Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of PPARG, P53 (tumor protein P53), and ATM (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except PPARG) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells.

Type 2 diabetes mellitus (T2DM) is a serious chronic disease with an alarmingly growing worldwide prevalence. Current treatment of T2DM mainly relies on drug combinations in order to control blood glucose levels and consequently prevent the onset of hyperglycaemia-related complications. The development of multiple-targeted drugs recently emerged as an attractive alternative to drug combinations for the treatment of complex diseases with multifactorial pathogenesis, such as T2DM. Protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AKR1B1) are two enzymes crucially involved in the development of T2DM and its chronic complications and, therefore, dual inhibitors targeted to both these enzymes could provide novel agents for the treatment of this complex pathological condition. In continuing our search for dual-targeted PTP1B/AKR1B1 inhibitors, we designed new (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids. Among them, 3-(4-phenylbutoxy)benzylidene derivatives 6f and 7f, endowed with interesting inhibitory activity against both targets, proved to control specific cellular pathways implicated in the development of T2DM and related complications.

Thiazolidinones are well-known heterocycles that demonstrate promising biological effects such as anticonvulsant activity. Hybridization of these chemicals with scaffold, which has necessary pharmacophores for binding to the benzodiazepine receptors, can prompt a novel structure possessing extensive anticonvulsant effects. In this study, novel derivatives of thiazolidinone as new benzodiazepine agonists were designed, synthesized, and biologically evaluated. Compound 5h, 4-chloro-2-(2-fluorophenoxy)-N-(4-oxo-2-(p-tolyl)thiazolidin-3-yl)benzamide, exhibited considerable anticonvulsant activity, proper sedative-hypnotic effect, no memory impairment, and no muscle relaxant effect. The pharmacological effects of the designed compounds were antagonized by flumazenil, which confirmed the benzodiazepine receptors\' involvement in their biological effects. Based on in silico calculations of ADME properties of our novel compounds, they could be active oral agents potentially. In this study, we designed novel structures by the hybridization of thiazolidinone moiety with scaffold which has necessary pharmacophores for binding to the benzodiazepine receptors. The results are very promising for developing new lead compounds as benzodiazepine agonists possess anticonvulsant effects.

Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1-17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.

A new series of 4-chloro-N-(2-(substitutedphenyl)-4-oxothiazolidin-3-yl)-2-phenoxybenzamide derivatives were designed, synthesized and biologically evaluated as anticonvulsant agents. The designed compounds have the main essential functional groups for binding to the benzodiazepine receptors and 4-thiazolidinone ring as an anticonvulsant pharmacophore. Some of the new synthesized compounds showed considerable anticonvulsant activity in electroshock and pentylenetetrazole-induced lethal convulsion tests. Compound 5i, 4-chloro-N-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)-2-phenoxybenzamide, with the best activity was selected for evaluation of other benzodiazepine pharmacological effects. This compound induced significant sedative-hypnotic activity. However, it does not impair the learning and memory in the experimental condition. Flumazenil was able to antagonize the sedative-hypnotic and anticonvulsant effects of compound 5i indicating that benzodiazepine receptors are highly involved in the pharmacological properties of the novel compounds.

P-glycoprotein (P-gp) is an active drug efflux pump, which exists widely in various MDR tumor cells, conferring drug resistance to tumor cells during chemotherapy. Some 4-thiazolidinone derivatives containing indolin-2-one moiety are novel anti-tumor compounds. The aim of this study was to evaluate the transport activity of P-gp towards 4-thiazolidinone derivatives containing indolin-2-one moiety (as mixtures of 2Z, 5Z and 2E, 5Z isomers) and the transport inhibition activities of the derivatives to P-gp, the results of which could provide crucial information for the further separation of and development on the derivatives with excellent anti-tumor activities. The results indicate that the further separation and development should be focused on compounds 7, 10, 12 and 13 (tumor cell cytotoxic P-gp modulators) and compounds 8, 9, 17 and 18 (non-substrates of P-gp), which exhibit anti-tumor activities and could overcome P-gp mediated MDR. Furthermore, the results of molecular docking indicate that Ser222, a residue in TM4 domain of P-gp, exhibits an intriguing feature in that it interacts with all of the derivatives related with P-gp transport in a significant way, including both typical substrates and modulators of P-gp. Meanwhile, the compounds showing no interaction with Ser222 are mainly from the category of non-substrates of P-gp. Therefore, the interaction between Ser222 and the tested derivative would provide useful information for the further development on 4-thiazolidinone derivatives containing indolin-2-one moiety.