November 2022 | Heterocyclic Building Blocks-Thiazolidine

Hildyard, John C. W.’s team published research in Biochimica et Biophysica Acta, Bioenergetics in 1707 | CAS: 853953-65-8

Biochimica et Biophysica Acta, Bioenergetics published new progress about 853953-65-8. 853953-65-8 belongs to thiazolidine, auxiliary class Metabolic Enzyme,MPC, name is 5-(5-(6-(4-Acetylpiperazin-1-yl)-3-nitropyridin-2-yl)-2-fluorobenzylidene)thiazolidine-2,4-dione, and the molecular formula is C21H18FN5O5S, COA of Formula: C21H18FN5O5S.

Hildyard, John C. W. published the artcileIdentification and characterization of a new class of highly specific and potent inhibitors of the mitochondrial pyruvate carrier, COA of Formula: C21H18FN5O5S, the publication is Biochimica et Biophysica Acta, Bioenergetics (2005), 1707(2-3), 221-230, database is CAplus and MEDLINE.

Two novel thiazolidine compounds, GW604714X and GW450863X, were found to be potent inhibitors of mitochondrial respiration supported by pyruvate but not other substrates. Direct measurement of pyruvate transport into rat liver and yeast mitochondria confirmed that these agents inhibited the mitochondrial pyruvate carrier (MPC) with K_i values <0.1 μM. Inhibitor titrations of pyruvate-dependent respiration by heart mitochondria gave values (±S.E.) for the concentration of inhibitor binding sites (pmol per mg protein) and their K_i (nM) of 56.0±0.9 and 0.057±0.010 nM for the more hydrophobic GW604714X; for GW450863X the values were 59.9±4.6 and 0.60±0.12 nM. [³H]-methoxy-GW450863X binding was also used to determine the MPC content of the heart, kidney, liver and brain mitochondria giving values of 56, 40, 26 and 20 pmol per mg protein resp. Binding to yeast mitochondria was <10% of that in rat liver mitochondria, consistent with the slow rate of pyruvate transport into yeast mitochondria. [³H]-methoxy-GW450863X binding was inhibited by GW604714X and by the established MPC inhibitor, UK5099. The absorbance spectra of GW450863X and GW604714X were markedly changed by the addition of β-mercaptoethanol suggesting that the novel inhibitors, like α-cyanocinnamate, possess an activated double bond that attacks a critical cysteine residue on the MPC. However, no labeled protein was detected following SDS-PAGE suggesting that the covalent modification is reversible. GW604714X and GW450863X inhibited L-lactate transport by the plasma membrane monocarboxylate transporter MCT1, but at concentrations more than four orders of magnitude greater than the MPC.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

He, Cheng-yan’s team published research in Chemical Research in Chinese Universities in 20 | CAS: 307510-92-5

Chemical Research in Chinese Universities published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, Category: thiazolidine.

He, Cheng-yan published the artcileSynthesis and characterization of a small molecule CFTR chloride channel inhibitor, Category: thiazolidine, the publication is Chemical Research in Chinese Universities (2004), 20(3), 334-337, database is CAplus.

A thiazolidinone CFTR inhibitor (CFTR_inh-172) was synthesized by a three-step procedure with trifluoromethylaniline as the starting material. The synthesized CFTR inhibitor was characterized structurally by ¹H-NMR and functionally in a CFTR-expressing cell line FRT/hCFTR/EYFP-H148Q by both fluorescent and electrophysiol. methods. A large amount (100 g) of high-quality small mol. thiazolidinone CFTR chloride channel inhibitor, CFTR_inh-172, can be produced with this simple three-step synthetic procedure. The structure of the final product 2-thioxo-3-(3-trifluoromethylphenyl)-5-[4-carboxyphenyl-methylene]-4-thiazolidinone was confirmed by ¹H NMR. The overall yield was 58% with a purity over 99% as analyzed by HPLC. The synthesized CFTR_inh-172 specifically inhibited CFTR chloride channel function in a cell-based fluorescence assay (K_d≈1.5 μmol/L) and in a Ussing chamber-based short-circuit current assay (K_d≈0.2 μmol/L), indicating better quality than that of the com. combinatorial compound The synthesized inhibitor is nontoxic to cultured cells at a high concentration and to mouse at a high dose. The synthetic procedure developed here can be used to produce a large amount of the high-quality CFTR_inh-172 suitable for antidiarrheal studies and for creation of cystic fibrosis models in large animals. The procedure can be used to synthesize radiolabeled CFTR_inh-172 for in vivo pharmacokinetics studies.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Nick, Heidi J.’s team published research in Scientific Reports in 11 | CAS: 307510-92-5

Scientific Reports published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, Formula: C18H10F3NO3S2.

Nick, Heidi J. published the artcileMeasurements of spontaneous CFTR-mediated ion transport without acute channel activation in airway epithelial cultures after modulator exposure, Formula: C18H10F3NO3S2, the publication is Scientific Reports (2021), 11(1), 22616, database is CAplus and MEDLINE.

Quantitation of CFTR function in vitro is commonly performed by acutely stimulating then inhibiting ion transport through CFTR and measuring the resulting changes in transepithelial voltage (V_te) and current (I_SC). While this technique is suitable for measuring the maximum functional capacity of CFTR, it may not provide an accurate estimate of in vivo CFTR activity. To test if CFTR-mediated ion transport could be measured in the absence of acute CFTR stimulation, primary airway epithelia were analyzed in an Ussing chamber with treatment of amiloride followed by CFTR(inh)-172 without acute activation of CFTR. Non-CF epithelia demonstrated a decrease in V_te and I_SC following exposure to CFTR(inh)-172 and in the absence of forskolin/IBMX (F/I); this decrease is interpreted as a measure of spontaneous CFTR activity present in these epithelia. In F508del/F508del CFTR epithelia, F/I-induced changes in V_te and I_SC were ∼ fourfold increased after treatment with VX-809/VX-770, while the magnitude of spontaneous CFTR activities were only ∼ 1.6-fold increased after VX-809/VX-770 treatment. Method-dependent discrepancies in the responses of other CF epithelia to modulator treatments were observed These results serve as a proof of concept for the anal. of CFTR modulator responses in vitro in the absence of acute CFTR activation. Future studies will determine the usefulness of this approach in the development of novel CFTR modulator therapies.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Leir, Shih-Hsing’s team published research in Cell & Tissue Research in 381 | CAS: 307510-92-5

Cell & Tissue Research published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, SDS of cas: 307510-92-5.

Leir, Shih-Hsing published the artcileAn organoid model to assay the role of CFTR in the human epididymis epithelium, SDS of cas: 307510-92-5, the publication is Cell & Tissue Research (2020), 381(2), 327-336, database is CAplus and MEDLINE.

Abstract: Organoid cultures derived from primary human tissues facilitate the study of disease processes and the development of new therapeutics. We used human epididymis epithelial cell (HEE) organoids and polarized HEE cell cultures to assay the CF transmembrane conductance regulator (CFTR) in the human epididymis. 3D HEE organoids and polarized 2D HEE cell cultures on membrane inserts were established from human caput epididymis. Single-cell RNA sequencing (scRNA-seq) was performed to map cell type-specific gene expression in the organoids. Using forskolin (FSK) to activate CFTR and inhibitor CFTRinh₁₇₂ to block its activity, we assessed how CFTR contributes to organoid swelling and epithelial barrier function. The scRNA-seq data showed key caput epididymis cell types present in HEE organoid cultures. FSK at 10 μM induced HEE organoid swelling by 20% at 16 h, while 5 and 10 μM CFTRinh₁₇₂ treatment significantly reduced HEE organoid size. FSK treatment significantly increased the flux of 4-kDa but not 70-kDa dextran, suggesting activation of CFTR mainly enhances transcellular diffusion. We have demonstrated that CFTR contributes to the maintenance of HEE cell TER and that cultured HEE organoids are a useful model to investigate human epididymis function. These results facilitate progress in elucidating how CFTR-dependent cellular processes impair fertility in CF.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Xu, Qianqian’s team published research in Zhongguo Yaoshi (Wuhan, China) in 18 | CAS: 307510-92-5

Zhongguo Yaoshi (Wuhan, China) published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C9H17NO, Safety of 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid.

Xu, Qianqian published the artcileApplication progress in CFTR inhibitors in the treatment of secretory diarrhea, Safety of 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, the publication is Zhongguo Yaoshi (Wuhan, China) (2015), 18(8), 1378-1382, database is CAplus.

A review. Secretory diarrhea provided a major health challenge worldwide which was one of the most important reasons for children morbidity and death. The activation of Cl^– channels in intestinal epithelial cells resulting in the excessive fluid secretion in the intestine was the main reason of diarrhea caused by enterotoxins. In diarrhea caused by cholera and the other bacterial enterotoxins, cystic fibrosis transmembrane conductance regulator (CFTR) was the main cAMP-control Cl^– channel to promote the fluid secretion in epithelial cells. Therefore, CFTR inhibitors were the new choices for secretory diarrhea. CFTR inhibitors included thiazolidinone, glycine hydrazide and quinoxalinedione chem. classes, and some components from natural plants also exhibited CFTR inhibition activity, however, further studies should be done.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Tian, Sheng’s team published research in Molecular Pharmaceutics in 9 | CAS: 307510-92-5

Molecular Pharmaceutics published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C8H6ClN, Application of 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid.

Tian, Sheng published the artcileDrug-likeness Analysis of Traditional Chinese Medicines: Prediction of Drug-likeness Using Machine Learning Approaches, Application of 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, the publication is Molecular Pharmaceutics (2012), 9(10), 2875-2886, database is CAplus and MEDLINE.

Quant. or qual. characterization of the drug-like features of known drugs may help medicinal and computational chemists to select higher quality drug leads from a huge pool of compounds and to improve the efficiency of drug design pipelines. For this purpose, the theor. models for drug-likeness to discriminate between drug-like and non-drug-like based on mol. physicochem. properties and structural fingerprints were developed by using the naive Bayesian classification (NBC) and recursive partitioning (RP) techniques, and then the drug-likeness of the compounds from the Traditional Chinese Medicine Compound Database (TCMCD) was evaluated. First, the impact of mol. physicochem. properties and structural fingerprints on the prediction accuracy of drug-likeness was examined We found that, compared with simple mol. properties, structural fingerprints were more essential for the accurate prediction of drug-likeness. Then, a variety of Bayesian classifiers were constructed by changing the ratio of drug-like to non-drug-like mols. and the size of the training set. The results indicate that the prediction accuracy of the Bayesian classifiers was closely related to the size and the degree of the balance of the training set. When a balanced training set was used, the best Bayesian classifier based on 21 physicochem. properties and the LCFP_6 fingerprint set yielded an overall leave-one-out (LOO) cross-validated accuracy of 91.4% for the 140,000 mols. in the training set and 90.9% for the 40,000 mols. in the test set. In addition, the RP classifiers with different maximum depth were constructed and compared with the Bayesian classifiers, and we found that the best Bayesian classifier outperformed the best RP model with respect to overall prediction accuracy. Moreover, the Bayesian classifier employing structural fingerprints highlights the important substructures favorable or unfavorable for drug-likeness, offering extra valuable information for getting high quality lead compounds in the early stage of the drug design/discovery process. Finally, the best Bayesian classifier was used to predict the drug-likeness of 33,961 compounds in TCMCD. Our calculations show that 59.37% of the mols. in TCMCD were identified as drug-like mols., indicating that traditional Chinese medicines (TCMs) are therefore an excellent source of drug-like mols. Furthermore, the important structural fingerprints in TCMCD were detected and analyzed. Considering that the pharmacol. of TCMCD and MDDR (MDL Drug Data Report) was linked by the important common structural features, the potential pharmacol. of the compounds in TCMCD may therefore be annotated by these important structural signatures identified from Bayesian anal., which may be valuable to promote the development of TCMs.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Begrow, Frank’s team published research in Pharmacology & Pharmacy in 4 | CAS: 307510-92-5

Pharmacology & Pharmacy published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, HPLC of Formula: 307510-92-5.

Begrow, Frank published the artcileEffect of Ap4A, UTP and Salbutamol on mucociliary clearance in a mouse model of cystic fibrosis (in situ), HPLC of Formula: 307510-92-5, the publication is Pharmacology & Pharmacy (2013), 4(2), 176-181, 6 pp., database is CAplus.

Cystic fibrosis is a life-threatening, wide spread genetic disease diagnosed in 1 to 3000 live births of the Caucasian population. Here a mouse model for this disease is described and optimized using the CFTR-channel selective inhibitor CFTR(inh 172). The target parameter was mucociliary clearance measured using microdialysis of the transported fluorescent dye rhodamine in the mouse trachea in situ. The impact of Ap4A (diadenosine tetraphosphate) as a potential drug was investigated. Its inhalation was effective at low concentrations; established compounds such as Salbutamol and UTP increased mucociliary clearance as well. Our data show a functioning model of cystic fibrosis and the effectiveness of the newly tested Ap4A.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Buyck, J. M.’s team published research in Journal of Cystic Fibrosis in 12 | CAS: 307510-92-5

Journal of Cystic Fibrosis published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, Category: thiazolidine.

Buyck, J. M. published the artcileP. aeruginosa LPS stimulates calcium signaling and chloride secretion via CFTR in human bronchial epithelial cells, Category: thiazolidine, the publication is Journal of Cystic Fibrosis (2013), 12(1), 60-67, database is CAplus and MEDLINE.

Background: Pseudomonas aeruginosa airway infection is associated with a high mortality rate in cystic fibrosis. Lipopolysaccharide (LPS), a main constituent of the outer membrane of P. aeruginosa, is responsible for activation of innate immune response but its role on airway epithelium ion transport, is not well known. The aim of this study was to determine the role for P. aeruginosa LPS in modulating chloride secretion and intracellular calcium in the human bronchial epithelial cell line, 16HBE14o -. Methods: We used intracellular calcium imaging and short-circuit current measurement upon exposure of cells to P. aeruginosa LPS. Results: Apical LPS stimulated intracellular calcium release and calcium entry and enhanced chloride secretion. This latter effect was significantly inhibited by CFTR(inh)-172 and BAPTA-AM (intracellular Ca² ⁺ chelator). Conclusions: Our data provides evidence for a new role of P. aeruginosa LPS in stimulating calcium entry and release and a subsequent chloride secretion via CFTR in human bronchial epithelium.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Sonawane, N. D.’s team published research in Bioorganic & Medicinal Chemistry in 16 | CAS: 307510-92-5

Bioorganic & Medicinal Chemistry published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C19H36BNO2Si, HPLC of Formula: 307510-92-5.

Sonawane, N. D. published the artcileThiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis, HPLC of Formula: 307510-92-5, the publication is Bioorganic & Medicinal Chemistry (2008), 16(17), 8187-8195, database is CAplus and MEDLINE.

The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTR_inh-172) inhibits cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTR_inh-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modifications in its two Ph rings, thiazolidinone core, and core-Ph connectors. Greatest CFTR inhibition potency was found for 3-CF₃ and polar group-substituted-Ph rings, and a thiazolidinone core. Two compounds with ∼1 μM CFTR inhibition potency and solubility >180 μM (>10-fold more than CFTR_inh-172) were identified: Tetrazolo-172, containing 4-tetrazolophenyl in place of 4-carboxyphenyl, and Oxo-172, containing thiazolidinedione in place of the thiazolidinone core. These water soluble thiazolidinone analogs had low cellular toxicity. The improved water solubility of Tetrazolo- and Oxo-172 make them potential lead candidates for therapy of secretory diarrheas and polycystic kidney disease.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Kelly, Mairead’s team published research in Journal of Pharmacology and Experimental Therapeutics in 333 | CAS: 307510-92-5

Journal of Pharmacology and Experimental Therapeutics published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, HPLC of Formula: 307510-92-5.

Kelly, Mairead published the artcileCystic fibrosis transmembrane regulator inhibitors CFTR_inh-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition, HPLC of Formula: 307510-92-5, the publication is Journal of Pharmacology and Experimental Therapeutics (2010), 333(1), 60-69, database is CAplus and MEDLINE.

Two highly potent and selective cystic fibrosis (CF) transmembrane regulator (CFTR) inhibitors have been identified by high-throughput screening: the thiazolidinone CFTR_inh-172 [3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone] and the glycine hydrazide GlyH-101 [N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide]. Inhibition of the CFTR chloride channel by these compounds has been suggested to be of pharmacol. interest in the treatment of secretory diarrheas and polycystic kidney disease. In addition, functional inhibition of CFTR by CFTR_inh-172 has been proposed to be sufficient to mimic the CF inflammatory profile. In the present study, we investigated the effects of the two compounds on reactive oxygen species (ROS) production and mitochondrial membrane potential in several cell lines: the CFTR-deficient human lung epithelial IB3-1 (expressing the heterozygous F508del/W1282X mutation), the isogenic CFTR-corrected C38, and HeLa and A549 as non-CFTR-expressing controls. Both inhibitors were able to induce a rapid increase in ROS levels and depolarize mitochondria in the four cell types, suggesting that these effects are independent of CFTR inhibition. In HeLa cells, these events were associated with a decrease in the rate of oxygen consumption, with GlyH-101 demonstrating a higher potency than CFTR_inh-172. The impact of CFTR inhibitors on inflammatory parameters was also tested in HeLa cells. CFTR_inh-172, but not GlyH-101, induced nuclear translocation of nuclear factor-κB (NF-κB). CFTR_inh-172 slightly decreased interleukin-8 secretion, whereas GlyH-101 induced a slight increase. These results support the conclusion that CFTR inhibitors may exert nonspecific effects regarding ROS production, mitochondrial failure, and activation of the NF-κB signaling pathway, independently of CFTR inhibition.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com