- A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4-Thiazolidinedione-Based Molecules as New Dual mPGES-1/5-LO Inhibitors
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Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (~2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile.
- Bifulco, Giuseppe,Bruno, Ines,Cantone, Vincenza,Fischer, Katrin,Lauro, Gianluigi,Pace, Simona,Ruggiero, Dafne,Terracciano, Stefania,Werz, Oliver
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- Synthesis and structure-activity relationship studies of 2,4-thiazolidinediones and analogous heterocycles as inhibitors of dihydrodipicolinate synthase
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Dihydrodipicolinate synthase (DHDPS), responsible for the first committed step of the diaminopimelate pathway for lysine biosynthesis, has become an attractive target for the development of new antibacterial and herbicidal agents. Herein, we report the di
- Christoff, Rebecca M.,Soares da Costa, Tatiana P.,Bayat, Saadi,Holien, Jessica K.,Perugini, Matthew A.,Abbott, Belinda M.
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supporting information
(2021/11/27)
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- Novel thiazolidinedione-hydroxamates as inhibitors of Mycobacterium tuberculosis virulence factor Zmp1
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Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS. Nine of the tested compounds were found to inhibit the enzymatic reaction more effectively than the generic metalloprotease inhibitor phosphoramidon. Furthermore, the synthesized thiazolidinedione-hydroxamate hybrids were evaluated for their in vitro antimycobacterial activity and acute cytotoxicity using whole-cell assays. Results showed that none of the hybrids exhibited acute cytotoxicity against RAW264.7 macrophages. Whereas extracellular antimycobacterial activity was limited, RAW264.7 macrophage infection results showed that a majority of the hybrids inhibited the intracellular growth of Mycobacterium tuberculosis at a concentration of 100 and 10 μM. The thiazolidinedione-hydroxamate compound 2n was considered to be the best candidate of the evaluated library.
- ?lachtová, Veronika,?ebela, Marek,Torfs, Eveline,Oorts, Lauren,Cappoen, Davie,Berka, Karel,Bazgier, Václav,Brulíková, Lucie
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- Synthesis and biological evaluation of thiazolidine-2,4-dione-pyrazole conjugates as antidiabetic, anti-inflammatory and antioxidant agents
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A series of fourteen novel thiazolidine-2,4-dione derivatives clubbed with pyrazole moiety were synthesized via four step reaction procedure. Reactions were monitored by thin layer chromatography and were characterized by physicochemical and spectrophotometric (IR, Mass, 1HNMR and 13CNMR) analysis. The spectral data were in good agreement with their structures. The title compounds were docked against peroxisome proliferated activated receptors (PPAR-γ) and alpha-amylase and further evaluated for in vivo and in vitro antidiabetic, in vitro anti-inflammatory and antioxidant activities. Compound GB14 exhibited significant blood glucose lowering activity and was also found to be active inhibitor of alpha-amylase. Compound GB7 was found to be potent anti-inflammatory agent in terms of reducing inflammatory markers (TNF-α, IL-β, MDA) and also showed antioxidant activity to good extent. Therefore, these compounds may be considered as promising candidates for the development of new antidiabetic agents.
- Bansal, Garima,Singh, Shamsher,Monga, Vikramdeep,Thanikachalam, Punniyakoti Veeraveedu,Chawla, Pooja
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- New thiazolidine-2,4-dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity
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Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine-2,4-dione framework (TZD-4) prompted us to explore compounds containing both the thiazolidine-2,4-dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene-based thiazolidine-2,4-dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine-resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD-4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD-4 against the P. falciparum parasite. All the synthesised compounds were non-toxic and often showed >90% viability of the HeLa cell line screened.
- Oderinlo, Ogunyemi O.,Tukulula, Matshawandile,Isaacs, Michelle,Hoppe, Heinrich C.,Taylor, Dale,Smith, Vincent J.,Khanye, Setshaba D.
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- HETEROCYCLIC INHIBITORS OF LYSINE BIOSYNTHESIS VIA THE DIAMINOPIMELATE PATHWAY
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The present invention relates to certain heterocyclic compounds of formula (1) that have the ability to inhibit lysine biosynthesis via the diaminopimelate biosynthesis pathway in certain organisms. As a result of this activity these compounds can be used
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Paragraph 0117
(2018/11/10)
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- Structural exploration, synthesis and pharmacological evaluation of novel 5-benzylidenethiazolidine-2,4-dione derivatives as iNOS inhibitors against inflammatory diseases
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In our previous work, 3I inhibited the LPS-induced iNOS activity and NO production in RAW 264.7 cells and improved joint inflammation and cartilage destruction in inflammatory model. In this study, we synthesized 59 derivatives and bioisosteres on the bas
- Ma, Liang,Pei, Heying,Lei, Lei,He, Linhong,Chen, Jinying,Liang, Xiaolin,Peng, Aihua,Ye, Haoyu,Xiang, Mingli,Chen, Lijuan
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supporting information
p. 178 - 190
(2015/03/13)
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- Synthesis and structure-activity-relationship studies of thiazolidinediones as antiplasmodial inhibitors of the Plasmodium falciparum cysteine protease falcipain-2
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Following a structure-based virtual screening, a series of 2,4 thiazolidinediones was synthesized in order to explore structure activity relationships for inhibition of the Plasmodium falciparum cysteine protease falcipain-2 (FP-2) and of whole cell antiparasitic activity. Most compounds exhibited low micromolar antiplasmodial activities against the P. falciparum drug resistant W2 strain. The most active compounds of the series were tested for in vitro microsomal metabolic stability and found to be susceptible to hepatic metabolism. Subsequent metabolite identification studies highlighted the metabolic hot spots. Molecular docking studies of a frontrunner inhibitor were carried out to determine the probable binding mode of this class of inhibitors in the active site of FP-2.
- Sharma, Rajni Kant,Younis, Yassir,Mugumbate, Grace,Njoroge, Mathew,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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p. 507 - 518
(2015/02/19)
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- Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles
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The thiazolidine and imidazolidine heterocyclic scaffolds, i.e., the rhodanines, 2,4-thiazolidinediones, 2-thiohydantoins, and hydantoins have been the subject of debate on their suitability as starting points in drug discovery. This attention arose from the wide variety of biological activities exhibited by these scaffolds and their frequent occurrence as hits in screening campaigns. Studies have been conducted to evaluate their value in drug discovery in terms of their biological activity, chemical reactivity, aggregation-based promiscuity, and electronic properties. However, the metabolic profiles and toxicities have not been systematically assessed. In this study, a series of five-membered multiheterocyclic (FMMH) compounds were selected for a systematic evaluation of their metabolic profiles and toxicities on TAMH cells, a metabolically competent rodent liver cell line and HepG2 cells, a model of human hepatocytes. Our studies showed that generally the rhodanines are the most toxic, followed by the thiazolidinediones, thiohydantoins, and hydantoins. However, not all compounds within the family of heterocycles were toxic. In terms of metabolic stability, 5-substituted rhodanines and 5-benzylidene thiohydantoins were found to have short half-lives in the presence of human liver microsomes (t1/2 30 min) suggesting that the presence of the endocyclic sulfur and thiocarbonyl group or a combination of C5 benzylidene substituent and thiocarbonyl group in these heterocycles could be recognition motifs for P450 metabolism. However, the stability of these compounds could be improved by installing hydrophilic functional groups. Therefore, the toxicities and metabolic profiles of FMMH derivatives will ultimately depend on the overall chemical entity, and a blanket statement on the effect of the FMMH scaffold on toxicity or metabolic stability cannot and should not be made.
- Tang, Shi Qing,Lee, Yong Yang Irvin,Packiaraj, David Sheela,Ho, Han Kiat,Chai, Christina Li Lin
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p. 2019 - 2033
(2015/11/02)
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- Synthesis, characterization, and biological evaluation of thiazolidine-2,4-dione derivatives
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As a part of our continuation studies in developing new derivatives as dual antimicrobial/antitumor agents we describe the synthesis of new (Z)-2-(5-arylidene-2,4-dioxothiazolidin-3-yl) acetic acid derivatives (3a-m). The chemical structures of the compound were elucidated by FTIR, 1H NMR, 13C NMR, and elemental analysis data. The antimicrobial activity of all products was examined. All newly synthesized compounds were tested for their in vitro anticancer activity against four cancer cell lines. Among the synthesized compounds, 3a exhibited notable activity against HeLa, HT29, A549, and MCF-7 cell lines with IC50 values of 55, 40, 38, and 50 μM, respectively. In order to predict the drug likeliness of the synthesized compounds on the guidelines of Lipinski rule of five studies was carried out using Pallas software.
- Alegaon, Shankar G.,Alagawadi, Kallanagouda R.,Pawar, Sneha M.,Vinod,Rajput, Udaysingh
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p. 987 - 994
(2014/03/21)
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- Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents
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A series of 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives (6-9) were synthesized as inhibitors of aldose reductase (AR), enzyme which plays a crucial role in the development of diabetes complications as well as in the inflammat
- Maccari, Rosanna,Vitale, Rosa Maria,Ottanà, Rosaria,Rocchiccioli, Marco,Marrazzo, Agostino,Cardile, Venera,Graziano, Adriana Carol Eleonora,Amodeo, Pietro,Mura, Umberto,Del Corso, Antonella
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- 5-Arylidene-4-thiazolidinone derivatives active as antidegenerative agents on human chondrocyte cultures
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5-Arylidene-2-oxo-4-thiazolidinones and 2-phenylimino analogues were evaluated for their antidegenerative activity on human chondrocyte cultures stimulated by IL-1β and for their inhibitory capability against matrix metalloproteinase- 13. Our results indicated that 5-arylidene-4-thiazolidinone derivatives 1-9 exhibit antidegenerative activity and could block multiple cartilage destruction during the osteoarthritic process. Out of the selected compounds, (5-arylidene- 2,4-dioxothiazolidin-3-yl)acetic acids 7-9 showed significant effectiveness in reducing NO release and restoring normal levels of GAGs in chondrocytes treated with IL-1β. Moreover, benzoic acids 1, 5 and 6 proved to be effective MMP-13 inhibitors and were able to restore normal levels of GAGs.
- Panico, Annamaria,MacCari, Rosanna,Cardile, Venera,Crascí, Lucia,Ronsisvalle, Simone,Ottanà, Rosaria
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- Synthesis of new potential anticancer agents based on 4-thiazolidinone and oleanane scaffolds
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The synthesis and evaluation of the anticancer activity of new acylated oximes derivatives of oleanolic acid with 4-thiazolidinone-3(5)-carboxylic acid moieties were described. Newly synthesized compounds were elucidated on the basis of elemental analyses
- Kaminskyy, Danylo,Bednarczyk-Cwynar, Barbara,Vasylenko, Olexandr,Kazakova, Oxana,Zimenkovsky, Borys,Zaprutko, Lucjusz,Lesyk, Roman
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p. 3568 - 3580
(2013/03/13)
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- Discovery of a novel submicromolar inhibitor of the lymphoid specific tyrosine phosphatase
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We report here a class of thiazolidine-2,4-diones and 2-thioxothiazolidin-4-ones as potent inhibitors of the lymphoid specific tyrosine phosphatase (Lyp) identified from high throughput screens. Chemical modification by incorporating the known phosphotyro
- Xie, Yuli,Liu, Yidong,Gong, Gangli,Rinderspacher, Alison,Deng, Shi-Xian,Smith, Deborah H.,Toebben, Udo,Tzilianos, Effie,Branden, Lars,Vidovic, Dusica,Chung, Caty,Schuerer, Stephan,Tautz, Lutz,Landry, Donald W.
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p. 2840 - 2844
(2008/12/21)
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- Evaluation of in vitro aldose redutase inhibitory activity of 5-arylidene-2,4-thiazolidinediones
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A number of 5-arylidene-2,4-thiazolidinediones containing a hydroxy or a carboxymethoxy group in their 5-benzylidene moiety have been synthesised and evaluated as in vitro aldose reductase (ALR2) inhibitors. Most of them exhibited strong inhibitory activi
- Maccari, Rosanna,Ottana, Rosaria,Ciurleo, Rosella,Vigorita, Maria Gabriella,Rakowitz, Dietmar,Steindl, Theodora,Langer, Thierry
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p. 3886 - 3893
(2008/02/13)
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- Structure-activity relationships and molecular modelling of 5-arylidene-2,4-thiazolidinediones active as aldose reductase inhibitors
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The structure-activity relationships (SARs) of 5-arylidene-2,4- thiazolidinediones active as aldose reductase inhibitors (ARIs) were extended by varying the substitution pattern on the 5-arylidene moiety and on N-3. In particular, the introduction of an a
- Maccari, Rosanna,Ottana, Rosaria,Curinga, Carmela,Vigorita, Maria Gabriella,Rakowitz, Dietmar,Steindl, Theodora,Langer, Thierry
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p. 2809 - 2823
(2007/10/03)
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