A series of thiazolidine derivatives were designed by docking into PPAR-γ active site. The structure of target was obtained from the protein data bank (PDB ID P37231). A library of 200 molecules was prepared on random basis. Molecular docking studies were performed using VLife MDS 4.3 software. After molecular docking studies, the 4-substituted-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid N-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-hydrazides (4a-4h) were selected for synthesis. The progress of reaction and purity of the synthesized compounds were monitored by TLC and melting point. Structures of title compounds were confirmed by elemental analysis, IR, 1H NMR and mass spectral data. The antidiabetic activity of title compounds was performed using the Wistar rats by alloxan-induced method. The compounds have shown antidiabetic activity comparable with the standard drug pioglitazone. These findings suggest that potent antidiabetics can be generated by substituting nonpolar, electron withdrawing substituents at the fourth position of pyrimidine skeleton and hydrogen bond acceptor at the nitrogen of the thiazolidine nucleus, to inhibit peroxisome proliferator-activated receptor-γ.

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2-15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC50 values using an MTT assay.

Sodium-glucose cotransporter 2 inhibitors, as well as thiazolidines, suppress nonalcoholic fatty liver disease (NAFLD); however, few comparative studies have been reported. Dapagliflozin has shown non-inferiority compared with pioglitazone for glycemic control, and superiority regarding weight reduction in patients with type 2 diabetes. We carried out a secondary analysis for the favorable effects of sodium-glucose cotransporter inhibitors for NAFLD.

Molecules bearing indole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated both to DNA and protein interactions. This study focused on the synthesis of new indole derivatives with thiazolidines and imidazolidine rings condensed as side chains as well as the evaluation of their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized and their structures were elucidated by mass spectrometry (MS), infrared (IR), spectroscopy 1H NMR, 13C NMR, COSY 1H-1H and HSQC 1H-13C. The antitumor activity was evaluated against different cancer cell lines using the antiproliferative MTT assay. DNA binding ability was analyzed by absorption spectroscopy and fluorescence technique using ethidium bromide (EB) as a fluorescent probe. Changes were observed in spectroscopic properties of the compounds after interacting with ctDNA (calf thymus DNA), with hypochromic and hyperchromic effects, besides blue or red shifts in the maxima of spectra. The indole derivative 5-(1H-Indol-3-ylmethylene)-thiazolidin-2,4-dione (4c) presented the best results in antitumor assay against the breast line tested (T47D), with IC50 value lower than the positive control, doxorubicin (1.93 and 4.61 μM, respectively). On the other hand, the compound 3-amino-5-(1H-indol-3-ylmethylene)-2-thioxo-thiazolidin-4-one (4a) was active against leukemia cell lines (HL60 and K562) with the high value of the DNA binding constant, Kb of 5.69 × 104. However, this compound (4a) did not inhibit the topoisomerase-I activity evaluated by relaxation assay. These results show that the indole nucleus contribute to the incorporation of molecules into the DNA. Moreover, it was highlighted that basic side chains, such as thiazolidines and imidazolidines, and free amino group, are relevant for design of promising antitumor and DNA binding compounds.

We have previously reported the synthesis, in vitro and in silico activities of new GABA analogues as inhibitors of the GABA-AT enzyme from Pseudomonas fluorescens, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds. With the goal of finding more potent inhibitors, we now report the synthesis of a new set of GABA analogues with a broader variation of heterocyclic scaffolds at the γ-position such as thiazolidines, methyl-substituted piperidines, morpholine and thiomorpholine and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These structural modifications led to compound 9b which showed a 73% inhibition against this enzyme. In vivo studies with PTZ-induced seizures on male CD1 mice show that compound 9b has a neuroprotective effect at a 0.50 mmole/kg dose. A QSAR study was carried out to find the molecular descriptors associated with the structural changes in the GABA scaffold to explain their inhibitory activity against GABA-AT. Employing 3D molecular descriptors allowed us to propose the GABA analogues enantiomeric active form. To evaluate the interaction with Pseudomonas fluorescens and human GABA-AT by molecular docking, the constructions of homology models was carried out. From these calculations, 9b showed a strong interaction with both GABA-AT enzymes in agreement with experimental results and the QSAR model, which indicates that bulky ligands tend to be the better inhibitors especially those with a sulfur atom on their structure.

A series of bis-thiazoles 5a-g were synthesized from bis-thiosemicarbazone 3 with hydrazonoyl chlorides 4a-g. Reaction of 3 with two equivalents of α-halocarbonyl compounds 6-8, 10, and 12a-d afforded the corresponding bis-thiazolidines 9, 11, and 13a-d, respectively. Condensation of bis-thiazolidin-4-one 9 with different aromatic aldehydes furnished bis-thiazolidin-4-ones 14a-d. Compounds 5a-g, 9, and 13a,c,d were screened in vitro for their cytotoxic activities in a panel of cancer cell lines. Compounds 5a-c, 5f-g, and 9 exhibited remarkable cytotoxic activities, especially compound 5c with potent IC50 value 0.6 nM (against cervical cancer, Hela cell line) and compound 5f with high IC50 value 6 nM (against ovarian cancer, KF-28 cell line). Compound 5f-induced appreciated apoptotic cell death was measured as 82.76% associated with cell cycle arrest at the G1 phase. The apoptotic pathways activated in KF-28 cells treated with 5a, 5b, and 5f were further investigated. The upregulation of some pro-apoptotic genes, bax and puma, and the downregulation of some anti-apoptotic genes including the Bcl-2 gene were observed, indicating activation of the mitochondrial-dependent apoptosis. Together with the molecular docking studies of compounds 5a and 5b, our data revealed potential Pim-1 kinase inhibition through their high binding affinities indicated by inhibition of phosphorylated C-myc as a downstream target for Pim-1 kinase. Our study introduces a set of bis-thiazoles with potent anti-cancer activities, in vitro.