolidin-4-one containing derivatives 33, 34, and 35 found strong tubulin polymerization inhibitor (IC 50 = 9.37, 2.89, and 6.13 μM). Results indicated that compounds 33, 34, and 35 (Fig. 17) displayed strong cytotoxic activity in response to breast cancer cell line MCF-7 (IC 50 value of 11.1, 16.7, and 21.2 µg/mL). The molecular modeling study discovered that compounds 33, 34, and 35 exhibited binding with pockets of the crystal structure of β-tubulin (a protein present in mitotic spindles) as showed by colchicine [160].  (Fig. 17) (MHPT) was found as a powerful and discriminating anti-rhabdomyosarcoma mediator. About 50% of the progression of the rhabdomyosarcoma tumor cell lines, RD and SJ-RH30, was inhibited by MHPT, at 0.44 ± 0.19 μM and 1.35 ± 0.58 μM, respectively. The above findings indicated that because of the low toxicity level of MHPT, it has the prospective to be auxiliary established into a discriminating anti-rhabdomyosarcoma medication [161].
In 2014, Zhang et al. produced a CDBT (2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene) thiazolidin-4-one) compound (37) (Fig. 18) and checked for its tubulin and HSP90 (heat shock protein 90) dual inhibitory activity using non-small cell lung tumor model. Results identified that the compound was identified as an excellent inhibitor of both tubulin and HSP20. CDBT compound 37 also evaluated against P-gp, paclitaxel resistant, and paclitaxel susceptible (lung cancer cell line) NSCLC H460 TaxR and H460 cells (IC 50 0.8 mM and 0.7 mM). HSP90 proteins like CRAF-1 and ERBB2 and α and β-tubulin proteins were also corrupted by CDBT compound 37. Results concluded that the activity of H460 TaxR is lesser than that of H460 cells. CDBT treated with Na 3 VO 4 express no P-gp ATPase activity but in nonappearance of Na 3 VO 4 showed better P-gp ATPase activity [162].
In another study (2013), Zhang et al. again synthesized CDBT compound 38 (Fig. 18) and assayed for their dual tubulin and HSP90 inhibitory activity. The resulted data suggested that both α, β-tubulin proteins and HSP90 proteins such as CRAF-1 and ERBB2 in NSCLC cells (H460 with IC 50 = 0.7 µM and H322 having IC 50 = 1.0 µM). Both the cells incubated with CDBT for 14 h showed corrupted filaments and small microtubule fragments. The molecular Fig. 17 Thiazolidin-4-one as tubulin polymerization inhibitors showed potent anticancer effect Fig. 18 Thiazolidin-4-one analogues as tubulin and HSP90 inhibitors 1 3 modeling study suggested that CDBT binds to the colchicine site and restricted its binding to colchicine pockets [163].

EGFR, VEGFR, FLT3, and HER-2 kinase inhibitors
VEGF kinase receptors present in human beings comprise VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, VEGFR belongs to the family of tyrosine kinases. VEGFR-1 is involved in the movement of monocytes and macrophages, while VEGFR-3 involves lymph angiogenesis [164]. Angiogenesis is a complex and highly controlled process crucial for tumor growth and metastasis [165]. The EGFR (epidermal growth factor receptor) which is a constituent of the ErbB family also comprises the HER-1, EGFR-2/HER-2, HER-3, and HER-4 tyrosine kinase receptors. Generally, VEGFR-2 is essential for the development of both local and distant cancer growth [166].
In year 2019, Qi et al. designed a sequence of innovative class of thaizoldin-4-one urea analogues and investigated for their FLT3 and VEGFR2 inhibitory action. Results proved that compound 39 (Fig. 19) acts as a multi-kinase inhibitor and presented powerful inhibitory activity against FLT3 and VEGFR2 having an IC 50 18.7 µM. From molecular docking, the way of binding of compound 39 with FLT3 kinase was investigated by molecular operating environment software to find out the structural resistance mechanism. Results of molecular docking revealed that with FLT3 compound 39 exhibited type II binding mode. In compound 39, two (hydrogen) bonds have been formed by urea moiety with Asp698 residues. Furthermore, the strength of binding of the compound was raised by three arene-H-interactions, one among Leu616 and benzene ring (O-linked) and the two other interactions among Val624 and quinoline ring. All the analogues were assayed for cytotoxic action in response to A549 (lung cancer cell line) and HT-29 (colon tumor cell line). The most active derivative 39, which was a FLT3/ VEGFR2 dual inhibitor, showed strong anticancer activity (by suppressing cell growth) toward A549 and HT-29 tumor cell lines with an IC 50 value of 0.65 µM and 0.11 µM, respectively. Results also exhibited that cytotoxic activity of compound 39 was stronger and long-lasting as compared to cabozantinib and compound 39 also inhibited cell migration more efficiently in contrast to cabozantinib after 48 h of treatment [167].
In 2019, Abbas et al. introduced a newer series of benzofuran-pyrazole-hydrazono-thiazolidin-4-one hybrids and tested for EGFR inhibitory performance. The consequences concluded that compound 42 showed strong EGFR inhibition (IC 50 [169]. In 2018, a newer series of pyrazolo oxothiazolidine analogues were reported by Yakaiah et al. and assayed for EGFR and VEGFR2 inhibitory action. Analogues 48-53 (Fig. 21) presented the most impressive EGFR and VEGFR2 inhibitory activity along with anticancer activity with regard to A549 human lung carcinoma cell line (IC 50 0.930 µg/mL, 1.207 µg/mL, 0.808 µg/mL, 1.078 µg/mL, 0.967 µg/mL, and 2.445 µg/mL, respectively). The molecular docking study discovered that all the potent analogues effectively bind to catalytic sites of EGFR and VEGFR2 enzymes. From in vitro results, compound 50 found potent EGFR and VEGFR2 inhibitor as it formed strong H-bond with MET 769 (hepatocyte growth factor receptor) [170].
In 2017, El-Miligy et al. described a novel sequence of piperazine-based thiazolidinone analogues and tested for VEGFR2 tyrosine kinase inhibitory action. Outcomes indicated that analogues 54, 55, 56, and 57 (Fig. 21) were found as the most potent VEGFR2 tyrosine kinase inhibitors. For molecular modeling study of the most persuasive compounds in the VEGFR2 kinase domain, AUTODOCK software is used. For the docking study, the VEGFR2 kinase domain of Homo sapiens was acquired from the protein databank. Receptor for AUTODOCK software was prepared by adding all hydrogens and by deleting water molecules and ligands. The reported compounds were also assayed for cytotoxic activity in response to the HepG2 cell line. The most potent analogues 54, 55, 56, and 57 exhibited good activity in response to the HepG2 cell line (IC 50 = 0.03-0.06 µM) [171].
In 2013, the antiproliferative activity of a new sequence of triazaspiro [4,5] dec-8-ene benzylidine derivatives comprising the thiazolidinone ring system was assayed for their EGFR inhibitory activity by Fleita et al. Among them, compound 58 displayed the greatest powerful EGFR inhibitory action with an IC 50 value of 6.355 µM. Analogues 59 and 60 expressed strong cytotoxic activity in response to MCF-7 (IC 50 = 10.8 ± 2.6 µM). The molecular modeling study demonstrated that compound 58 showed hydrogen binding interaction with ATP molecule [172]. The structures of the analogues 58-60 are displayed in Fig. 21.
In 2010, Lv et al. evaluated two sequences of thiazolidinones for EGFR and HER-2 kinase inhibition action. Only analogue 61 (Fig. 22) was found to exhibit strong EGFR and HER-2 kinase inhibition (IC 50 = 0.09 µM and 0.42 µM, respectively). Analogue 61 also showed anti-proliferative action in response to breast carcinoma cell line MCF-2 in contrast to erlotinib used as the reference drug. The outcomes of molecular docking showed that compound 61 effectively anticipated with hydroxyl group against a mercapto group of Met-769 and also H-bond is formed by nitrogen atom of thiazolidin-4-one with mercapto group of Cys 751. Thus, compound 61 could be used by scientists to produce effective anticancer drugs for cancer treatment in upcoming years [173].

COX inhibitors
Cyclooxygenase (COX) is an enzyme that plays an important role as a catalyst for the transformation of arachidonic acid to prostaglandins (PGs) in the cell. PGs play a vital role in cancer cell progression. This enzyme is divided into two different isoforms, i.e., COX-1 and COX-2. In

Additional anticancer activities of thiazolidin-4-one derivatives
Current scientific literature evidences that thiazolidin-4-one analogues have demonstrated significant cytotoxic activity. A large number of scientists across the globe are pursuing their research endeavors to explore the maximum medicinal utility of these heterocycles as possible anticancer agents. This review paper is an intense endeavor to compile and present vital reports from recent scientific literature related to anticancer activity exhibited by thiazolidin-4-one heterocyclic compounds and their derivatives. Important reports from scientific literature related to the anticancer action of thiazolidin-4-one analogues are presented in the following text: In 2019, Silveira et al. presented 2-(2-methoxyphenyl)-3-((piperidin-1-yl) ethyl) thiazolidin-4-one which have loaded by polymeric nanocapsules and investigated them for in vitro antiglioma activity and in vivo toxicity. Results indicated that treatment of human U138MG and rat C6 cell lines with analogue 72 (Fig. 25) (thiazolidin-4-one nanoparticles) reduced viability and proliferation of cell line more efficiently as compared to normal thiazolidin-4-one derivative at 6.25-50-μM concentration [178].
In the year 2019, Holota et al. explored a new sequence of 5-amine-4-thiazolidinone analogues and assayed for cytotoxic activity. Results identified that compound 75 (Fig. 26) exhibited strong anticancer activity in response to all 59 cancer cell lines having a GI 50 value of 2.57 µM. Hence, the results of the study concluded that in the coming years compound 75 can be used by scientists for the invention of    [183].
In the year 2016, Barbosa et al. scrutinized a sequence of newer hybrids of β-carboline-4-thiazolidinones and assayed for in vitro cytotoxic action in response to human carcinoma cell lines. Results concluded that compounds 92 and 93 (Fig. 27) were found most active with GI 50 values less than 5 µM for all carcinoma cell lines. The study revealed that treatment with compound 92(25-µM concentration) induces cell death after 15 h of treatment [184].
In 2016, Kumar et al. have described the synthesis and anti-proliferative assay of chalcone-thiazolidinone hybrids toward three tumor cell lines including A-549 (human lung tumor cell line), U-87 (human glioma cell line), and COLO-205 (human colon adenocarcinoma cell line). Out of the tested compounds, it was concluded that only analogues (94, 95) (Fig. 27) were found to be the most potent on A-549 and COLO-205 (IC 50 = 38.89 µM and 52.23 µM, respectively). Certainly, this work discovered novel molecules for the treatment of lung and colorectal cancers [185].
In 2015, a novel class of thiazolidinone analogues of 6-aminoflavone was investigated and assayed for their cytotoxic activity in response to human cervical cancer cell line HeLa, melanoma tumor cell line MDA-MB-435, and kidney tumor cell lines by Moorkoth et al. Almost all the prepared analogues displayed anti-tumor activity but compound 100 (Fig. 28) showed the most potent anti-tumor activity against HeLa, MDA-MB-435, and Vero (kidney) tumor cell lines (IC 50 = 1.19 ± 0.96, 2.36 ± 0.70, and > 100 µg/mL, respectively) [187].
In the year 2015, Sharath Kumar et al. reported a newly discovered class of 2, 3-disubstituted-4-thiazolidinone equivalents and assayed in vitro for anti-cancer activity against leukemic cell lines. Analogue 101 (Fig. 28) exhibited the promising cytotoxic activity toward blood cancer cell lines Reh cells and Nalm6 cells having IC 50 = 11.9 and 13.5 µM, respectively [188].
In Major findings specified that analogue 103 (Fig. 28) suppresses tumor growth metastasis and also increases the survival rate [190].
In 2013, a sequence of 5-alkyl/aryl thiadiazole substituted thiazolidin-4-one derivatives were prepared and assessed for anti-proliferative action in response to breast cancinoma cell line MCF-7 by Joseph et al. Results indicated that almost all the analogues displayed good anti-tumor activity with IC 50 less than 150 µmol L −1 . Compounds 116, 117, and 118 ( Fig. 30) were found effective among all the tested compounds (IC 50 = 66.84, 60.71, and 46.34 µM) [195].
In  breast cancer cell line) by standard MTT assay. Several prepared analogues showed noteworthy cytotoxicity. Few potent analogues were further assayed toward the (WI-38) cell line. Among the synthesized analogues, analogue 124 ( Fig. 31) was found to have the most powerful anticancer action in response to HT-29, H460 and MDA-MB-231 cell lines with IC 50 values of 0.016 µmol/L, 0.0037 µmol/L, and 10.5 µmol/L, respectively. Major findings from the study indicated that if the 2 nd position of thiazolidin-4-one ring substituted with the mixture of the indolin-2-one core structure and 5-benzylidene-4-thiazolidinone nucleus, it could improve the anticancer activities [198].
In 2010, Kamel et al. identified an innovative succession of various compounds with thiazolidinone derivatives and assayed for their anti-proliferative activity in response to MCF7 (breast cancer cells) and HeLa (cervical cancer cells). Among the thiazolidinone derivatives, analogues 127 and 128 were displayed potent anti-proliferative activity in response to cell lines MCF7 and HeLa with IC 50 values of 2.68 and 2.01 µg/mL for MCF7 tumor cell line and 1.07 and 1.95 µg/mL for HeLa tumor cell line respectively [201]. The structures of the analogues 127 and 128 are stated in Fig. 31.
In 2010, Chandrappa et al. reported a group of new thioxothiazolidin-4-one analogues. All the synthesized analogues were assessed for their capability to inhibit tumor growth and angiogenesis brought by tumor by means of mouse EAT (Ehrlich ascites tumor) as a model system. Compounds 134 to 138 (Fig. 32) exhibited significant anticancer activity and can be evaluated for anticancer therapy owing to their tumor angiogenesis and cell proliferation inhibitory potential. Compounds 134, 135, and 138 indicated mean ascites volumes of 5.2 ± 0.68 mL, 4.8 ± 0.49 mL, and 5.7 ± 1.26 mL, respectively [205].
In another study (2009), Havrylyuk et al. reported some novel non-fused bicyclic thiazolidin-4-one derivatives. About eight synthesized analogues were assayed for antiproliferative activity and three analogues showed a different level of anti-cancer activity. Results demonstrated that compound 141 (Fig. 33) was the most effective analogue and exhibited antineoplastic activity, contrary to melanoma, CNS, renal, breast, leukemia, colon, ovarian, lung, and prostate tumor cell lines having a mean logGI 50 and logTGI values of − 5.35 and − 4.78 µM, respectively [59].
In 2009, Kumar et al. designed a few coumarinyl heterocycles and also described their potential role as cytotoxic mediators toward Dalton's lymphoma ascites cancer cells (DLA) and Ehrlich ascites carcinoma cells (EAC). Few synthesized Fig. 30 Thiazolidin-4-one analogues showed noteworthy cytotoxic action derivatives exhibited good in vitro antioxidant and cytotoxic activity. The result indicated that compound 144 (Fig. 33) at 0.1 mmol L -1 concentration exhibited comparable free radical scavenging activity (95%) toward standard ascorbic acid. Cytotoxicity studies showed that compound 144 was found to be a noble cytotoxic mediator in response to DLA cells at a concentration of 100 mg mL -1 and to be effective cytotoxic agents in response to EAC cells at a concentration of 50 mg mL −1 [207].
In 2009, some new xanthotoxin analogues were arranged and assayed for their cytotoxic potential in response to HeLa (cervical cancer cells) and MCF-7 (breast cancer cells) by Hafez et al. Among all the produced analogues, five compounds demonstrated activity in preventing the growth of HeLa cells. The outcomes concluded that compound 145 (Fig. 34) (IC 50 = 40 µg/mL) was found to have substantial anticancer activity in response to cancerous cell lines [208].
In 2009, several novel pyrazoline substituted thiazolones have been manufactured by Havrylyuk et al. The prepared derivatives were testified for in vitro cytotoxic potential in response to lung, colon, leukemia, melanoma, ovarian, CNS, Fig. 31 Thiazolidin-4-one bearing compounds as potent anticancer agents prostate, and renal, along with breast, cancerous cell lines. The prepared analogue's structures were ascertained based on data obtained by analysis employing NMR, LC-MS, and X-ray technique. Among the synthesized compounds, analogue 146 (Fig. 34) was found most active towards colon cancer cell lines with average log GI 50 and log TGI − 5.61 and − 5.14, respectively [209].
In 2009, Shashank et al. reported some novel benzothiazole derivatives having thiazolidinone moiety. All synthesized analogues were assayed for their antineoplastic activities by MTT assay against melanoma cancer cell M-14, human normal epithelial breast cancer cell HLB-100, and human colon cancer cell SW-620. Analogue 149 was found most effective in response to M-14 cancer cell (IC 50 = 54.15 ± 0.152 μg/mL), compound 150 showed highest activities against HLB-100 cancer cell having IC 50 value 126.15 ± 0.4454 μg/mL, and compound 151 was found most potent against SW-620 cancer cell (IC 50 = 49.23 ± 0.593 μg/ mL). Major findings from the study concluded that analogues possessing chloro group at p-position showed better antitumor activity [211]. The structures of analogues 149-151 are shown in Fig. 34.
In 2009, a new array of 2-thioxo-thiazolidin-4-ones with benzothiazole analogues was identified by Mosula et al. All the synthesized analogues were assayed in response to various tumor cell lines including non-small cell lung tumor, renal cancer, and ovarian tumor cell lines. Among examined compounds, compound 156 (Fig. 35) disclosed the maximum anticancer activity (logGI 50 and logTGI = − 5.38 and − 4.45 µM) [213].
In 2008, Chen et al. synthesized some new '2-aryl-3-[5deoxy-1, 2-O-isopropylidene-α-D-xylofuranose-5-C-yl] thiazolidin-4-ones.' The structures of the new moieties were confirmed by NMR (nuclear magnetic resonance) spectroscopy, mass spectrometry (MS), and X-ray crystallography analysis. Glycosidase inhibition and antitumor activities of such compounds toward human cervical cancer cell line HeLa were preliminarily evaluated. Some of the analogues, 157 to 160 (Fig. 35), exhibited antitumor activity with % inhibition of 31.8, 28.0, 20.5, 20.2, at 100 µM, respectively [214]. In 2007, Santamaria et al. described the innovation and application of zk-thiazolidinone (TAL) 161 as a potent small-molecule inhibitor of mammalian polo-like kinase 1 (Plk 1 ) which is a significant mitotic progression regulator and cell division and has been well thought out as a probable target for cancer treatment. As (TAL) 161 (Fig. 35) was tested against a panel of 93 serine/threonine and tyrosine kinases, it was found to be highly selective in inhibiting human Plk1 with IC 50 value of 19 ± 12 nM. Major findings from the study concluded that thiazolidinones signify a new chemical class of kinase inhibitors [215].
In 2007, a novel series of 5-substituted thiazolo [3, 2-b][1,2,4]triazol-6-ones analogues was reported by Lesyk et al. The structural characterization of the prepared analogues was done by appropriate methods such as 1 H NMR, 13 C NMR, and X-ray analysis. Synthesized analogues were confirmed for antineoplastic potential on a panel of nearly 60 human cancer cell lines. Among them, derivative 162 (Fig. 36) displayed the most significant action with a discriminating effect on leukemia cell lines having logGI 50 /logTGI of − 5.08/ − 4.47 to − 6.45/ − 4.70 µM [216].
Structurally, integrins are heterodimeric receptors having an α and αβ subunit, which bind in a noncovalent manner in defined combinations. An important role has been found in tumor progression and metasis involving integrin α v β 3 receptors. So, this receptor is a tremendous target for anticancer drugs. In 2006, a series of novel α v β 3 antagonists has been discovered by Dayamet al. through a database of small-molecule drug-like analogues using pharmacophore screening. Based on structural specificity, twenty-nine analogues were selected for the screening of binding assay ofthe α v β 3 receptor and four analogues were found to have a strong binding affinity. Compound 163 (Fig. 36) was found most active having an IC 50 value of 0.34 µM toward human melanoma cell line MDA-MB-435, 13 ± 8 µM toward human ovarian adenocarcinoma cell line  [217].
In 2006, a series of rhodanine moieties were explored by Ahn et al. The prepared analogues were observed in vitro for inhibitory activity toward recombinant human PRL-3. PRL proteins promote cell motility, invasion action, and metastasis, which are directly reliant on their catalytic action; thus, PRL-3 acts as an important therapeutic target for metastastic tumors. Out of all synthesized compounds, compound 164 (Fig. 36) displayed a potent analogue with an IC 50 value of 0.9 µM [218].
In 2005, Rahman et al. designed innovative long alkyl chain substituted 4-thiazolidinone and thiazan-4-one derivatives. Out of the prepared analogues, few moieties were designated by the National Cancer Institute (NCI) and verified them for anti-malignant action in contrast to sixty cell lines of human cancers (nine types). From the study, it was concluded that analogue 165 (Fig. 36) was found to have momentous anti-malignant potential. For lung, melanoma, and renal tumors, the compound shows a decrease in growth of 75%, 97%, and 84%, respectively, at the concentration of 1.0 × 10 -4 M [219].
In another study (2004), Gududuru et al. synthesized asequence of 2-aryl-4-oxo-thiazolidin-3-yl amides intending to enhance the selectivity and improve the potency as compared to serine amide phosphates (SAPs) as a  (Fig. 36) was screened at five dissimilar concentrations towards sixty cell lines of nine types of human tumors: namely, ovarian, lung, renal, melanoma, leukemia, colon, CNS, prostate, and breast for cytotoxic activity. The newly synthesized compounds depicted antitumor activity only at higher concentrations and cause a reduction in the growth of melanoma, colon, and renal cancer cells 52, 80, and 91%, respectively. Compound 170 demonstrated potent antitumor activity with log GI 50 value of 0.75-5.67 µM, respectively [222].

Key structural feartures of thiazolidinones responsible for potent anticancer activity
From the description presented in this manuscript and from critical analysis of the scientific information contained herein, the following key structural features have been found pivotal in determining anticancer activity of thiazolidin-4-one derivatives. The important strututral features are (Fig. 37): Substitution of 5-bromophenyl, n-butyl group, and amino acids along with sulfonamide moiety at R 1 exhibits anticancer activity via inhibition of HDAC, VEGFR, and BCl-2 enzymes Compounds containing electron withdrawing groups, i.e., 3-chlorophenyl moiety at R 2 inhibits carbonic anhydrase IX, tubulin polymerase enzyme, and protein tyrosin phosphates to regulate cancer development. Presence of phenylimino moiety at R 2 enhances the hydrophobic character of the compounds which increases regulation of protein tyrosine phosphatase enzyme and inhibits various types of human cancers When R 3 position substituted with electron withdrawing and H-bond acceptor groups, i.e., p-NO 2 , p-F, and p-CF 3 moieties displayed anti-tumor activity by hindering carbonic anhydrase I enzyme Adding halogen atoms to the phenyl ring at position R3 made the chemical more lipophilic, which enhanced its anticancer potential by inhibiting the EGFR enzyme Presence of amino acid side chain and sulfonamide moiety at R 3 displayed antiproliferative effect by exhibiting better BCl-2 inhibitory activity

Various patents filed/granted on thiazolidin-4-one derivatives as anticancer agents
In organic chemistry, the expansion of new synthetic methodologies giving structures which combine numerous pharmacologically active molecules into a single molecule bears attracted considerable interest. In this direction, heterocyclic compounds occupy a superior place among pharmaceutically active compounds and the production of a simple and effective synthesis of analogues containing multi-heterocyclic ring has given the drug discovery new aspects. Hundreds of patents in the field of thiazolidinones with a diverse diversity of biological activities have been published over the last few decades. This paper is an intense effort to accumulate the key patents filed or granted to thiazolidinone analogues as anticancer agents with an aim that the data delivered in paper will be beneficial for future research in this field (Table 1) [223].

Future perspectives
As heterocyclic chemistry is the emerging field which promotes readily selectable interactions with the biological targets and resulting in a combination of structural and However, a few of the analogues exhibited less inhibitory action in response to cancer cells and were also linked to a few undesirable side effects. Moreover, drug-sensitive and drug-resistant tumor cells are making the cancer much worse. Therefore, the SAR method is thought to be the best for improving their selectivity towards cancer cells by substituting the thiazolidinone core structure with efficient substitutions. Some nanoparticle-based conjugation can also bring better targeted effects against cancer. As per recent technological approach, a number of heterocyclic compounds has been developed with potent anticancer activity. As therapeutically active pharmacophores, thiazolidin-4-one has a myriad of applications in development of novel derivatives against various cancer cell lines. Thiazolidin-4-one has become one of the prime drug research scaffold and its analogues have proved to be desirable compounds because of their exceptional pharmacological activities. Hence, the research inceptions will persist decisive to the innovation of such lead compounds to meet all the required criteria both pharmacologically and pharmacokinetically for development of potent anticancer medications. As the above study reveals, derivatives based on thiazolidin-4-one core nucleus are likely to be considered as several target enzyme inhibitors and mentioned downsides should also be taken into consideration in future research development of more potent thiazoldinones for oncotherapy.

Conclusion
Thiazolidin-4-one derivatives possess an important and unique place in the medicinal chemistry of antineoplastic agents. Their derivatives have been reported to demonstrate promising anticancer activities in the recent scientific literature. A great volume of research has been carried out for the progression of new and effective anticancer agents from these heterocyclic scaffolds. Expansion of novel synthetic strategies for the production of newer compounds, structural characterization, and evaluation of biological potential is gaining increasing attention of the scientific community across the globe. The current review highlights new horizons of thiazolidin-4-one-based heterocyclic derivatives with anticancer potential and chemical aspects. A detailed discussion on the structural activity relationship studies of thiazolidin-4-ones as possible multi-target enzyme  [237] inhibitors and possible synthesis through click chemistry and green chemistry for the developments of future promising thiazolidin-4-one-containing compounds has also been provided. Several patents granted on 4-thiazolidinone derivatives related to anticancer activity have also been presented in tabular form. The scientific data compiled herein indicates that these compounds have promising potential as possible anticancer agents. It is predicted that scientific information enclosed in this paper might be suitable for the forthcoming researchers functioning on this heterocyclic scaffold as possible anticancer agents. Information compiled in this paper can be helpful for medicinal chemists and other researchers for further exploration of these heterocyclic compounds as possible anticancer agents.