Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017–2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.

As breast cancer remains a significant challenge for the current medical field, molecules with a 4-thiazolidinone scaffold can become promising candidates for addressing the increasing threat of cancer. This study aims to develop and evaluate the novel 4-thiazolidinone derivatives with anticancer potential. New compounds were synthesized through two different pathways, one as a two-step process and the other as a one-pot method. The second approach fits the requirements of cost-effective methodologies and allows for the reduction of synthetic steps, reagents, and reaction time. The obtained data from in vitro research showed a potent cytotoxic activity of the novel structures in micromolar concentrations against MCF-7 breast cancer cells. Further investigations into their anticancer activity revealed that the tested compounds induced apoptosis through intrinsic and extrinsic pathways, which was evidenced by their capability to reduce the mitochondrial membrane potential and induce the activation of caspases 7, 8, 9, and 10. A more detailed analysis uncovered that one of the novel compounds can affect the expression of key apoptotic proteins, tumor protein P53 (p53), cytochrome C, and Bax in treated cells. Additionally, these compounds displayed an enhanced generation of reactive oxygen species (ROS) in MCF-7 cells, which suggests that ROS-mediated mechanisms can take part in the anticancer potential of the synthesized compounds.

Background/Objectives: Cancer persists as a leading concern in the current medical field. As such, scientists are continuously researching new compounds with anticancer potential. In this study, we explored fifteen new 4-thiazolidinone derivatives as potential anticancer compounds. 4-Thiazolidinones are a well-established group of active structures, most commonly applied for the treatment of Parkinson’s disease and diabetic neuropathy. However, they are actively researched as potential anticancer agents. A number of derivatives have qualified for Phase II and III clinical trials as antitumor agents. Methods: MTT cytotoxicity assay was applied to identify the most active compounds. Three out of the fifteen tested structures displayed a significant inhibitory effect on the MCF-7 and MDA-MB-231 cell lines. To further investigate the influence of compounds on breast cancer cells, we analyzed their capability to induce apoptosis using flow cytometry assessment with Annexin V and propidium iodide dyes. Next, flow cytometry analysis of JC-1 dye was utilized to research their capability to affect mitochondrial membrane. Afterwards, concentrations of important proapoptotic proteins such as Bax and cytochrome C were assessed with a highly sensitive ELISA method. Results: Further analysis with a fluorescent microscope displayed that novel compounds significantly increase the generation of reactive oxygen species. Conclusions: The results represented in this article displayed that the most active compounds positively affected the activation of the intrinsic apoptotic pathway in the tested breast cancer cells.

With global cancer cases projected to reach 35 million by 2050 and drug resistance to existing chemotherapeutic drugs remaining a significant threat in cancer therapy, accounting for up to 90% of chemotherapy failures, the search for novel anticancer compounds continues to be increasingly important. This systematic review (2021–2025) examined the role of thiazoles and 4-thiazolidinones/thiazolidinediones as popular scaffolds in existing anticancer drug design. While researchers continue to focus on well-established molecular targets, such as EGFR, VEGFR-2, and tubulin, there is a notable difference regarding other preferred choices for thiazoles and 4-thiazolidinones/thiazolidinediones. Among analyzed mechanisms of anticancer activity notably favored for thiazoles was the inhibition of serine/threonine protein kinases (CDK-2, BRAF^V600E), while for 4-thiazolidinones/thiazolidinediones more studied were ROS generation and PPARγ activation. Furthermore, less-researched mechanisms of anticancer activity with no FDA-approved drugs such as PTP1B, SIRT2, PKM2, eIF4E, CA XI and XII inhibition for thiazole derivatives and pan-PIM kinase and BAG3 protein inhibition for 4-thiazolidinones/thiazolidinediones were evaluated as well. Notable was the popularity of the multi-targeting approach for modern drug design, with ~30% reporting two or more targets for their compounds. Despite these advancements, the review identified critical gaps in ADMET evaluations, safety analyzing against normal human cells and the lack of mechanistic studies connecting the targeted protein and the compounds anticancer effects.

4-Thiazolidinone derivatives, a group of compounds with a broad spectrum of activity and anticancer properties, are used in medicine as anti-inflammatory, antiviral, antibacterial, antidiabetic, and blood pressure-lowering drugs; some of them are now in phase II and III clinical trials as anticancer drugs. Here, we evaluated the anticancer potential of 4-thiazolidinones (2b, 12b, 14b) targeting tubulin and metastasis-related pathways in breast cancer models. Molecular docking revealed that compound 14b exhibited the strongest binding affinity to the paclitaxel-binding site of β-tubulin, outperforming 2b and 12b, though slightly weaker than Taxol. Biological assays confirmed significant tubulin inhibition, with 14b reducing β-tubulin levels up to eight-fold in MCF-7 cells and two-fold in MDA-MB-231 cells. All compounds promoted tubulin polymerization, showing paclitaxel-like activity, with comparable the maximum velocity (V_max) values. Cell cycle analysis demonstrated G2/M arrest in MCF-7 cells and S-phase accumulation in MDA-MB-231 cells. Overall, compound 14b demonstrated the most promising multitarget anticancer activity in vitro.

Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and high chemoresistance partly associated with β-tubulin overexpression. In this study, we synthesized and biologically evaluated a series of 4-thiazolidinone derivatives, identifying Les-6666 and Les-5549 as potent anticancer candidates. An optimized microwave-assisted synthetic protocol enabled efficient and environmentally friendly production of selected derivatives. In silico ADMET profiling predicted favorable drug-like properties, high gastrointestinal absorption, and no blood-brain barrier penetration. Molecular docking studies revealed strong binding affinity of selected compounds to the colchicine and combretastatin A4 (CA4) sites of β-tubulin. Biological evaluation through the NCI-60 screening program demonstrated pronounced antiproliferative activity, with Les-6666 exhibiting submicromolar GI₅₀ values across multiple cancer cell lines. In pancreatic MIA PaCa-2 cells, both Les-6666 and Les-5549 showed potent cytotoxicity (IC₅₀ = 0.08 μM and 0.10 μM, respectively), inhibited DNA synthesis, suppressed clonogenic survival, reduced migration, arrested cells at the G₂/M phase of the cell cycle and induced apoptosis. Tubulin polymerization assays confirmed significant depolymerizing activity comparable to CA4. Furthermore, Les-6666 reduced β-tubulin protein expression, consistent with tubulin autoregulatory feedback mechanisms. Collectively, these findings identify Les-6666 as a promising antiproliferative agent that inhibits tubulin polymerization in pancreatic cancer cells warranting further investigation.