- Benzthiazole-derived chromogenic, fluorogenic and ratiometric probes for detection of hydrazine in environmental samples and living cells
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Benzothiazole-based chromogenic and ratiometric fluorescent chemodosimetric probes CD1 and CD2, were synthesized and characterized. The probes are designed in such a way that the excited state intramolecular proton transfer (ESIPT) of the benzothiazole moiety gets blocked. Upon treatment with hydrazine in organo-aqueous medium[DMSO: H2O; 2:1 (v/v)] at physiological pH, the aectyl protective group of probes CD1 and CD2 were removed readily in presence hydrazine and ESIPT of the probes were switched on, which resulted remarkable photo-physical changes. These two ESIPT–based ratiometric fluorescent probes were shown to be selective and sensitive for hydrazine among different cations, anions and amines studied in organo-aqueous medium[DMSO: H2O; 2:1 (v/v)] at physiological pH, by fluorescence, absorption, and visual emission color change. These key features allows the two probes to be employed for hydrazine detection by simple visual inspection. DFT and TDDFT calculations were performed in order to demonstrate the sensing mechanism and the electronic properties of probe and hydrazinolysis product. An easy-to-prepare test strips, obtained by dipping the TLC plates into the solution of CD1 and CD2, were able to detect hydrazine in practical samples. Moreover, the utility of the probes CD1 in showing the hydrazine recognition in live cells has also been demonstrated using Vero cells as monitored by fluorescence imaging.
- Mahapatra, Ajit Kumar,Karmakar, Parthasarathi,Manna, Srimanta,Maiti, Kalipada,Mandal, Debasish
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- A simple and effective ratiometric fluorescent probe for the selective detection of cysteine and homocysteine in aqueous media
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Biothiols such as cysteine (Cys) and homocysteine (Hcy) are essential biomolecules participating in molecular and physiological processes in an organism. However, their selective detection remains challenging. In this study, ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (NL) was synthesized as a ratiometric fluorescent probe for the rapid and selective detection of Cys and Hcy over glutathione (GSH) and other amino acids. The fluorescence intensity of the probe in the presence of Cys/Hcy increased about 3-fold at a concentration of 20 equiv. of the probe, compared with that in the absence of these chemicals in aqueous media. The limits of detection of the fluorescent assay were 0.911 μM and 0.828 μM of Cys and Hcy, respectively. 1H-NMR and MS analyses indicated that an excited-state intramolecular proton transfer is the mechanism of fluorescence sensing. This ratiometric probe is structurally simple and highly selective. The results suggest that it has useful applications in analytical chemistry and diagnostics.
- Na, Risong,Zhu, Meiqing,Fan, Shisuo,Wang, Zhen,Wu, Xiangwei,Tang, Jun,Liu, Jia,Wang, Yi,Hua, Rimao
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- Biological evaluation of mitochondria targeting small molecules as potent anticancer drugs
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Cancer therapy targets specific metabolic pathways or a single gene. This may result in low therapeutic effects due to drug selectivity and drug resistance. Recent studies revealed that the mitochondrial membrane potential and transmembrane permeability of cancerous mitochondria are differed from normal mitochondria. Thus, chemotherapy targeting cancerous mitochondria could be an innovative and competent strategy for cancer therapy. Previously, our work with a novel group of mitochondria targeting small molecules presented promising inhibitory capability toward various cancer cell lines and suppressed adenosine triphosphate (ATP) generation. Therefore, it is critical to understand the anticancer effect and targeting mechanism of these small molecules. This study investigated the inhibitory activity of mitochondria targeting small molecules with human cervical cancer cells – HeLa to further explore their therapeutic potential. HeLa cells were exposed to 10 μM of synthesized compounds and presented elevation in intracellular reactive oxygen species (ROS) level, impaired mitochondrial membrane potential and upregulation of apoptosis as well as necrosis. In vivo, HeLa cell tumor-bearing BALB/c nude mice were treated with mitochondria targeting small molecules for 12 days consecutively. Throughout this chemotherapy study, no deleterious side effects nor the appearance of toxicity was observed. Furthermore, mitochondria targeting small molecules treated groups exhibited significant down-regulation with both tumor volume and tumor weight compared to the Doxorubicin (DOX) treated group. Thus, inhibition of mitochondrial ATP synthesis, activation of intracellular ROS production, down-regulation of mitochondrial membrane potential and upregulation of apoptosis and necrosis rates are the indications of cancer therapy. In this work, we examined the anticancer capability of four mitochondria targeting small molecules in vitro and in vivo, and demonstrated a novel therapeutic approach in cancer therapy with tremendous potential.
- Luo, Shuhua,Dang, Xin,Wang, Juntao,Yuan, Chang,Hu, Yixin,Lei, Shuwen,Zhang, Yang,Lu, Dan,Jiang, Faqin,Fu, Lei
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- Reaction-based ratiometric fluorescent probe for selective recognition of sulfide anions with a large Stokes shift through switching on ESIPT
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An ESIPT-based, highly selective, ratiometric fluorescent probe BNPT has been synthesized and characterized, which shows turn-on fluorescence response in the presence of S2-, attributed to the removal of a protective 2,4-dinitrobenzene (DNB) moiety, and the resulting fluorescent product has been used for the selective detection of Zn2+. UV-vis and fluorescence spectroscopy analysis, and DFT and TDDFT calculations were carried out to understand the sensing mechanism. The probe BNPT displays a rapid response time and good sensitivity. The probe can detect quantitatively in a concentration range of 0-6.0 μM. The detection limit is 31.3 nM. The sensing ability of BNPT has been successfully applied in real water samples. Applicability as an in-field test kit has been demonstrated by sensing with a BNPT-coated TLC plate. The probe BNPT has been successfully used for visualization of intracellular environment in living cells. The uniqueness lies in the fact that starting with the probe BNPT, sensing can be achieved by two different mechanisms-first, by selective de-protection of the probe BNPT and second, by reacting with the Zn2+ ensemble with S2-.
- Karmakar, Parthasarathi,Manna, Srimanta,Ali, Syed Samim,Guria, Uday Narayan,Sarkar, Ripon,Datta, Pallab,Mandal, Debasish,Mahapatra, Ajit Kumar
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- Design, synthesis, cytotoxic evaluation and molecular docking studies of novel thiazolyl α-aminophosphonates
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Abstract: A new class of thiazolyl α-aminophosphonate derivatives was synthesized by one-pot Kabachnik–Fields reaction of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate with various aryl amines and diethyl phosphite under solvent-free conditions using β-cyclodextrin supported sulfonic acid (β-CD-SO3H) as an efficient, reusable and heterogeneous solid acid catalyst. The products were obtained in good to excellent yields at shorter reaction time. All the title compounds were screened for cytotoxic activity against human breast cancer (MCF-7 and MDA-MB-231), prostate cancer (DU-145) liver cancer (HepG2) and HeLa cancer cell lines using sulfarodamine-B (SRB assay). Compounds (8b, –4OMe), (8h, –4NO2) and (8j, –2I, –4CF3) showed better anticancer activity when compared with standard drug Adriamycin. Further in-silico target hunting reveals the anticancer activity of the designed compounds by inhibiting DNA topoisomerase II. Graphical abstract: [Figure not available: see fulltext.].
- Gundluru, Mohan,Badavath, Vishnu Nayak,Shaik, Haroon Yasmin,Sudileti, Murali,Nemallapudi, Bakthavatchala Reddy,Gundala, Sravya,Zyryanov, Grigory V.,Cirandur, Suresh Reddy
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- Design, synthesis and biological evaluation of novel thiazole-derivatives as mitochondrial targeting inhibitors of cancer cells
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Mitochondria are pivotal energy production sources for cells to maintain necessary metabolism activities. Targeting dysfunctional mitochondrial features has been a hotspot for mitochondrial-related disease researches. Investigation with cancerous mitochondrial metabolism is a continuing concern within tumor therapy. Herein, we set out to assess the anti-cancer activities of a novel family of TPP-thiazole derivatives based on our earlier research on mitochondrial targeting agents. Specifically, we designed and synthesized a series of TPP-thiazole derivatives and revealed by the MTT assay that most synthesized compounds effectively inhibited three cancer cell lines (HeLa, PC3 and MCF-7). After structure modifications, we explored the SAR relationships and identified the most promising compound R13 (IC50 of 5.52 μM) for further investigation. In the meantime, we performed ATP production assay to assess the selected compounds inhibitory effect on HeLa cells energy production. The results displayed the test compounds significantly restrained ATP production of cancer cells. Overall, we have designed and synthesized a series of compounds which exhibited significant cytotoxicity against cancer cells and effectively inhibited mitochondrial energy production.
- Dang, Xin,Lei, Shuwen,Luo, Shuhua,Hu, Yixin,Wang, Juntao,Zhang, Dongdong,Lu, Dan,Jiang, Faqin,Fu, Lei
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- Synthesis, molecular docking, DFT study of novel N-benzyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxamide derivatives and their antibacterial activity
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A series of febuxostat based new chemical entities was synthesized using microwave method and characterized by NMR, mass and FT-IR spectral studies. Molecular docking of febuxostat amide nucleus substitution compounds 8c (-7.91kcal/mol), 8g (-7.94 kcal/mol) exhibiting high binding energy against ALK receptors. Theoretical investigation of MEPs, HOMO, LUMO and energy gap of HOMO-LUMO were calculated by B3LYP/6-31G method. Among the tested compounds, methoxy substituted compound 8g showed highest antibacterial activity against S. aereus and B. subtilis.
- Sam Daniel Prabu,Lakshmanan, Sivalingam,Thirumurugan,Ramalakshmi,Arul Antony
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p. 619 - 626
(2020/02/06)
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- New preparation method of febuxostat intermediate
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The invention relates to a new preparation method of a febuxostat intermediate. The method includes: taking cheap 4-hydroxybenzaldehyde as an initial raw material, firstly preparing aldoxime from 4-hydroxybenzaldehyde and hydroxylamine hydrochloride, then adding a corresponding thio reagent, and preparing a compound 4-hydroxythiobenzamide (152A1-00) by Beckmann rearrangement reaction; utilizing one-pot process, adopting cheap 4-hydroxybenzaldehyde as an initial raw material, carrying out a series of reactions, and then performing cyclization with 2-halogenated ethyl acetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate or different salt forms (152A2x) thereof; and using isobutyl sulfonate (152H1x) with more easily controllable quality to replace bromo-isobutane soas to prepare ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (152A4-00). In conclusion, the method provided by the invention is more beneficial to safe, simple and cost-efficientindustrial scale preparation of the febuxostat intermediate with higher purity.
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- One-pot synthesis of 2 - (4 - hydroxy phenyl) -4 - methyl - 1, 3 - thiazole -5 - carboxylic acid ethyl ester (by machine translation)
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The present invention discloses a one-pot synthesis of 2 - (4 - hydroxy-phenyl) - 4 - methyl - 1, 3 - thiazole - 5 - carboxylic acid ethyl ester method, the method to the benzaldehyde as the starting material, including cyano reaction, sulfur acylation reaction, the cyclization reaction step. For the method of the invention synthetic anti-Gout medicine febuxostat important intermediate 2 - (4 - hydroxy-phenyl) - 4 - methyl - 1, 3 - thiazole - 5 - carboxylic acid ethyl ester, synthetic short process flow, after treatment is simple, the operation is simplified, and reduces the production difficulty and labor intensity, is suitable for industrial production; the method of the invention low cost, high yield, high purity, at the same time reduce industrial discharge of three wastes, raw materials can be recycled, saving resources and environmental protection. The invention can result in significant social and economic benefits. (by machine translation)
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Paragraph 0022; 0026-0033
(2019/02/27)
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- 2 - (3 - aldehyde - 4 - isobuoxy phenyl) - 4 - methyl thiazole - 5 - carboxylic acid ethyl ester
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The invention provides a method for synthesizing high-purity ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate. The method comprises the following steps of carrying out thioacylation reaction on p-cyanophenol and thioacetamide as starting materials to obtain 4-hydroxythiobenzamide (II), directly carrying out thiazole reaction on the reaction product which is not separated and separating to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole formate (III); carrying out formylation reaction on the compound as shown in the formula (III) to obtain ethyl 2-(3-carbaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazole formate (IV), directly carrying out isobutylation reaction on the reaction product which is not separated to obtain ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate (I) of which the purity is equal to or greater than 99% and the content is equal to or greater than 99%. The production process is optimized and thus the quality of the product is greatly improved and the high yield is achieved.
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- Process method for synthesizing thioamide
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The invention discloses a process method for synthesizing thioamide. The process method comprises the step of synthesizing a thioamide compound from aliphatic nitrile or aromatic nitrile as raw materials and sodium sulfide metal salt or ammonium sulfide salt and amine salt or ammonium salt in one step in a certain solvent. The method for synthesizing thioamide is high in safety and low in environmental pollution, and expensive raw materials are not used, so that the method is economic and environment-friendly.
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Paragraph 0068; 0069
(2017/08/30)
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- A NOVEL PROCESS FOR PREPARATION OF ETHYL 2-(4-HYDROXY-3-NITROPHENYL)-4-METHYL-5-THIAZOLECARBOXYLATE
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A novel process for preparation of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate is disclosed. The process involves reaction of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate with metal nitrate in presence of acid chloride and N,N-Dimethylformamide to produce title compound with improved yield and economics than that reported in the prior art.
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- Synthesis, characterization and antimicrobial activity of ethyl 2-(3-formyl-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)-alkoxy-)phenyl)-4-methylthiazole-5-carboxylate derivatives
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During the present study, a number of substituted thiazole derivatives have been synthesized by the reaction of 4-hydroxybezene-1-carbothiomide and ethyl-2-chloro acetoacetate to give ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. The latter reacts with PPA, HMTA and acetic acid to yield ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. These compounds further react with di-bromo alkane and 4-hydroxy coumarin to give the final thiazole derivatives. These are characterized by elemental analysis, IR and 1H NMR spectra, and have been screened for their antimicrobial activity and found to have significant effect against the tested microorganisms. Some of the synthesized thiazole derivatives are found to exhibit promising activity.
- Malik,Naik, Chirag G.
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p. 1005 - 1010
(2015/08/19)
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- Synthesis of the major metabolites of febuxostat
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Total synthesis of three Febuxostat metabolites, named 67M-1, 67M-2, and 67M-4,is described in this article. Through condensation of the key intermediate compound A with different side chains, and then oxidation and hydrolysis, we obtained three target compounds with an overall yield of 19.5%-28.0%.
- Li, Xiao Long,Qiu, Rui,Wan, Wei Li,Cheng, Xu,Hai, Li,Wu, Yong
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p. 217 - 221
(2015/06/23)
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- IMPROVED PROCESS FOR THE PREPARATION OF FEBUXOSTAT
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An improved and efficient process for the preparation of 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (febuxostat) that is substantially free from amide by-product is provided.
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Page/Page column 12
(2012/02/13)
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- PROCESS FOR FEBUXOSTAT
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The present invention provides a process for the preparation of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. The present invention also provides a process for the preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. The present invention further provides novel crystalline Forms of febuxostat, processes for their preparation and pharmaceutical compositions comprising them. The present invention further provides febuxostat crystalline particles having a mean particle size of less than about 25 μm, the methods for the manufacture of said crystalline particles, and pharmaceutical compositions comprising said crystalline particles.
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Page/Page column 10
(2013/02/27)
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- COMPOUNDS AND METHODS FOR MODULATING FXR
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Compounds of formula. wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
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Page/Page column 14
(2008/06/13)
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- Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARα agonists. 1. Discovery of a novel series of potent HDLc raising agents
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The peroxisome proliferator activated receptors PPARα, PPARγ, and PPARδ are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARα agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARα agonists. Modification of the selective PPARδ agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARα agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARα and at least 500-fold selectivity versus PPARγ and PPARγ. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
- Sierra, Michael L.,Beneton, Véronique,Boullay, Anne-Bénédict,Boyer, Thierry,Brewster, Andrew G.,Donche, Frédéric,Forest, Marie-Claire,Fouchet, Marie-Hélène,Gellibert, Fran?oise J.,Grillot, Didier A.,Lambert, Millard H.,Laroze, Alain,Le Grumelec, Christelle,Linget, Jean Michel,Montana, Valerie G.,Nguyen, Van-Loc,Nicodème, Edwige,Patel, Vipul,Penfornis, Annie,Pineau, Olivier,Pohin, Danig,Potvain, Florent,Poulain, Géraldine,Ruault, Cécile Bertho,Saunders, Michael,Toum, Jér?me,Xu, H. Eric,Xu, Robert X.,Pianetti, Pascal M.
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p. 685 - 695
(2007/10/03)
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- Substituted thiazoles
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This invention is directed to processes for making substituted thiazoles. The substituted thiazole, ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate, also known as TEI-6720, is useful for treatment of gout and hyperuricemia. This compound belongs to a class of substituted thiazoles that inhibit xanthine oxidase and thus block uric acid production.
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- Substituted thiazoles
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This invention is directed to processes for making substituted thiazoles. The substituted thiazole, ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate, also known as TEI-6720, is useful for treatment of gout and hyperuricemia. This compound belongs to a class of substituted thiazoles that inhibit xanthine oxidase and thus block uric acid production.
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Page/Page column 3
(2008/06/13)
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