- Design and synthesis of a new class of 2,4-thiazolidinedione based macrocycles suitable for Fe3+ sensing
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A new class of three 2,4-thiazolidinedione based macrocycles (3a-c) have been synthesized and then characterized from spectral data and X-ray crystallography. The fluorescence quenching of the compounds caused by the addition of nineteen separate metal cations to their solutions in ethanol-water (3 : 1) was investigated, when it was observed that among the cations, the response to Fe3+ was distinctive. Again, among the macrocycles, 3c gave the best result.
- Sepay, Nayim,Mallik, Sumitava,Saha, Pranab C.,Mallik, Asok K.
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- 5-(4-Methoxybenzylidene)thiazolidine-2,4-dione-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations
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A novel series of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione derivatives, 5a–g and 7a–f, was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT116, and MCF-7 cells. HepG2 and HCT116 were the most sensitive cell lines to the influence of the new derivatives. In particular, compounds 7f, 7e, 7d, and 7c were found to be the most potent derivatives of all the tested compounds against the HepG2, HCT116, and MCF-7 cancer cell lines. Compound 7f (IC50 = 6.19 ± 0.5, 5.47 ± 0.3, and 7.26 ± 0.3 μM, respectively) exhibited a higher activity than sorafenib (IC50 = 9.18 ± 0.6, 8.37 ± 0.7, and 5.10 ± 0.4 μM, respectively) against HepG2 and MCF-7, cells but a lower activity against HCT116 cancer cells, respectively. Also, this compound displayed a higher activity than doxorubicin (IC50 = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 μM, respectively) against HepG2 and MCF-7 cells, but nearly the same activity against HCT116 cells, respectively. All derivatives, 5a–g and 7a–f, were evaluated for their inhibitory activities against vascular endothelial growth factor receptor-2 (VEGFR-2). Among them, compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC50 value of 0.12 ± 0.02 μM, which is nearly the same as that of sorafenib (IC50 = 0.10 ± 0.02 μM). Compounds 7e, 7d, 7c, and 7b exhibited the highest activity, with IC50 values of 0.13 ± 0.02, 0.14 ± 0.02, 0.14 ± 0.02, and 0.18 ± 0.03 μM, respectively, which are more than the half of that of sorafenib. Furthermore, molecular docking was performed to investigate their binding mode and affinities toward the VEGFR-2 receptor. The data obtained from the docking studies highly correlated with those obtained from the biological screening.
- El-Adl, Khaled,Sakr, Helmy,Nasser, Mohamed,Alswah, Mohamed,Shoman, Fatma M. A.
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- Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to P. aeruginosa PhzS
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The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit P. aeruginosa PhzS (PaPzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PaPhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (A- Kd = 18 μM and LE = 0.20), is not required for PaPzhS inhibition, but unsubstituted nitrogen at the thiazolidinone ring is. The molecular simplification approach, pursued in this work, afforded an optimised lead compound (13- 5-(2,4-dimethoxyphenyl)thiazolidine-2,4-dione) with 10-fold improvement in affinity (Kd= 1.68 μM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).Executive summary PhzS is a key enzyme in the pyocyanin biosynthesis pathway in P. aeruginosa. Orthogonal assays (TSA and FITC) show that fragment-like thiazolidinedione derivatives bind to PaPhzS with one-digit micromolar affinity. Fragment-like thiazolidinedione derivatives bind to the cofactor (NADH) binding site in PaPhzS. The molecular simplification optimised the ligand efficiency and affinity of the lead compound.
- Froes, Thamires Quadros,Chaves, Bianca Trindade,Mendes, Marina Sena,Ximenes, Rafael Matos,da Silva, Ivanildo Mangueira,da Silva, Priscila Brand?o Gomes,de Albuquerque, Julianna Ferreira Cavalcanti,Castilho, Marcelo Santos
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- Selective cytotoxic and genotoxic activities of 5-(2-bromo-5-methoxybenzylidene)-thiazolidine-2,4-dione against NCI-H292 human lung carcinoma cells
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Background: Thiazolidine-2,4-dione ring system is used as a pharmacophore to build various heterocyclic compounds aimed to interact with biological targets. In the present study, benzylidene-2,4-thiazolidinedione derivatives (compounds 2–5) were synthesized and screened against cancer cell lines and the genotoxicity and cytotoxicity of the most active compound (5) was investigated on normal and lung cancer cell line. Methods: For in vitro cytotoxic screening, the MTT assay was used for HL60 and K562 (leukemia), MCF-7 (breast adenocarcinoma), HT29 (colon adenocarcinoma), HEp-2 (cervix carcinoma) and NCI-H292 (lung carcinoma) tumor cell lines and Alamar-blue assay was used for non-tumor cells (PBMC, human peripheral blood mononuclear cells) were used. Cell morphology was visualized after Giemsa-May-Grunwald staining. DNA content, phosphatidylserine externalization and mitochondrial depolarization were measured by flow cytometry. Genotoxicity was assessed by Comet assay. Results: 5-(2-Bromo-5-methoxybenzylidene)-thiazolidine-2,4-dione (5) presented the most potent cytotoxicity, especially against NCI-H292 lung cancer cell line, with IC50 value of 1.26 μg/mL after 72 h incubation. None of the compounds were cytotoxic to PBMC. After 48 h incubation, externalization of phosphatidylserine, mitochondrial depolarization, internucleosomal DNA fragmentation and morphological alterations consistent with apoptosis were observed in NCI-H292 cells treated with compound (5). In addition, compound (5) also induced genotoxicity in NCI-H292 cells (2.8-fold increase in damage index compared to the negative control), but not in PBMC. Conclusion: Compound 5 presented selective cytotoxic and genotoxic activity against pulmonary carcinoma (NCI-H292 cells).
- Rodrigues, Maria do D.,Santiago, Priscila B.G.S.,Marques, Karla M.R.,Pereira, Valéria R.A.,de Castro, Maria C.A.B.,Cantalice, Jeanne C.L.L.,da Silva, Teresinha G.,Adam, M?nica L.,do Nascimento, Silene C.,de Albuquerque, Julianna F.C.,Militao, Gardenia C.G.
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- Design, synthesis and molecular modeling studies of novel thiazolidine-2,4-dione derivatives as potential anti-cancer agents
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A series of novel thiazolidine-2,4-dione derivatives 4a-x have been designed, synthesized and evaluated for potential anti-cancer activity. The anti-cancer activity of synthesized compounds 4a-x were evaluated against selected human cancer cell line of breast (MCF-7) using sulforhodamine B (SRB) method. Among the synthesized compounds, 4x having 2-cyano phenyl group showed significant cytotoxic activity which is comparable to that of adriamycin as standard anti-cancer drug. The SAR study revealed that the substituted phenyl group on oxadiazole ring attached to thiazolidine-2,4-dione moiety showed significant growth inhibitory activity against MCF-7 cell line. The result of molecular modeling studies showed that compounds 4f, 4o and 4x having similar structural alignment as crystal ligand of protein (PDB code: 4DTK) and exhibited hydrogen bond interaction with amino acid residues LYS67, GLU171, ASP128 and ASP186 of PIM-1 kinase. The results of biological activity and docking study revealed that the presence of electron withdrawing group at 2 position of phenyl ring attached to oxadiazole of thiazolidine-2,4-dione scaffold is crucial for better anti-cancer activity.
- Asati, Vivek,Bharti, Sanjay Kumar
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- Synthesis of novel 2-seleno-1,8-naphthyridines derivatives
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Synthesis of series of new 2-phenyl-3-(2-seleno-1,8-naphthyridin-3-yl)-2,3, 3a,6-tetrahydro-5H-pyrazolo[3,4-d][1,3]thiazol-5-ones (4a-e) has been reported. The replacement of halogen with NaHSe in the substituted 2-chloro-3-formyl-1,8- naphthyridi afforded 2-seleno-3-formyl-1,8-naphthyridins (2a - e). The reaction between (2a-e) and 1,3-thiazolidine-2,4-dione produced corresponding derivatives of substituted compounds (3a-e), which on reflux with phenyl hydrazine in DMF to generate (4a-e), with good to excellent yields. Structure of newly synthesized compounds were established based on elemental analysis, IR, 1H NMR, and mass spectral data. Copyright Taylor & Francis Group, LLC.
- Naik, Tangali R. Ravikumar,Naik, Halehatty S. Bhojya,Naik, Halehatty R. Prakash,Raghavendra,Ramesha
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- Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme
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Novel series of 5-benzylidenethiazolidine-2,4-dione derivatives 4a-c-8a-f were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 8f was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = 11.19 ± 0.8, 8.99 ± 0.7 and 7.10 ± 0.4 μM respectively. Compound 8f exhibited lower activity than sorafenib, (IC50 = 9.18 ± 0.6, 8.37 ± 0.7 and 5.10 ± 0.4 μM respectively), against HepG2 and HCT116 but exhibited nearly the same activity against MCF-7 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM respectively), against HepG2 and HCT116 but nearly the same activity against MCF-7cell lines respectively. The most active derivatives 6c,d,f,g and 8a-f were evaluated for their inhibitory activities against VEGFR-2. The elongation of the structures to have distal moieties enhanced anticancer and VEGFR-2 inhibitory activities as in compounds 8a-f. Among them, compounds 8f was found to be the most potent derivative that inhibited VEGFR-2 at IC50 value of 0.22 ± 0.02 μM, which is nearly the half as that of sorafenib IC50 value (0.10 ± 0.02 μM). Furthermore, molecular design was performed to investigate their binding mode and affinities towards VEGFR-2 receptor. The data obtained from docking studies were highly correlated with that obtained from the biological screening.
- Eissa, Ibrahim H.,El-Adl, Khaled,El-Hddad, Sanadelaslam S. A.,El-Helby, Abdel-Ghany A.,M. I. A. Shoman, Fatma,Sakr, Helmy
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- Synthesis and characterization via molecular quantum parameters of 2H-thiazolo[3,2-a]pyrimidine-3,5,7(6H)-trione
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2H-Thiazolo[3,2-a]pyrimidine-3,5,7(6H)-trione (2) was synthesized and characterized via molecular quantum parameters using the PM3-semiempirical MO method. This is considered the only route not previously reported in the literature to synthesize compound 2 from 2-imino-4-thiazolidinone (1).
- Hamama, Wafaa S.,Ismail, Mohamed A.,Soliman, Mamdouh S.,Shaaban, Saad,Zoorob, Hanafi H.
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- It is thiazolidine-2,4-dione and not thiohydantoins as the reaction product of monosubstituted thioureas and chloroacetylchloride
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The reaction products of monosubstituted phenylthioureas with chloroacetylchloride in a polyethylene glycol (PEG-400) medium and K2CO3 as base/catalyst at an elevated temperature are exclusively thiazolidine-2,4-diones and not thiohydantoins as has been reported. The core unit thiazolidine-2,4- dione is essentially derived from chloroacetylchloride and the thioamidic part of the phenylthiourea. The scope of this unprecedented transformation has been evaluated with electron-rich and electron-poor phenylthioureas.
- Yella, Ramesh,Singh, Raman Kumar,Majji, Ganesh,Patel, Bhisma K.
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- 2-ALLYLAMINOTHIAZOLIN-4-ONE IN ACYLATION REACTIONS
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2-Acetylallylamino-4-acetoxythiazole is obtained via treatment of 2-allylaminothiazolin-4-one with acetic anhydride for a short period of time.After extended reaction times with a mixture of acetic anhydride and acetic acid a noncondensed bicyclic derivative of thiazolidin-4-one is obtained.
- Levshin, I. B.,Chistyakov, V. V.,Pol'shakov, V. I.,Sheinker, Yu. N.
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- Design, synthesis and evaluation of novel thiazolidinedione derivatives as anti-hyperglycemic and anti-hyperlipidemic agents
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A novel series of thiazolidine-2,4-diones was designed, synthesized and investigated for anti-diabetic activity. The (2,4-dioxo-1,3-thiazolidin-5-yl)methylphenylbenzamide derivatives contain an amide linkage between the central aryl ring and the hydrophobic tail. Structures of the compounds were confirmed by spectroscopic techniques fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance and elemental (C, H, N) analysis. The synthesized compounds were evaluated for their in-vivo pharmacological activity (blood glucose and triglyceride lowering activity), where compounds thiazolidinediones-C and thiazolidinediones-E showed significant effects, comparable to the standard pioglitazone. Computational studies positively substantiated the nature and interaction of the designed compounds with peroxisome proliferator-activated receptor gamma.
- Shrivastava, Sushant K.,Batham, Ankit,Sinha, Saurabh K,Parida, Tanmaya K.,Garabadu, Debapriya,Choubey, Priyanka K.
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- COUPLING KINETICS OF 4-SULFOBENZENEDIAZONIUM ION WITH 2,4-THIAZOLIDINEDIONE, ITS 3-METHYL DERIVETIVE AND 3-METHYL-5-ISOXAZOLONE
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3- and 4-substituted derivatives of 2,4-thiazolidinedione were prepared as potential biologically active fungicides.The kinetics of coupling of 4-sulfobenzenediazonium salt with 2,4-thiazolidinedione and 3-methyl-2,4-thiazolidine dione have been studied and the results have been compared with kinetic data od coupling reaction of 3-methyl-5-isoxazolone.
- Kavalek, Jaromir,Machacek, Vladimir,Sterba, Vojeslav
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- PREPARATIVE SYNTHESIS METHOD FOR THIAZOLIDINE-2,4-DIONE AND ITS N-DERIVATIVES
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A procedure has been proposed for the synthesis of thiazolidine-2,4-dione and its N-derivatives, including bicyclic unfused thiazolidine-2,4-diones with alkylene and arylene bridges.The procedure is based on acid hydrolysis of the appropriate S-thiocarbaminylthiohydroacrylic acids with α-halocarboxylic acids.
- Orlinskii, M. M.
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- INVESTIGATION OF THE REACTIVITIES AND TAUTOMERISM OF AZOLIDONES. 52. SYNTHESIS OF 2- AND 3-ALLYL-SUBSTITUTED PSEUDOTHIOHYDANTOINS
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The effect of the solvent on the cyclization of N-allylthiourea with monochloroacetic acid was studied; the structures of the products were proved by alternative synthesis, as well as by acidic hydrolysis.
- Levshin, I. B.,Grigor'eva, I. V.,Tsurkan, A. A.,Tarasyavichus, E. L.,V'yunov, K. A.,Ginak, A. I.
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- Experimental and theoretical studies of a pyrazole-thiazolidin-2,4-di-one hybrid
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The present work describes synthesis, characterization and biological evaluations of a hybrid compound 10 composed of two intriguing scaffolds pyrazole and thiazolidin-2,4-di-one. The title compound was obtained via multi-step reaction and characterized by a number of techniques (viz. IR, UV–Visible, 1H-NMR, 13C-NMR and MS) including X-ray crystallography. The structural and photophysical data of compound 10 were well supported by theoretical calculations performed at density functional (DFT) level. In-vitro anticancer studies on different human cancer cell lines indicated moderate to low activity of the compounds. The molecular target of the compound was predicted through in-silico studies. Finding of the studies are presented herein.
- Mushtaque, Md.,Avecilla, Fernando,Haque, Ashanul,Perwez, Ahmad,Khan, Md. Shahzad,Rizvi, M. Moshahid Alam
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- The synthesis and characterization of new asymmetrical dihydropyridine derivatives containing a 2,4-dichloro-5-thiazolyl substituent
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Dihydropyridines (DHP) having a heterocyclic aryl substituent at position-4 are calcium channel antagonists. In this report a new group of DHP derivatives with different esters at the C3 and C5 position (asymmetrical diesters) containing 2,4-dichloro-5-thiazolyl at position-4 were synthesized by a condensation reaction of alkyl, cycloalkyl, and aryl acetoacetate in the presence of ammonium acetate in a new shorter pathway. The structure of all compounds was confirmed by IR, 1H NMR, and mass spectrometry. The calcium channel antagonist activity of compounds 6a-6f demonstrated that the compound 6a was the most active compound. Copyright Taylor & Francis Group, LLC.
- Ghodsi, Shahram,Alipour, Eskandar,Amini, Mohsen,Miri, Ramin,Tagi-Ganji, Karim Masoud,Hosseini, Marjan,Mirkhani, Hossein,Shafiee, Abbas
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- Synthesis of novel thiazolidinic-phthalimide derivatives evaluated as new multi-target antiepileptic agents
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Epilepsy is a disease that affects millions of people around the globe and has a multifactorial cause. Inflammation is a process that can be involved in the development of seizures. Thus, the present study proposed the design and synthesis of new candidates for antiepileptic drugs that would also control the inflammatory process. Nine new derivatives of the substituted thiazophthalimide hybrid core were obtained with satisfactory purity ≥99% and yields between 27% and 87%. All compounds showed cell viability values greater than 90% in the culture of PBMC cells from healthy volunteers and, therefore, were not considered cytotoxic. These compounds modulated proinflammatory cytokines IFN-y and IL-17A and can mitigate inflammation. Acute toxicity studies of compound 7i in an animal model indicated that the compound has low toxicity and an LD50 greater than 2 g/kg in healthy adult rats. The same compound did not show positive results for anticonvulsant activity through the PTZ test. However, 7i demonstrates the interaction with the target GABA-A receptor in silico, indicating a possible activity as an agonist of that receptor. Thus, further studies are needed to investigate the anticonvulsant activity, in particular, using models in which the inflammatory process triggers epileptic seizures.
- de Oliveira, Maria Cecilia V.A.,Viana, Douglas C.F.,Silva, Anderson A.,Pereira, Michelly C.,Duarte, Filipe S.,Pitta, Maira G.R.,Pitta, Ivan R.,Pitta, Marina G.R.
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- Design, synthesis,: In silico molecular modelling studies and biological evaluation of novel indole-thiazolidinedione hybrid analogues as potential pancreatic lipase inhibitors
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Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered as a promising target for the management and/or treatment of obesity. A new series of indole-thiazolidinedione (TZD) hybrid analogues were synthesized using a molecular hybridisation approach and evaluated for their anti-obesity effects via PL inhibition. The targeted analogues were synthesized via the condensation reaction between various substituted isatin with TZD in the presence of aqueous KOH in methanol. Amongst the synthesized analogues, 7k and 7m exhibited a potential PL inhibitory activity (IC50-7.30 and 9.51 μM, respectively). Kinetic study of these potent analogues revealed their competitive mode of enzyme inhibition. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking of the synthesized analogues was performed using human PL (PDB ID: 1LPB). The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson's r = 0.9108, p 0.05). Moreover, a stable conformation of the 1LPB-ligands suggested the stability of these complexes in the dynamic environment. These studies provided a basis for the potential role of the indole-TZD hybrids in PL inhibition and further optimization might result in the development of new lead candidates for obesity treatment.
- George, Ginson,Auti, Prashant S.,Paul, Atish T.
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p. 1381 - 1394
(2021/02/06)
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- Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5-[(4-chloro/2,4-dichloro)benzylidene]thiazolidine-2,4-dione derivatives as VEGFR-2 inhibitors
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The anticancer activity of novel thiazolidine-2,4-diones was evaluated against HepG2, HCT-116, and MCF-7 cells. MCF-7 was the most sensitive cell line to the cytotoxicity of the new derivatives. In particular, compounds 18, 12, 17, and 16 were found to be the most potent derivatives over all the tested compounds against the cancer cell lines HepG2, HCT116, and MCF-7, with IC50 = 9.16 ± 0.9, 8.98 ± 0.7, 5.49 ± 0.5 μM; 9.19 ± 0.5, 8.40 ± 0.7, 6.10 ± 0.4 μM; 10.78 ± 1.2, 8.87 ± 1.5, 7.08 ± 1.6 μM; and 10.87 ± 0.8, 9.05 ± 0.7, 7.32 ± 0.4 μM, respectively. Compounds 18 and 12 have nearly the same activities as sorafenib (IC50 = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 μM, respectively), against HepG2 cells, but slightly lower activity against HCT116 cells and slightly higher activity against the MCF-7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against HepG2 and HCT-116 cells but higher activity against MCF-7 cells (IC50 = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 μM, respectively). In contrast, compounds 17 and 16 exhibited lower activities than sorafenib against HepG2 and HCT116 cells, but nearly equipotent activity against the MCF-7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against the three cell lines. All the synthesized derivatives 7–18 were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to medium inhibitory activity, with IC50 values ranging from 0.17 ± 0.02 to 0.27 ± 0.03 μM. Compounds 18, 12, 17, and 16 potently inhibited VEGFR-2 at IC50 values of 0.17 ± 0.02, 0.17 ± 0.02, 0.18 ± 0.02, and 0.18 ± 0.02 μM, respectively, which are nearly more than half of that of the IC50 value for sorafenib (0.10 ± 0.02 μM).
- El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Ayyad, Rezk R.,Mahdy, Hazem A.,Nasser, Mohamed,Abulkhair, Hamada S.,El-Hddad, Sanadelaslam S. A.
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- Design, synthesis, docking, ADMET profile, and anticancer evaluations of novel thiazolidine-2,4-dione derivatives as VEGFR-2 inhibitors
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The anticancer activity of novel thiazolidine-2,4-diones was evaluated against HepG2, HCT-116, and MCF-7 cells. Among the tested cancer cell lines, HCT-116 was the most sensitive one to the cytotoxic effect of the new derivatives. In particular, compounds 18, 11, and 10 were found to be the most potent derivatives among all the tested compounds against the HepG2, HCT-116, and MCF-7 cancer cell lines, with IC50 values ranging from 38.76 to 53.99 μM. The most active antiproliferative derivatives (7–14 and 15–19) were subjected to further biological studies to evaluate their inhibitory potentials against VEGFR-2. The tested compounds displayed a good-to-medium inhibitory activity, with IC50 values ranging from 0.26 to 0.72 μM. Among them, compounds 18, 11, and 10 potently inhibited VEGFR-2 at IC50 values in the range of 0.26–0.29 μM, which are nearly three times that of the sorafenib IC50 value (0.10 μM). Although our derivatives showed lower activities than the reference drug, they could be useful as a template for future design, optimization, adaptation, and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs. The ADMET profile showed that compounds 18, 11, and 10 do not violate any of Lipinski's rules and have a comparable intestinal absorptivity in humans. Also, the new derivatives could not inhibit cytochrome P3A4. Unlike sorafenib and doxorubicin, compounds 18, 11, and 10 are expected to have prolonged dosing intervals. Moreover, compounds 10 and 18 displayed a wide therapeutic index and higher selectivity against cancer cells as compared with their cytotoxicity against normal cells.
- El-Adl, Khaled,Sakr, Helmy,El-Hddad, Sanadelaslam S. A.,El-Helby, Abdel-Ghany A.,Nasser, Mohamed,Abulkhair, Hamada S.
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- 5-Benzylidene, 5-benzyl, and 3-benzylthiazolidine-2,4-diones as potential inhibitors of the mitochondrial pyruvate carrier: Effects on mitochondrial functions and survival in Drosophila melanogaster
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A series of thiazolidinediones (TZDs) were synthesized and screened for their effect on the mitochondrial respiration as well as on several mitochondrial respiratory system components of Drosophila melanogaster. Substituted and non-substituted 5-benzylidene and 5-benzylthiazolidine-2,4-diones were investigated. The effect of a substitution in position 3, at the nitrogen atom, of the thiozolidine heterocycle was also investigated. The designed TZDs were compared to UK5099, the most potent mitochondrial pyruvate carrier (MPC) inhibitor, in in vitro and in vivo tests. Compared to 5-benzylthiazolidine-2,4-diones 6–7 and 3-benzylthiazolidine-2,4-dione 8, 5-benzylidenethiazolidine-2,4-diones 2–5 showed more inhibitory capacity on mitochondrial respiration. 5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione (3) and 5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (5) were among the best compounds that compared well with UK5099. Additionally, TZDs 3 and 5, showed no effects on the non-coupled respiration and weak effects on pathways using substrates such as proline, succinate, and G3P. 5-Benzylidenethiazolidine-2,4-dione 3 showed a positive effect on survival and lifespan when added to Drosophila standard and high fat diet. Interestingly, analog 3 completely reversed the effects of high fat diet on Drosophila longevity and induced metabolic changes which suggests an in vivo inhibition of MPC at the mitochondrial level.
- Touaibia, Mohamed,St-Coeur, Patrick-Denis,Duff, Patrick,Faye, Diene Codou,Pichaud, Nicolas
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- Synthesis, anticancer, and antibacterial studies of benzylidene bearing 5-substituted and 3,5-disubstituted-2,4-thiazolidinedione derivatives
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Aim: To develop novel compounds having potent anticancer and antibacterial activities. Background: Several studies have proved that benzylidene analogues of clinical 2,4-TZDs, such as troglitazone and ciglitazone, have more potent antiproliferative activity than their parent com-pounds. Literature studies also revealed that the attachment of more heterocyclic rings, containing nitrogen on 5th position of 2,4-TZD, can enhance the antimicrobial activity. Hence, attachment of various moieties on the benzylidene ring may produce safe and effective compounds in the future. Objective: The objective of the present study was to synthesize a set of novel benzylidene ring containing 5-and 3-substituted-2,4-thiazolidinedione derivatives and evaluate them for their anti-cancer and antibacterial activity. Method: The synthesized compounds were characterized by IR, NMR, mass, and elemental stud-ies. The in vitro cytotoxicity studies were performed for human breast cancer (MCF-7) and human lung cancer (A549) cells and HepG2 cell-line and compared to standard drug doxorubicin by MTT assay. Antimicrobial activity of the synthesized 2,4-thiazolidinediones derivatives was carried out using the cup plate method with slight modification. Result: The results obtained showed that TZ-5 and TZ-13 exhibited good antiproliferative activity against A549 cancer cell-line, whereas TZ-10 exhibited moderate antiproliferative activity against HepG2 cell-line when compared to standard drug doxorubicin. TZ-5 also exhibited reasonable activity against the MCF-7 cell-line with doxorubicin as standard. TZ-4, TZ-5, TZ-6, TZ-7, and TZ-16 exhibited remarkable antibacterial activity against Gram positive and moderate activity against Gram negative bacteria with the standard drug ciprofloxacin. Conclusion: Attachment of heterocyclic rings containing nitrogen as the hetero atom improves the anticancer and antimicrobial potential. Attachment of electronegative elements like halogens can also enhance the antimicrobial activity. Further structure modifications may lead to the development of more potent 2,4-TZD leads that can be evaluated for further advanced studies.
- Sethi, Navjot Singh,Prasad, Deo Nandan,Singh, Rajesh K.
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p. 369 - 379
(2021/03/03)
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- Design, synthesis and biological evaluation of N-substituted indole-thiazolidinedione analogues as potential pancreatic lipase inhibitors
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Pancreatic Lipase (PL) is a key enzyme responsible for the digestion of 50%–70% of dietary triglycerides, hence its inhibition is considered as a viable approach for the management of obesity. A series of indole-TZD hybrid analogues were synthesized, characterized and evaluated for their PL inhibitory activity. Knoevenagel condensation of various substituted indole-3-carboxaldehyde with substituted thiazolidinediones resulted in the formation of titled analogues. Analogues 6d and 6e exerted potent PL inhibitory activity (IC50-6.19 and 8.96?μM, respectively). Further, these analogues exerted a competitive mode of PL inhibition. Moreover, molecular modelling studies were in agreement with the in vitro results (Pearson's r?=.8682, p?.05). The fluorescence spectroscopic analysis further supported the strong binding affinity of these analogues with PL. A molecular dynamics study (20?ns) indicated that these analogues were stable in a dynamic environment. Thus, the present study highlighted the potential role of indole-thiazolidinedione hybrid analogues as potential PL inhibitors and further optimization might result in the development of new PL inhibitory lead candidates.
- George, Ginson,Auti, Prashant S.,Paul, Atish T.
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- Synthesis, Characterization, and Antidiabetic Evaluation of Substituted 5-(2-Chloro-Quinolin-3-Ylmethylene)-Thiazolidine-2,4-Dione
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Diabetes is a major public health problem that severely affects the quality of life of many people. The discovery of new antidiabetic agents remains the cornerstone for controlling this challenging disease in which heterocyclic compounds contributed greatly. Thiazolidinedione and quinoline nuclei exhibit different pharmacological potentials, the combination of these nuclei leads to the development of novel effective compounds. In this study, a series of substituted 5-(2-Chloro-quinolin-3-ylmethylene)-thiazolidine-2,4-dione (4a-h) derivatives were synthesized and characterized using different analytical instruments. These derivatives were evaluated for its anti-diabetic potentials at the dose of 30 mg/kg on streptozotocin-induced diabetic Wistar albino rat model. Among all the derivatives, compounds 3-[(2-Chloro-4-nitro-phenylamino)-methyl]-5-(2-chloro-quinolin-3-ylmethylene)-thiazolidine-2,4-dione (4e) and 5-(2-Chloro-quinolin-3-ylmethylene)-3-[(4-nitro-phenylamino)-methyl]-thiazolidine-2,4-dione (4d) were shown excellent activity, compound 2-{[5-(2-Chloro-quinolin- 3-ylmethylene)-2,4-dioxo-thiazolidin-3-ylmethyl]-phenyl amino}-benzoic acid (4c) was shown moderate activity, in comparison to the activity of standard pioglitazone drug. Furthermore, this study on quinoline derivatives containing thiazolidinedione will surely help researchers to develop new antidiabetic agents with more potent activity.
- Ahsan, Mohamed Jawed,Kumar, Ajay,Kumar, Rajnish,Mazumder, Avijit,Mishra, Shivali,Sahu, Rakesh,Salahuddin,Singh, Chanchal,Yar, Mohammad Shahar
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p. 357 - 364
(2021/11/22)
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- Antileishmanial activity evaluation of thiazolidine-2,4-dione against Leishmania infantum and Leishmania braziliensis
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Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which makes the development of new drugs urgent. To achieve this goal, the integration of kinetic and DSF assays against parasitic validated targets, along with phenotypic assays, can help the identification and optimization of bioactive compounds. Pteridine reductase 1 (PTR1), a validated target in Leishmania sp., is responsible for the reduction of folate and biopterin to tetrahydrofolate and tetrahydrobiopterin, respectively, both of which are essential for cell growth. In addition to the in vitro evaluation of 16 thiazolidine-2,4-dione derivatives against Leishmania major PTR1 (LmPTR1), using the differential scanning fluorimetry (ThermoFluor), phenotypic assays were employed to evaluate the compound effect over Leishmania braziliensis (MHOM/BR/75/M2903) and Leishmania infantum (MHOM/BR/74/PP75) promastigotes viability. The ThermoFluor results show that thiazolidine-2,4-dione derivatives have micromolar affinity to the target and equivalent activity on Leishmania cells. 2b is the most potent compound against L. infantum (EC50 = 23.45 ± 4.54 μM), whereas 2a is the most potent against L. braziliensis (EC50 = 44.16 ± 5.77 μM). This result suggests that lipophilic substituents on either—meta and/or—para positions of the benzylidene ring increase the potency against L. infantum. On the other hand, compound 2c (CE50 = 49.22 ± 7.71 μM) presented the highest selectivity index.
- Castilho, Marcelo Santos,Froes, Thamires Quadros,Júnior, David Bacelar Costa,Leite, Franco Henrique Andrade,Moreira, Paulo Otávio Louren?o,Neri, Flávio Simas Moreira,Teixeira-Neto, Rafael Gon?alves,da Silva, Priscila Brand?o Gomes,de Albuquerque, Jullianna Ferreira Cavalcanti,de Pilla Varotti, Fernando,do Egito, Micalyne Soares
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- Synthesis and Anticancer Activity of (E)-5-[(1-Aryl-1H-1,2,3-triazol-4-yl)methylene]thiazolidine-2,4-diones
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Abstract: A novel series of 1,2,3-triazolylthiazolidinedione analogs have been synthesized by the condensation of the corresponding 1-aryl-1H-1,2,3-triazole-4-carbaldehydes with thiazolidine-2,4-dione in the presence of KOH. The title compounds were evaluated for their in vitro anticancer activity using MTT assay against four cancer cell lines: A549 (lung), HT-29 (colon), MCF-7 (breast), and A375 (melanoma). Most compounds displayed good anticancer activity, but hydroxy- and nitro-substituted derivatives showed higher activity than the others.
- Manikala, V. K.,Rao, V. M.
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p. 863 - 868
(2020/07/03)
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- A class of carbonic anhydrase IX/XII–selective carboxylate inhibitors
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A small series of 2,4-dioxothiazolidinyl acetic acids was prepared from thiourea, chloroacetic acid, aromatic aldehydes, and ethyl-2-bromoacetate. They were assayed for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, the cytosolic hCA I and II, and the transmembrane hCA IX and XII, involved among others in tumorigenesis (hCA IX and XII) and glaucoma (hCA II and XII). The two cytosolic isoforms were not inhibited by these carboxylates, which were also rather ineffective as hCA IX inhibitors. On the other hand, they showed submicromolar hCA XII inhibition, with KIs in the range of 0.30–0.93 μM, making them highly CA XII-selective inhibitors.
- Alhameed, Rakia Abd,Almarhoon, Zainab,Berrino, Emanuela,El-Faham, Ayman,Supuran, Claudiu T.
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p. 549 - 554
(2020/02/13)
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- De-novo design and synthesis of conformationally restricted thiazolidine-2,4-dione analogues: highly selective PPAR-γ agonist in search of anti-diabetic agent
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In the present investigation, design, molecular docking simulations, and synthesis of few 2,4-thiazolidinedione for selective modulation of PPAR-gamma are reported. Further evaluation of anti-diabetic activity of few thiazolidine-2,4-diones is assessed using cell line analysis. The structures of the synthesized compounds were confirmed on the basis of FT-IR, 1H-NMR, and mass analyses. Acute toxicity study was done to by using Trypan blue assay and MTT assay of the synthesized compounds. Synthesized compounds were evaluated for their antihyperglycemic effect by glucose absorption assay. The compound code TZD4 showed highest percentage of glucose absorption by 3T3-L1 cells compared with control.
- Chhajed, Santosh S.,Shinde, Pooja E.,Kshirsagar, Sanjay J.,Sangshetti, Jayprakash N.,Gupta, PramodKumar P.,Parab, Mala M.,Dasgupta, Debjani
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p. 1375 - 1385
(2020/02/27)
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- Synthesis of a novel series of (Z)-3,5-disubstituted thiazolidine-2,4-diones as promising anti-breast cancer agents
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A novel series of (Z)-3,5-disubstituted thiazolidine-2,4-diones 4–16 has been designed and synthesized. Preliminary screening of these compounds for their anti-breast cancer activity revealed that compounds 5, 7, and 9 possess the highest anti-cancer activities. The anti-tumor effects of compounds 5, 7, and 9 were evaluated against human breast cancer cell lines (MCF-7 and MDA-MB-231) and human breast cancer cells. They were also evaluated against normal non-cancerous breast cells, isolated from the same patients, to conclude about their use in a potential targeted therapy. Using MTT uptake method, these three compounds 5, 7, and 9 blunt the proliferation of these cancer cells in a dose-dependent manner with an IC50 of 1.27, 1.50 and 1.31 μM respectively. Interestingly, using flow cytometry analysis these three compounds significantly mediated apoptosis of human breast cancer cells without affecting the survival of normal non-cancerous breast cells that were isolated from the same patients. Mechanistically, these compounds blunt the proliferation of MCF-7 breast cancer cells by robustly decreasing the phosphorylation of AKT, mTOR and the expression of VEGF and HIF-1α. Most importantly, compounds 5, 7, and 9 without affecting the phosphorylation and expression of these crucial cellular factors in normal non-cancerous breast cells that were isolated from the same patients. Additionally, using Western blot analysis the three compounds significantly (P XL and Mcl-1) and increased the expression of the pro-apoptotic Bcl-2 members (Bak, Bax and Bim) in MCF-7, MDA-MB-231 and human breast cancer cells making these breast cancer cells susceptible for apoptosis induction. Taken together, these data provide great evidences for the inhibitory activity of these compounds against breast cancer cells without affecting the normal breast cells.
- Abd El-Khalek, Rofida,Abo El-Maali, Nagwa,Badr, Gamal,El-Kashef, Hussein,Lebegue, Nicolas,Melnyk, Patricia,Sayed, Douaa
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- Synthesis and anti-diabetic activity evaluation of phosphonates containing thiazolidinedione moiety
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A sequence of substituted phosphonates containing the thiazolidinedione moiety was synthesized with good yields. The structures of all the synthesized compounds were confirmed by NMR (31P, 1H and 13C) and IR spectroscopy, mass spectrometry and C, H, N elemental analyses. In silico molecular docking study was also carried out to evaluate their interaction and binding modes on ligands against human PPAR γ protein for their anti-diabetic activity. From the docking results, it was determined that the compounds (Z)-dimethyl 5-(3-nitrobenzylidene)?2,4-dioxothiazolidin-3-ylphosphonate (7a), (Z)-dimethyl 5-(3-chloro-4-fluorobenzylidene)?2,4-dioxothiazolidin-3-ylphosphonate (7f), (Z)-dimethyl 5-(2,4-dichlorobenzylidene)?2,4-dioxothiazolidin-3-ylphosphonate (7e) and (Z)-dimethyl 5-((5-methoxypyridin-2-yl)methylene)?2,4-dioxothiazolidin-3-ylphosphonate (7j) have shown better binding energies (?7.8, ?7.6, ?7.5 and ?7.6 Kcal/mol) with the target gene, PPAR γ than the reference drug, Rosiglitazone (?7.4 Kcal/mol). In vitro anti-diabetic activity of the title compounds was also screened by standard α-amylase inhibition assay. Some of the tested compounds proved to possess promising activity when compared with the reference drug.
- Sujatha, Bogiri,Chennamsetty, Subramanyam,Chintha, Venkataramaiah,Wudayagiri, Rajendra,Prasada Rao, Kammela
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p. 586 - 591
(2020/03/23)
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- Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors
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Thymidylate synthase (TS) has been an attention-grabbing area of research for the treatment of cancers due to their role in DNA biosynthesis. In the present study, we have synthesised a library of thiazolidinedione-1,3,4-oxadiazole hybrids as TS inhibitors. All the synthesised hybrids followed Lipinski and Veber rules which indicated good drug likeness properties upon oral administration. Among the synthesised hybrids, compound 9 and 10 displayed 4.5 and 4.4 folds activity of 5-Fluorouracil, respectively against MCF-7 cell line whereas 3.1 and 2.5 folds cytotoxicity against HCT-116 cell line. Furthermore, compound 9 and 10 also inhibited TS enzyme with IC50 = 1.67 and 2.21 μM, respectively. Finally, the docking studies of 9 and 10 were found to be consistent with in vitro TS results. From these studies, compound 9 and 10 has the potential to be developed as TS inhibitors.
- Alam, Mohammad Mahboob,Alzhrani, Zohor Mohammad Mahdi,Nazreen, Syed,Neamatallah, Thikryat
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p. 1116 - 1123
(2020/05/13)
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- Synthesis, antitumor activity and molecular docking studies on seven novel thiazacridine derivatives
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Aim and Objective: In the last decades, cancer has become a major problem in public health all around the globe. Chimeric chemical structures have been established as an important trend on medicinal chemistry in the last years. Thiazacridines are hybrid molecules composed of a thiazolidine and acridine nucleus, both pharmacophores that act on important biological targets for cancer. By the fact it is a serious disease, seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized, characterized, analyzed by computer simulation and tested in tumor cells. In order to find out if the compounds have therapeutic potential. Materials and Methods: Seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized through Michael addition and Knoevenagel condensation strategies. Characterization was performed by NMR and Infrared spectroscopy techniques. Regarding biological activity, thiazacridines were tested against solid and hematopoietic tumoral cell lines, namely Jurkat (acute T-cell leukemia); HL-60 (acute promyelocytic leukemia); DU 145 (prostate cancer); MOLT-4 (acute lymphoblastic leukemia); RAJI (Burkitt's lymphoma); K562 (chronic myelogenous leukemia) and normal cells PBMC (healthy volunteers). Molecular docking analysis was also performed in order to assess major targets of these new compounds. Cell cycle and clonogenic assay were also performed. Results: Compound LPSF/AA-62 (9f) exhibited the most potent anticancer activity against HL-60 (IC50 3,7±1,7 μM), MOLT-4 (IC50 5,7±1,1 μM), Jurkat (IC50 18,6 μM), Du-145 (IC50 20±5 μM) and Raji (IC50 52,3±9,2 μM). While the compound LPSF/AA-57 (9b) exhibited anticancer activity against the K562 cell line (IC50 51,8±7,8 μM). Derivative LPSF/AA-62 (9f) did not interfere in the cell cycle phases of the Molt-4 lineage. However, the LPSF/AA-62 (9f) derivative significantly reduced the formation of prostate cancer cell clones. The compound LPSF/AA-62 (9f) has shown strong anchorage stability with enzymes topoisomerases 1 and 2, in particular due the presence of chlorine favored hydrogen bonds with topoisomerase 1. Conclusion: The 3-(acridin-9-ylmethyl)-5-((10-chloroanthracen-9-yl)methylene)thiazolidine-2,4-dione (LPSF/AA-62) presented the most promising results, showing anti-tumor activity in 5 of the 6 cell types tested, especially inhibiting the formation of colonies of prostate tumor cells (DU-145).
- Almeida, Marcel L.,Dos Santos, Flaviana A.,Pereira, Michelly C.,Pitta, Ivan R.,Pitta, Maira G. R.,Pitta, Marina G. R.,Viana, Douglas C. F.,da Costa, Valécia C. M.,de Melo Rêgo, Moacyr J. B.
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p. 359 - 368
(2020/07/16)
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- Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
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Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26b, 29a, 29b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 μM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC50 value of 2.5 ± 0.04 μM, almost equal to that of sorafenib (IC50 = 2.4 ± 0.05 μM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities.
- Belal, Amany,Eissa, Ibrahim H.,El-Gamal, Kamal M. A.,El-Sharkawy, Abdou,Elhendawy, Mostafa A.,Elsohly, Mahmoud A.,Ibrahim, Mohammed K.,Mahdy, Hazem A.,Mehany, Ahmed B. M.,Metwaly, Ahmed M.,Radwan, Mohamed M.
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- Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents
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Thalidomide and its analogs are immunomodulatory drugs that inhibit the production of certain inflammatory mediators associated with cancer. In the present work, a new series of thalidomide analogs was designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against a panel of four cancer cell lines (HepG-2, HCT-116, PC3 and MCF-7). Compounds 33h, 33i, 42f and 42h showed strong potencies against all tested cell lines with IC50 values ranging from 14.63 to 49.90 μM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 μM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 33h and 42f showed a significant reduction in TNF-α. Furthermore, compounds 33i and 42f exhibited significant elevation in CASP8 levels. Compounds 33i and 42f inhibited VEGF. In addition, compound 42f showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42f, were performed. The results indicated that compound 42f significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase.
- El-Zahabi, Mohamed Ayman,Sakr, Helmy,El-Adl, Khaled.,Zayed, Mohamed,Abdelraheem, Adel S.,Eissa, Sally I.,Elkady, Hazem,Eissa, Ibrahim H.
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- Synthesis, biological evaluation and molecular docking studies of novel 3,5-disubstituted 2,4-thiazolidinediones derivatives
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A series of thirteen novel 2,4-thiazolidinedione derivatives were synthesized through three step reaction procedure. The title compounds were synthesized by Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione ring. Various physicochemical and spectral studies were conducted to characterize the synthesized derivatives including- IR, Mass, 1H NMR, 13C NMR and elemental analysis. The derivatives were screened for in vivo anti diabetic, in vivo anti-inflammatory and in vitro free radical scavenging activities by carrageenan induced rat paw edema method, alloxan induced diabetes in wistar rats method and FRAP (ferric reducing antioxidant power) method respectively. Some of the derivatives emerged out as potent antidiabetic, anti inflammatory and free radical scavenging agents. Molecular docking was carried out to investigate some possible structural insights into the potential binding patterns of the most potent anti-diabetic molecules NB7,NB12 and NB13 with the active sites of target PPARγ (PDB ID: 2PRG) using MOE software. Dichloro derivative compound NB-7 has shown great potential in the present study as it not only has maximum antidiabetic activity but also possess excellent anti-inflammatory and antioxidant potential.
- Ranjan Srivastava, Alok,Bhatia, Rohit,Chawla, Pooja
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- NOVEL 5-[4-(2-BIPHENYL-4-YL-2-OXO-ETHOXY)-BENZYLIDENE]-THIAZOLIDINE-2,4-DIONES, THEIR SYNTHESIS AND USES THEREOF
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Disclosed are novel 5-[4-(2-biphenyl-4-yl-2-oxo-ethoxy)-benzylidene]-thiazolidine-2,4-dione compounds of general formula (I), their pharmaceutically acceptable salts, solvates their synthesis and uses thereof, to pharmaceutical compositions containing compounds and to the use of such compounds and composition in medicines either alone or in combination with other compounds.
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Page/Page column 22
(2019/02/06)
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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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- Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some 5-Arylidene-thiazolidine-2,4-dione Derivatives
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Derivatives of the thiazolidine-2,4-dione core represent a heterocyclic class with several correlated properties. In this context, the synthesis of structural analogues of these bioactive substances becomes attractive in the field of medicinal chemistry. These analogues act as antimicrobial agents against Gram-positives pathogens. The present work aimed to synthesize 10 different derivatives of 5-arylidene-thiazolidine-2,4-dione, employing urea as the catalyst in a solvent-free reaction medium, with yields that ranged from 45 to 99percent. The compounds obtained were submitted to an antimicrobial assay against S. aureus ATCC 29213. Two compounds presented minimum inhibitory concentration of 62.5 and 32.5 μg mL-1 and minimum bactericidal concentration -1, demonstrating their antibacterial potential. Principal component analysis was carried out to discriminate the compounds in active and inactive classes. Four geometric and electronic molecular descriptors were required to completely discriminate the compounds. The selected descriptors can guide us in designing new 5-arylidene-thiazolidine-2,4-dione derivatives with enhanced activity.
- De Paiva, Raíssa K.C.,Da Silva, Jamerson F.,Moreira, Hudieyllen A.,Pinto, Osvaldo G.,Camargo, Lilian T.F.M.,Naves, Plínio L.F.,Camargo, Ademir J.,Ribeiro, Luciano,Ramos, Luciana M.
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p. 164 - 172
(2018/12/13)
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- Novel Furochromone Derivatives: Synthesis and Anticancer Activity Studies
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Medicinal plant extracts have been used for medical purposes throughout human history. In this study, khellin, having furochromone structure, which is obtained from a well-known traditional medicinal plant, was selected. A series of furochromonyl compounds (K1–K14) were synthesized for their anticancer activities. Furochromonyl compounds (K1–K14) were synthesized by Knoevenagel reaction of substituted 2,4-thiazolidinediones (Ia–j)/rhodanines (Ik–n) with khellin-2-carboxaldehyde (V), and their cytotoxicity was investigated in 22 cancer cell lines, which were originated from tissues such as the liver, breast, colon, and cervix. As the first step, two hepatocellular carcinoma cell lines Huh7 and PLC/PRF/5 (Alexander cells) were treated with 10?μM of each compound for 72?h, and then sulforhodamine B assay was performed to analyze their anti-growth activities. Ethyl 2-(5-((4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-7-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetate (K11) was found as the most cytotoxic compound of primary screening. Afterwards, 12 hepatocellular carcinoma, seven breast cancer, two colon cancer, and a cervical cancer cell lines were selected to test K11 for 72?h at multiple concentrations to determine 50% effective doses. Results showed that the 14 cell lines were affected by K11 quantities lower than 10?μM. The structure of K11, which is particularly effective on breast cancers, can be used to slow down the progression of tumors. Furthermore, the discovery of more effective compounds can be carried out on the basis of this structure.
- Demir, Senem,?zen, Cigdem,Ceylan-ünlüsoy, Meltem,?ztürk, Mehmet,Bozda?-Dündar, Oya
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p. 1341 - 1351
(2019/03/07)
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- Biological evaluation of synthesised thiazolidinedione derivatives for anti-diabetic activity on STZ caused diabetes in rats
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Diabetes Mellitus is the most common disease that poses a challenge to human health due to its secondary complications and resistance. Therefore, an attempt was made to synthesize novel compounds from thiazolidinedione moiety to treat the disease effectively and target diabetic complications. The synthesized compounds were tested for their physical parameters and characterised using NMR and IR spectra. They were also evaluated for STZ induced anti-diabetic activity in albino rats. The Compounds P5, II A8 and A9 were found effective in comparison with a standard drug, Pioglitazone. The other compounds were also effective but a reduction in activity is seen might be due to the inefficient binding to the PPAR receptors.
- Geetha,Swarnalatha,Subba Reddy
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p. 1042 - 1048
(2019/06/28)
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- Anti-hepatitis-C virus activity and QSAR study of certain thiazolidinone and thiazolotriazine derivatives as potential NS5B polymerase inhibitors
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The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4–6(a–f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13–15(a–f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 μM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 μM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 μM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 μM) relative to VCH-759 (EC50 = 5.29 μM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 μM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 μM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.
- Hassan, Ghaneya S.,Georgey, Hanan H.,Mohammed, Esraa Z.,Omar, Farghaly A.
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- Benzoxazole/benzothiazole-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations
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A novel series of benzoxazole/benzothiazole derivatives 4a–c–11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT-116, and MCF-7 cells, with IC50 values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 μM, respectively. Compounds 4b, 9f, and 9c showed the highest anticancer activities against HepG2 cells with IC50 values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 μM, respectively, HCT-116 cells with IC50 values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 μM, respectively, and MCF-7 cells with IC50 values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 μM, respectively, in comparison with sorafenib as reference drug with IC50 values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 μM, respectively. The most active compounds 4a–c, 9b,c,e,f,h, and 11c,e were further evaluated for their VEGFR-2 inhibition. Compounds 4c and 4b potently inhibited VEGFR-2 at IC50 values of 0.12 ± 0.01 and 0.13 ± 0.02 μM, respectively, which are nearly equipotent to the sorafenib IC50 value (0.10 ± 0.02 μM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
- El-Helby, Abdel-Ghany A.,Sakr, Helmy,Eissa, Ibrahim H.,Al-Karmalawy, Ahmed A.,El-Adl, Khaled
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- Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists
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Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.
- Darwish, Khaled M.,Salama, Ismail,Mostafa, Samia,Gomaa, Mohamed S.,Khafagy, El-Sayed,Helal, Mohamed A.
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p. 1595 - 1602
(2018/04/05)
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- Synthesis and in vitro cytotoxicity evaluation of β-carboline-linked 2,4-thiazolidinedione hybrids: potential DNA intercalation and apoptosis-inducing studies
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A series of new β-carboline-thiazolidinedione hybrids was synthesized and assessed for in vitro cytotoxicity potential against selected human cancer cell lines, namely, PC-3, A549, MG-63, HCT-15, MDA-MB-231, A431, and PANC-1 along with a normal human cell line (L-132). Among this new series, compound 19e was found to exhibit promising cytotoxic effects against triple negative breast cancer cell line (MDA-MB-231) with IC50 value of 0.97 ± 0.13 μM. Hence, further mechanistic studies of the apoptosis-inducing effect of 19e were conducted on the MDA-MB-23 cell line. Moreover, characteristic apoptotic features such as membrane blebbing, chromatin condensation, and apoptotic body formation were observed with the effect of 19e on MDA-MB-231 cells using AO/EB and DAPI staining. The Annexin V-Alexa Flour 488/PI assay confirmed significant early apoptosis induction. Notably, DCFDA assay indicated that 19e induced ROS generation. Moreover, mitochondrial membrane potential collapse was observed through JC-1 staining by 19e. Furthermore, cell cycle analysis revealed that 19e arrested cells in the sub G1 phase. In addition, clonogenic and wound healing assays indicated inhibition of colony formation and cell migration by 19e in a dose-dependent manner. Next, molecular modelling and DNA binding affinity studies such as relative viscosity, circular dichroism and UV-visible spectroscopy denoted classic intercalation of 19e with CT-DNA with binding constant of 1 × 105 M?1.
- Tokala, Ramya,Thatikonda, Sowjanya,Sana, Sravani,Regur, Phanindranath,Godugu, Chandraiah,Shankaraiah, Nagula
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p. 16226 - 16236
(2018/10/04)
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- Coumarin thiadione compound and preparation method and application thereof
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The invention relates to a coumarin thiadione compound and a preparation method and application thereof, and belongs to the technical field of chemical synthesis. The coumarin thiadione compound and medicinal salt thereof are shown in formulas I to VIII; and the compound has a certain inhibiting activity for growth of gram positive bacteria, gram negative bacteria and fungi, and can be used for preparing an antibacterial and/or antifungal medicament, so that the coumarin thiadione compound gets a chance of providing diversified safer and more efficient candidate medicaments for clinical antimicrobial treatment and is helpful for solving clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, emerging harmful microorganisms and the like. Thecoumarin thiadione compound is simple in preparation raw material, cheap, easy to obtain and short in synthetic route, and has the important significance for application in the aspect of infection resistance. (The formulas are shown in the description.).
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Paragraph 0043; 0044; 0045; 0046
(2018/12/14)
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- Design, synthesis, molecular docking, and in vitro antidiabetic activity of novel PPARγ agonist
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Abstract: The present work describes the design, synthesis, molecular docking, biological evaluation, and assessment of structure–activity relationship of new derivatives based upon the molecular skeleton of the drug pioglitazone, a compound which is currently used for the management of type 2 diabetes mellitus. Pioglitazone has several side effects such as weight gain, edema, congestive heart failure, and bladder cancer. Therefore, there is a strong demand for identification of new lead candidates in the treatment of type 2 diabetes mellitus. A series of 24 compounds were prepared and evaluated for their peroxisome proliferator-activated receptor-γ (PPARγ) binding affinity assay and the IC50 values were determined. Among these compounds, six compounds exhibited promising IC50 values as compared to standard drugs pioglitazone and rosiglitazone. Furthermore, in order to confirm the target of these molecules, molecular docking study was carried out with peroxisome proliferator-activated receptor-γ (PPARγ) protein. Molecular modeling studies suggested that these compounds appropriately interact in the active sites of receptor. Graphical abstract: [Figure not available: see fulltext.].
- Chaturvedi, Radha Nandan,Pendem, Krishnaiah,Patel, Vipul P.,Sharma, Mukta,Malhotra, Sunita
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p. 2069 - 2084
(2018/08/22)
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- Exploring sulfonate esters of 5-arylidene thiazolidine-2,4-diones as PTP1B inhibitors with anti-hyperglycemic activity
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Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signaling pathway, hence considered as a new therapeutic target of intervention for the treatment of type 2 diabetes. A series of eleven aryl/alkyl sulfonyloxy-5-arylidene thiazolidine-2,4-dione derivatives were synthesized and screened in vitro for PTP1B inhibitory activity and in vivo for anti-hyperglycemic activity. The introduction of aryl/alkyl sulfonate ester moiety was anticipated to yield PTP1B inhibitors with significant potency. Docking results revealed their bidentate nature of binding, and further helped in understanding the binding mode of ligands inside PTP1B enzyme. Compounds 13 and 14 were found to be potent PTP1B inhibitors with IC50 8.53 and 6.89 μM, respectively. Compounds 13, 14, and 18 have also shown significant lowering of blood glucose level as compared to pioglitazone.
- Mahapatra, Manoj Kumar,Kumar, Rajnish,Kumar, Manoj
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p. 476 - 487
(2017/10/07)
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- N-alkylated thiazolidine-2,4-dione analogs as PTP1B inhibitors: synthesis, biological activity, and docking studies
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Protein tyrosine phosphatase 1B enzyme has been found to be a negative regulator of insulin and leptin signaling pathway. It has gained considerable attention to medicinal chemists as a new therapeutic target for intervention in the treatment of type2 diabetes. A series of N-substituted-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione derivatives were synthesized and screened in vitro for protein tyrosine phosphatase 1B inhibitory activity and in vivo for anti-hyperglycaemic activity. The introduction of alkyl/halo alkyl moiety onto the amidic nitrogen of thiazolidine-2,4-dione ring was intended to enhance the inhibitor-enzyme affinity and hence, good protein tyrosine phosphatase 1B inhibition. The nature of interactions which governs the binding mode of ligands inside the active site of protein tyrosine phosphatase 1B was further studied by molecular docking simulation. Compound 7 was found to be a potent protein tyrosine phosphatase 1B inhibitor with IC50 9.96 μM. The synthesized compounds have also shown significant lowering of blood glucose level.
- Mahapatra, Manoj K.,Kumar, Rajnish,Kumar, Manoj
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p. 1176 - 1183
(2017/05/04)
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- Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors
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A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz., methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively. Compound 11e exhibited potent PL inhibitory activity (IC50?=?4.81?μM and Xi50?=?10.01, respectively in method A and B), comparable to that of the standard drug, orlistat (IC50?=?0.99?μM and Xi50?=?3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking studies validated the rationale of pharmacophoric design and are in accordance to the in vitro results. Compound 11e exhibited a potential MolDock score of ?153.349?kcal/mol. Further, the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the hydrophobic lid domain. Moreover, the carbonyl group at 2nd position of the TZD ring existed adjacent to Ser 152 (≈3??) similar to that of orlistat. A 10?ns molecular dynamics simulation of 11e–PL complex revealed a stable binding conformation of 11e in the active site of PL (Maximum RMSD?≈?3??). The present study identified novel thiazolidinedione based leads with promising PL inhibitory activity. Further development of the leads might result in potent PL inhibitors.
- S.N.C., Sridhar,Bhurta, Deendyal,Kantiwal, Dharmvir,George, Ginson,Monga, Vikramdeep,Paul, Atish T.
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supporting information
p. 3749 - 3754
(2017/07/27)
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- Conventional and microwave-assisted synthesis of new 1H-benzimidazole-thiazolidinedione derivatives: A potential anticancer scaffold
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A series of new benzimidazole bearing thiazolidinedione derivatives has been designed, synthesized by using conventional as well as microwave-assisted methods. Microwave-assisted synthesis caused a significant reduction in the reaction times and improvement in the yields of all the derivatives. All the new synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines of breast (MDAMB-231), prostate (PC-3), cervical (HeLa), lung (A549) and bone (HT1080) along with a normal kidney cells (HeK-293T). The compounds 17n, 17p and 17q were found to be potent cytotoxic with IC50 values in the range of 0.096–0.63 μM on PC-3, HeLa, A549 and HT1080 cancer cells. Most of the compounds have found to be safe on normal HeK-293T kidney cells in comparison to cancer cells. The treatment of cells with 17p and 17q showed the typical apoptotic morphological features like fragmentation and shrinkage of nuclei. Further, test compounds resulted in inhibition of cell migration through disruption of F-actin protein assembly. Hoechst, DCFH-DA staining, mitochondrial membrane and annexin binding assays revealed that the cancer cell proliferation was inhibited through induction of apoptosis in A549 cells.
- Sharma, Pankaj,Reddy, T. Srinivasa,Kumar, Niggula Praveen,Senwar, Kishna Ram,Bhargava, Suresh K.,Shankaraiah, Nagula
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p. 234 - 245
(2017/07/04)
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- Copper(II)-complex functionalized magnetite nanoparticles: a highly efficient heterogeneous nanocatalyst for the synthesis of 5-arylidenthiazolidine-2,4-diones and 5-arylidene-2-thioxothiazolidin-4-one
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Abstract: Magnetite nanoparticles (MNPs) have proved to be a useful support for heterogeneous catalysis. We have synthesized Fe3O4 MNPs functionalized with a copper(II) complex, and tested the resulting material as a heterogeneous nanocatalyst. The catalyst was tested for aldol condensation reactions between aliphatic/aromatic aldehydes and rhodanine or thiazolidine-2,4-dione (TZD) derivatives under reflux in ethanol, giving the target products in high yield. Environmentally benign chemistry, short reaction times, simple work-up, excellent yields, and the reusability of the new nanocatalyst are beneficial features of the present study. The nanocatalyst was characterized by scanning electron microscopy, vibrating sample magnetometery, thermogravimetry, X-ray diffraction, and energy-dispersive X-ray analyses. The data showed that the magnetic nanoparticles are super-paramagnetic with a size range of 10–20?nm. Graphical Abstract: [Figure not available: see fulltext.].
- Akhavan, Malihe,Foroughifar, Naser,Pasdar, Hoda,Khajeh-Amiri, Alireza,Bekhradnia, Ahmadreza
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p. 543 - 552
(2017/08/15)
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- Compound capable of inhibiting activity of NEDD8 kinase as well as preparation method and pharmaceutical application of compound
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The invention belongs to the field of medicines and in particular relates to a compound with the structure of a formula I, a stereomer of the compound or pharmaceutically acceptable salts of the compound as well as a preparation method of the compound and application of the compound to preparation of anti-tumor medicines. A pharmacological experiment result shows that the compound can be used for inhibiting the activity of NEDD8 kinase and has the inhibition effect on proliferation of a plurality of types of tumor cells, so that the compound can be used as an NEDD8 kinase activity inhibitor for preparing the anti-tumor medicines. The formula I is shown in the description.
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Paragraph 0107; 0108; 0109
(2016/10/10)
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- Synthetic optimization of rosiglitazone and related intermediates for industrial purposes
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As an important newly Food and Drug Administration (FDA)-approved drug for treating diabetes, rosiglitazone (1) has received much attention from researchers in many areas. To search for an economical and convenient synthesis method for 1, we explored the reaction conditions and workup of a scalable five-step synthetic route by an orthogonal method to determine the best condition for each reaction step. The starting materials are commercially available, including 2-chloropyridine (2), N-methylethanolamine (3), 4-fluorobenzaldehyde (4a) or 4-hydroxybenzaldehyde (4b), and 1,3-thiazolidine-2,4-dione (5). The five sequential reaction steps are cyclization, alkylation, etherification, condensation, and reduction, having optimal yield of 90, 99, 59, 75, and 91 %, respectively. The best overall yield to synthesize rosiglitazone based on compound 2 was 40 %, being suitable for industrial purposes, using water as a green solvent and avoiding column chromatography during the last three reaction steps.
- Meng, Ge,Zheng, Meilin,Dong, Mengshu,Gao, Yang,Zheng, Aqun,Li, Zhenyu,Hu, Ruizhi
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p. 2023 - 2033
(2016/03/16)
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- Synthesis, anti-hyperglycaemic activity, and in-silico studies of N-substituted 5-(furan-2-ylmethylene)thiazolidine-2,4-dione derivatives
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Thiazolidinedione derivatives have been used as anti-hyperglycemic agents in diabetic patients since last decade. In the present study, a series of N-substituted-5-(furan-2-ylmethylene)thiazolidine-2,4-dione derivatives were synthesized and characterized by 1H-NMR, 13C-NMR and mass spectra. The introduction of the alkyl/haloalkyl moiety onto the amidic nitrogen of the thiazolidine-2,4-dione ring was intended to enhance the anti-hyperglycaemic activity, which was further tested in vivo by using alloxan-induced diabetic laca mice. Molecular docking simulation studies further helped in understanding the nature of the interactions and the binding mode of ligands inside the active site of the protein tyrosine phosphatase 1B enzyme, which negatively regulates the insulin signaling pathway. The compounds were screened for in-vivo anti-hyperglycaemic activity in which compounds 9 and 10 have exhibited significant decreases in blood glucose level comparable to that of pioglitazone.
- Mahapatra, Manoj Kumar,Saini, Rajnish,Kumar, Manoj
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p. 8239 - 8251
(2016/11/25)
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- Design, synthesis, and biological evaluation of novel thiazolidinediones as PPAR3/FFAR1 dual agonists
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Diabetes mellitus is a chronic metabolic disorder that affects more than 180 million people worldwide. Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors that have been targeted by the thiazolidinedione (TZD) class of compounds for the management of type II diabetes. PPAR3 is known to regulate adipogenesis and glucose metabolism. Another emerging target for the design of antidiabetic agents is the free fatty acid receptor 1 (FFAR1), previously known as GPR40. Agonists of this receptor were found to enhance insulin secretion in diabetic patients. It has been reported that some thiazolidinediones (TZDs) activate FFAR1 with micromolar potency. In this study, based on docking studies into the crystal structure of PPAR3 and a homology model of FFAR1, nineteen compounds were designed, synthesized, and biologically tested for agonistic activity on both receptors. Nine compounds showed promising dual activity, with two compounds, 11a and 5b, having affinities in the low micromolar range on both targets. These molecules represent the first antidiabetic agents that could act as insulin sensitizers as well as insulin secretagogues.
- Darwish, Khaled M.,Salama, Ismail,Mostafa, Samia,Gomaa, Mohamed S.,Helal, Mohamed A.
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p. 157 - 172
(2016/01/16)
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- Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors
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Leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L.?major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm?=?11?°C, p?=?0,01). Kinetic assays reveal that 2d has IC50?=?44.67?±?1.74?μM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50?000?ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors.
- Leite, Franco Henrique A.,Santiago, Priscila Brand?o Gomes da Silva,Froes, Thamires Quadros,da Silva Filho, Jo?o,da Silva, Suellen Gon?alves,Ximenes, Rafael M.,de Faria, Ant?nio Rodolfo,Brondani, Dalci José,de Albuquerque, Julianna F.C.,Castilho, Marcelo Santos
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p. 639 - 648
(2016/08/19)
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- Synthesis and biological evaluation of new benzimidazole-thiazolidinedione hybrids as potential cytotoxic and apoptosis inducing agents
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A series of new benzimidazole-thiazolidinedione hybrids has been synthesized and evaluated for their cytotoxic potential against a selected human cancer cell lines of prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal breast epithelial cells (MCF10A). Among the tested compounds, 11p exhibited promising cytotoxicity with IC50value of 11.46?±?1.46?μM on A549 lung cancer cell line and did not show significant toxicity on normal MCF10A cells. Lung cancer cells (A549) have been used to know the mechanism of cell growth inhibition and apoptosis inducing effect with compound 11p. The treatment of A549?cells with 11p showed typical apoptotic morphology like cell shrinkage, chromatin condensation and horseshoe shaped nuclei formation. Flow-cytometry analysis revealed the G2/M phase of cell cycle arrest in a dose dependent manner. Preliminary mechanistic studies suggested that the cell migration was inhibited through the disruption of F-actin protein. Acridine orange-ethidium bromide (AO-EB), DAPI, annexin V-FITC/propidium iodide, rhodamine-123 and MitoSOX assays suggested the induction of apoptosis in A549 cells by compound 11p.
- Sharma, Pankaj,Srinivasa Reddy,Thummuri, Dinesh,Senwar, Kishna Ram,Praveen Kumar, Niggula,Naidu,Bhargava, Suresh K.,Shankaraiah, Nagula
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p. 608 - 621
(2016/09/14)
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- Design and synthesis of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs as bacterial peptide deformylase inhibitors
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Herein, we report the synthesis and screening of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC50 value?=?139.28?μm), 11g (IC50 value?=?136.18?μm), and 11h (IC50 value?=?131.65?μm) had shown good PDF inhibition activity. The compounds 11b (MIC range?=?103.36–167.26?μg/mL), 11g (MIC range?=?93.75–145.67?μg/mL), and 11h (MIC range?=?63.61–126.63?μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range?=?100.00–250.00?μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.
- Khan, Firoz A. Kalam,Patil, Rajendra H.,Shinde, Devanand B.,Sangshetti, Jaiprakash N.
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p. 938 - 944
(2016/11/11)
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