- Phenylthiazole antibiotics: A metabolism-guided approach to overcome short duration of action
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Antibacterial resistance is a pressing global health challenge that necessitates the development of new therapeutic agents. Phenylthiazole antibacterial agents have been extensively studied, by our group, as a potential novel class of antibiotics to circumvent the scourge of antibacterial resistance. Previously, the phenylthiazole lead compound 1 was shown to possess potent activity against clinical isolates of methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). The promising activity of this novel class of antibiotics is hampered by their short half-life due to rapid hepatic metabolism. In the present study, a metabolic methylene soft spot in the lead 1 was identified and replaced with an oxygen atom. The newly developed phenylthiazoles, with alkoxy side chains, demonstrate high metabolic stability (t1/2> 4 h), while maintaining their potent anti-MRSA activity. Furthermore, compound 5p demonstrated a selective advantage over vancomycin with its ability to kill intracellular MRSA.
- Yahia, Eman,Mohammad, Haroon,Abdelghany, Tamer M.,Fayed, Eman,Seleem, Mohamed N.,Mayhoub, Abdelrahman S.
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Read Online
- Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents
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Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound 15cwas found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC50= 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC50values in the range of 30-144 nM. Compound 15cinhibited B16-F10 cancer cell migration and colony formation. In addition, 15cdemonstrated significantin vivoantitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, 15cpresented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity. Collectively, this work shows that compound 15crepresents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.
- Chen, Jianjun,Chen, Jingxuan,Huang, Junli,Li, Ling,Liu, Jin,Peng, Xiaopeng,Ren, Yichang,Sun, Zhiqiang
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p. 8447 - 8473
(2021/06/28)
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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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Paragraph 0027; 0054-0058; 0063-0068
(2020/03/06)
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- SSAO INHIBITOR
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The present invention provides an SSAO inhibitor and an application thereof in preparing a drug for treating a disease related to SSAO. In particular, the present invention provides a compound shown in formula (IV) and a pharmaceutically acceptable salt thereof.
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Paragraph 0435; 0436; 0437; 0589; 0590; 0591
(2020/04/02)
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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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- 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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- TOLL-LIKE RECEPTOR SIGNALING INHIBITORS
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Di- and triaryl-substituted heteroaromatic compounds have Toll-like receptor inhibitory activity, including at TLR2, TLR4, TLR7, and/or TLR9. Compounds and compositions have applications in the treatment of diseases and conditions mediated by Toll-like receptors and related receptors, such as bacterial sepsis, autoimmune disease, lupus erythematosus, ischemia-reperfusion injury, stroke, metabolic disease, obesity-related metabolic inflammation, gout, and cancer.
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Paragraph 00336-00340
(2019/07/20)
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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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supporting information
p. 76 - 84
(2017/12/28)
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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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Paragraph 0049
(2017/08/25)
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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 0043; 0044; 0046; 0048; 0063; 0065; 0067; 0071
(2017/08/30)
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- 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 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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Page/Page column 3
(2016/04/20)
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- Arylthioamides as H2S donors: L-cysteine-activated releasing properties and vascular effects in vitro and in vivo
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A small library of arylthioamides 1-12 was easily synthesized, and their H2S-releasing properties were evaluated both in the absence or in the presence of an organic thiol such as l-cysteine. A number of arylthioamides (1-3 and 7) showed a slow and l-cysteine-dependent H2S-releasing mechanism, similar to that exhibited by the reference slow H2S- releasing agents, such as diallyl disulfide (DADS) and the phosphinodithioate derivative GYY 4137. Compound 1 strongly abolished the noradrenaline-induced vasoconstriction in isolated rat aortic rings and hyperpolarized the membranes of human vascular smooth muscle cells in a concentration-dependent fashion. Finally, a significant reduction of the systolic blood pressure of anesthetized normotensive rats was observed after its oral administration. Altogether these results highlighted the potential of arylthioamides 1-3 and 7 as H 2S-donors for basic studies, and for the rational design/development of promising pharmacotherapeutic agents to treat cardiovascular diseases.
- Martelli, Alma,Testai, Lara,Citi, Valentina,Marino, Alice,Pugliesi, Isabella,Barresi, Elisabetta,Nesi, Giulia,Rapposelli, Simona,Taliani, Sabrina,Da Settimo, Federico,Breschi, Maria C.,Calderone, Vincenzo
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supporting information
p. 904 - 908
(2013/10/22)
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- METHOD FOR PRODUCING 4-SUBSTITUTED BENZOTHIOAMIDE DERIVATIVE
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Disclosed is a method appropriate for safely, economically and easily producing at a high yield a 4-substituted benzothioamide derivative which is useful as an intermediate in the production of a 2-(3-cyanophenyl)thiazole derivative useful as a drug for gout. Specifically disclosed is a method for producing a 4-substituted benzothioamide derivative represented by formula (A).
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Page/Page column 4
(2012/04/05)
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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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- Synthesis and biological activities of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors
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A novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues possessing potent in vitro inhibitory activity against p38 mitogen-activated protein kinase and the release of tumor necrosis factor-α (TNF-α) from human monocytic THP-1 cells stimulated by lipopolysaccharide has been identified. Subsequent structure-activity relationship (SAR) studies and optimization for absorption, distribution, metabolism, and elimination (ADME) profiles led to the identification of compounds 7g and 10b as orally active lead candidates that block the in vivo production of proinflammatory cytokine (TNF-α). In pharmacokinetic studies, compound 10b showed good oral administration in mice and demonstrated significant in vivo anti-inflammatory activity in an anti-collagen monoclonal antibody-induced arthritis mouse model (minimum effective dose (MED)=30 mg/kg). Further elucidation of this class of compounds may provide novel anti-inflammatory agents, such as anti-rheumatoid arthritis drugs.
- Miwatashi, Seiji,Arikawa, Yasuyoshi,Naruo, Ken-Ichi,Igaki, Keiko,Watanabe, Yasumasa,Kimura, Hiroyuki,Kawamoto, Tomohiro,Ohkawa, Shigenori
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p. 410 - 418
(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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- Simple microwave-assisted method for the synthesis of primary thioamides from nitriles
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Primary thioamides are prepared in excellent yield from the corresponding nitrile by treatment with ammonium sulfide in methanol, at room temperature for electron-deficient aromatic nitriles or under microwave irradiation at 80 °C or 130 °C in 15-30 minutes for other aromatic and aliphatic nitriles. This procedure avoids the use of gaseous H2S under high pressure, proceeds in the absence of base and provides thioamides usually without the need for chromatographic purification.
- Bagley, Mark C.,Chapaneri, Krishna,Glover, Christian,Merritt, Eleanor A.
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p. 2615 - 2617
(2007/10/03)
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- SUBSTITUTED THIAZOLE DERIVATIVES BEARING 3-PYRIDYL GROUPS, PROCESS FOR PREPARING THE SAME AND USE THEREOF
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The present invention provides a pharmaceutical composition having a steroid C17,20-lyase inhibitory activity, which is useful as a prophylactic or therapeutic agent of prostatism, tumor such as breast cancer and the like, more particularly, a steroid C17,20-lyase inhibitor containing a compound represented by the formula: wherein A1 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, one of A2 and A3 is a hydrogen atom, a halogen atom, a C1-4 aliphatic hydrocarbon group optionally having substituents or an optionally esterified carboxyl group, the other of A2 and A3 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and at least one of A1, A2 and A3 is a 3-pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.
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Page/Page column 40
(2008/06/13)
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- Bita3 adrenergic receptor agonists and uses thereof
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The instant invention provides β3 adrenergic receptor agonists of structural Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R1, R2, R3, R4, R5, R6, R7, R8, X, and Y, are as defined herein. The invention further provides intermediates useful in the preparation of the compounds of Formula (I), to combinations of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, with anti-obesity agents; to pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, or pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, and anti-obesity agents; and methods of treating β3 adrenergic receptor-mediated diseases, conditions, or disorders in a mammal which methods comprise administering to the mammal an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a combination of a compound of Formula (I), a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof.
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- 4-(Cyclic amidino)phenols-preparation and use in a diamidine synthesis
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The Pinner synthesis was applied to the preparation of 4-(cyclic amidino)phenols in high yields from readily available 4-hydroxybenzimidic acid methyl ester hydrochloride and diaminoalkanes. An alternative attempt was made to convert 4-(hydroxy)thiobenzamide to 4-(1,4,5,6-terahydro-5- hydroxy-2-pyrimidinyl)phenol. A procedure for the preparation of 3,6-bis(4- hydroxyphenyl)-1,2,4,5-tetrazine is reported here. The syntheses of 2,4- bis[4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy]pyrimidine and 2-chloro-4-[4- (4,5-dihydro-1H-imidazol-2-yl)-phenoxy]pyrimidine exemplify the use of the title synthetic intermediates.
- Spychala, Jaroslaw
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p. 1083 - 1094
(2007/10/03)
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- DETERMINATION OF THE SUBSTITUENT CONSTANT ?-p FOR THE THIOAMIDE GROUP -CSNH2 FROM THE IONIZATION OF ANILINES AND PHENOLS
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Thermodynamic ionization constants pKa 2.62 +/- 0.01 for the primary aromatic amino group of 4-aminothiobenzamide and pKa 8.28 +/- 0.01 for the phenolic hydroxy group of 4-hydroxythiobenzamide have been determined by ultra-violet spectrophotometry at 25 deg C.By using these pKa values and the Hammett equations (log Ka vs ?) for the ionization of fourteen 3- or 4-substituted phenols and thirteen 3- or 4-substituted anilines the substituent constant ?p- = 0.68 (from the ionization of anilines) or ?p- = 0.73 (from the ionization of phenols) of the thioamide group -CSNH2 was calculated.
- Polasek, Miroslav,Waisser, Karel,Boucek, Tomas
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p. 2964 - 2968
(2007/10/02)
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- THE REACTION OF NITRILES WITH O,O-DIALKYL-DITHIOPHOSPHORIC ACIDS
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Nitriles react with dialkyldithiophosphoric acids 2a-c to give a mixture of corresponding thioamides and O,O-dialkyl-N-thioacetyl-phosphoroamidothioates 3a-e.The structure of compounds 3 are elucidated chemically and from electronic spectra.The yield of thioamides are improved from the reaction of nitriles with compound 2b in presence of water.Mechanistic consideration on the formation of the products are discussed.
- Yousif, N. M.
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p. 4599 - 4604
(2007/10/02)
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- STUDIES ON ORGANOPHOSPHORUS COMPOUNDS PART 55 THE TRANSFORMATION OF NITRILES TO THIOAMIDES WITH O,O-DIALKYLDITHIOPHOSPHORIC ACID
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The reaction between nitriles and O,O-dialkyldithiophosphoric acid (2) under anhydrous conditions produces O,O-diethyl-N-thiobenzoylamidophosphate (5), contrary to literature.When water is present the same reaction gives the corresponding thioamides in reasonable to good yields.Mechanistic considerations and spectral data are presented for the products.
- Shabana, R.,Meyer, H.J.,Lawesson, S.-O.
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p. 297 - 306
(2007/10/02)
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