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Enhanced Proapoptotic Effects of Water Dispersed Complexes of 4-Thiazolidinone-Based Chemotherapeutics with a PEG-Containing Polymeric Nanocarrier

Aim: To study whether water formulation of the complex of 4-thiazolidinone derivatives with a PEG-containing polymeric nanocarrier enhances their pro-apoptotic action towards rat glioma C6 cells. Methods: Mechanisms of antineoplastic effects of 4-thiazolidinone derivatives were investigated in vitro with rat glioma C6 cells. Cell nativity, cell cycling pattern, and Annexin V expression were evaluated and DNA damage was estimated by DNA comet analysis. A novel water-based formulation of 4-thiazolidinone derivatives complexed with a polymeric nanocarrier was utilized for enhancing pro-apoptotic action towards C6 cells. Results: The studied 4-thiazolidinone derivatives use apoptosis mechanisms for killing rat glioma C6 cells, as confirmed by FACS analysis of these cells in pre-G1 stage, the appearance of Annexin V positive C6 cells, and an increased number of DNA comets of higher classes. Complexation of the studied compounds with a PEG-containing polymeric nanocarrier significantly increased pro-apoptotic effects in rat glioma C6 cells measured by all methods mentioned above. Conclusion: Complexation of 4-thiazolidinone derivatives with a PEG-containing polymeric nanocarrier provided them with water solubility and enhanced pro-apoptotic effects in rat glioma C6 cells.

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Synthesis of new 1, 8-dioxo-octahydroxanthene derivatives containing 4-Thiazolidinone moiety

A series of novel 1, 8-dioxo-octahydroxanthene derivatives containing 4-thiazolidinone framework (4a-f) were synthesized through a four-step reaction starting from the reduction of nitro derivatives of 1, 8-dioxo-octahydroxanthenes. The resulting aminoxanthenes converted to thiourea derivatives via their reaction with methyl isothiocyanate. The final products were synthesized through the reaction of thiourea derivatives with dialkylacetylene dicarboxylates. All of the steps were carried out under easy and mild reaction conditions in the absence of expensive catalysts or esoteric starting materials. The structures of compounds 3a-c and the final products were characterized according to their physical constants, spectral data such as NMR, IR spectra and also elemental analysis.

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Design, synthesis and pharmacological evaluation of new series ofthiazole based thiazolidin-4-one derivatives

In the present investigation, a series of substituted 2-(6-methoxynaphthalen-1-yl)-3-(4-phenylthiazol-2- yl)thiazolidin-4-one (5a-f)have been prepared by the condensation of N-((6-methoxynaphthalen-1-yl)methylene)-4- phenylthiazol-2-amine (4a-f) with mercaptoacetic acid in zinc chloride and ethanol. The structures of newly synthesized compounds were confirmedby IR, 1H NMR, mass and elemental analysis. All the synthesized compounds were evaluated for anti-inflammatory (in-vitro) and antimicrobial activity.

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Structural features and inhibitors of bromodomains

Bromodomains are conserved structural modules responsible for recognizing acetylated-lysine residues on histone tails and other transcription-associated proteins, such as transcription factors and co-factors. Owing to their important functions in the regulation of ordered gene transcription in chromatin, bromodomains of the BET family proteins have recently been shown as druggable targets for a wide array of human diseases, including cancer and inflammation. Here we review the structural and functional features of the bromodomains and their small-molecule inhibitors. Additional new insights provided herein highlight the landscape of the ligand binding sites in the bromodomains that will hopefully facilitate further development of new inhibitors with optimal affinity and selectivity.

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Synthesis, characterization and pharmacological activity of new 2-imino ?thiazolidine-4-one derivatives

A new 2-iminothiazolidin-4-ones compound and its derivatives were synthesized and characterized by FT-IR, CHN, and1HNMR techniques. The target compounds were assessed for their anti-inflammatory and analgesic activities, and the study was performed using Swiss albino mice (25-30 g) for investigation. A hind edema model caused by carrageenan, while the analgesic activity was assessed using an acetic acid-induced writhing and a hot plate test evaluated the anti-inflammatory activity.

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2-(2-arylidenehydrazinyl) thiazol-4(5H)-ones as epidermal growth factor receptor inhibitors: A combined quantitative structure activity relationship and pharmacophore study

2-(2-Arylidenehydrazinyl) thiazol-4(5H)-ones having epidermal growth factor receptor (EGFR) inhibitory activity were subjected to quantitative structure activity relationship (QSAR) (2 and 3 dimensional) analysis and pharmacophore study in the present work. The best 2 dimensional (2D) QSAR model had r2 (squared correlation coefficient), q2 (cross validated correlation coefficient) and pred_r2 (predictive correlation coefficient) values of 0.8630, 0.7652 and 0.9533 respectively with Partial least square regression (PLSR) analysis. This model showed that count of number of nitrogen atoms separated from oxygen atom by four bonds (T_N_O_4) and Radius Of Gyration (size descriptor) descriptors contribute positively and count of number of any atoms separated from carbon atom by four bonds (T_T_C_4) contributes inversely to the biological activity. The k-nearest neighbor (kNN) method produced a significant 3 dimensional (3D) QSAR model exhibiting q2 and pred_r2 values of 0.6615 and 0.8833 respectively. PLSR gave a significant 3D QSAR model having r2, q2 and pred_r2 values of 0.8449, 0.7816 and 0.7834 respectively. Both 3D QSAR models depict the need of less bulky substituents at R2 position while PLSR 3D QSAR model also portrays the need of more bulky substituent at R4 position. The identified common pharmacophore features are one aromatic (AroC) and three hydrogen bond acceptors (HAc) obtained from Molsign and Pharmagist approaches. The present work may be useful for further lead optimization and designing of potent anticancer agents.

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2D QSAR analysis of substituted quinoxalines for their antitubercular and antileptospiral activities

Background: The Quantitative structure activity relationship for thirty two novel substituted quinoxalines was performed for their antitubercular (Mycobacterium tuberculosis H37Rv) and antileptospiral (Leptospirainterrogans) activities. The quinoxalines were substituted with azetidinones, thiazolidinones and fluoroquinolones. Several compounds exhibited good activity against both the infections and they all possess fluoroquinolone moiety with the quinoxaline. Methods: The models developed showed good linear relationship (r2 = 0.71-0.88), with an internal predictive ability (q2> 0.61) and good external predictive ability (pred_r2>0.71). The compounds were separated into a training set on which regression was performed and a test set on which the predictive ability of the model was tested. Other statistical parameters including Ro2, Ro?2, k, k? and Z-score were in the acceptable range. Results and Conclusion: The descriptors obtained explained the necessity of spatial orientation of atoms including branching and adjacency, presence of electronegative groups, balance between lipophilic elements and their binding strengths.

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Protein targets of thiazolidinone derivatives in Toxoplasma gondii and insights into their binding to ROP18 11 Medical and Health Sciences 1108 Medical Microbiology

Background: Thiazolidinone derivatives show inhibitory activity (IC50) against the Toxoplasma gondii parasite, as well as high selectivity with high therapeutic index. To disclose the target proteins of the thiazolidinone core in this parasite, we explored in silico the active sites of different T. gondii proteins and estimated the binding-free energy of reported thiazolidinone molecules with inhibitory effect on invasion and replication of the parasite inside host cells. This enabled us to describe some of the most suitable structural characteristics to design a compound derived from the thiazolidinone core. Results: The best binding affinity was observed in the active site of kinase proteins, we selected the active site of the T. gondii ROP18 kinase, because it is an important factor for the virulence and survival of the parasite. We present the possible effect of a derivative of thiazolidinone core in the active site of T. gondii ROP18 and described some characteristics of substituent groups that could improve the affinity and specificity of compounds derived from the thiazolidinone core against T. gondii. Conclusions: The results of our study suggest that compounds derived from the thiazolidinone core have a preference for protein kinases of T. gondii, being promising compounds for the development of new drugs with potential anti-toxoplasmosis activity. Our findings highlight the importance of use computational studies for the understanding of the action mechanism of compounds with biological activity.

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A convenient synthesis of thiazolidin-2-ones from thiazolidine-2-thiones: Antibiotic activity and revisiting the mechanism

Various substituted thiazolidin-2-ones were synthesized from the corresponding thiazolidine-2-thiones with bromoethanol in ethanol with sodium ethoxide as a base. The optimal reaction conditions and mechanism were reinvestigated in detail. The bioassay indicated that (S)-4-isobutyl and (S)-4-benzylthiazolidin-2-ones show certain inhibitive activities against Candida albicans and Escherichia coli. Supplemental materials are available for this article. Go to the publisher’s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

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Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids

The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.

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