- Convenient one-pot formation of highly functionalized 5-bromo-2-aminothiazoles, potential endocannabinoid hydrolase MAGL inhibitors
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Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents could be easily prepared by a rapid and efficient one-pot method, using simple starting materials and mild conditions while avoiding the use of metal catalysts or inconvenient reagents such as elemental halogens. These useful products can serve as starting materials for other reactions or as pharmacologically interesting compounds. In our work we have shown that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL) inhibition in the μM range.
- Prevost, Julien R.C.,Kozlova, Arina,Es Saadi, Bouazza,Yildiz, Esra,Modaffari, Sara,Lambert, Didier M.,Pochet, Lionel,Wouters, Johan,Dolu?ic?, Eduard,Frédérick, Rapha?l
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supporting information
p. 4315 - 4319
(2018/11/03)
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- Synergism of fused bicyclic 2-aminothiazolyl compounds with polymyxin B against: Klebsiella pneumoniae
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A series of fused bicyclic 2-aminothiazolyl compounds were synthesized and evaluated for their synergistic effects with polymyxin B (PB) against Klebsiella pneumoniae (SIPI-KPN-1712). Some of the synthesized compounds exhibited synergistic activity. When 4 μg ml-1 compound B1 was combined with PB, it showed potent antibacterial activity, achieving 64-fold reduction of the MIC of PB. Furthermore, compound B1 showed prominent synergistic efficacy in both concentration gradient and time-kill curves in vitro. In addition, B1 combined with PB also exhibited synergistic and partial synergistic effect against E. coli (ATCC25922 and its clinical isolates), Acinetobacter baumannii (ATCC19606 and its clinical isolates), and Pseudomonas aeruginosa (Pae-1399).
- Wang, Rong,Hou, Shuang,Dong, Xiaojing,Chen, Daijie,Shao, Lei,Qian, Liujia,Li, Zhong,Xu, Xiaoyong
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supporting information
p. 2060 - 2066
(2017/11/22)
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- PHARMACEUTICAL COMPOSITION FOR TREATING OR PREVENTING FOOT-AND-MOUTH DISEASE
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The present invention refers to benzothiazole derivatives and its pharmaceutically acceptable salt as active ingredients opening including inverse number relates to a pharmaceutical composition for treating or preventing is. In addition, opening the present invention refers to treatment or prevention of inverse number relates to method. (by machine translation)
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Paragraph 0248; 0251
(2017/01/02)
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- Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules
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DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.
- Rothweiler, Ulli,Stensen, Wenche,Brandsdal, Bj?rn Olav,Isaksson, Johan,Leeson, Frederick Alan,Engh, Richard Alan,Svendsen, John S. Mj?en
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p. 9814 - 9824
(2016/11/19)
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- IMIDAZOTHIADIAZOLE DERIVATIVES AS PROTEASE ACTIVATED RECEPTOR 4 (PAR4) INHIBITORS FOR TREATING PLATELET AGGREGATION
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The present invention provides imidazothiadiazole compounds of Formula (I) wherein A, B, D, Rx, R1, R2, R3, X1, X2 and s are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments.
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Paragraph 00211
(2013/11/18)
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- Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis
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A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl) -1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 μM or 0.008 μg/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low-level resistance with a frequency of ~10-5.
- Meissner, Anja,Boshoff, Helena I.,Vasan, Mahalakshmi,Duckworth, Benjamin P.,Barry III, Clifton E.,Aldrich, Courtney C.
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p. 6385 - 6397
(2013/10/22)
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- 4-Pyridylanilinothiazoles that selectively target von Hippel - Lindau deficient renal cell carcinoma cells by inducing autophagic cell death
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Renal cell carcinomas (RCC) are refractory to standard therapy with advanced RCC having a poor prognosis; consequently treatment of advanced RCC represents an unmet clinical need. The von Hippel-Lindau (VHL) tumor suppressor gene is mutated or inactivated in a majority of RCCs. We recently identified a 4-pyridyl-2-anilinothiazole (PAT) with selective cytotoxicity against VHL-deficient renal cells mediated by induction of autophagy and increased acidification of autolysosomes. We report exploration of structure-activity relationships (SAR) around this PAT lead. Analogues with substituents on each of the three rings, and various linkers between rings, were synthesized and tested in vitro using paired RCC4 cell lines. A contour map describing the relative spatial contributions of different chemical features to potency illustrates a region, adjacent to the pyridyl ring, with potential for further development. Examples probing this domain validated this approach and may provide the opportunity to develop this novel chemotype as a targeted approach to the treatment of RCC. 2009 American Chemical Society.
- Hay, Michael P.,Turcotte, Sandra,Flanagan, Jack U.,Bonnet, Muriel,Chan, Denise A.,Sutphin, Patrick D.,Nguyen, Phuong,Giaccia, Amato J.,Denny, William A.
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supporting information; experimental part
p. 787 - 797
(2010/07/05)
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- HETEROARYL COMPOUNDS, COMPOSITIONS, AND METHODS OF USE IN CANCER TREATMENT
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Provided herein are novel heteroaryl compounds, compositions comprising the compounds, and methods of treatment or prevention comprising administration of the compounds. The compounds are effective in the targeting of cells defective in the von Hippel-Lindau gene and in inducing autophagic cell death. The methods are directed to treating or preventing diseases such as cancer, and in particular cancers resulting from von Hippel-Lindau disease. The compounds of the invention may be administered in combination with another therapeutic agent.
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Page/Page column 143
(2009/10/22)
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- 4′-Methyl-4,5′-bithiazole-based correctors of defective ΔF508-CFTR cellular processing
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The synthesis and ΔF508-CFTR corrector activity of a 148-member methylbithiazole-based library are reported. Synthetic routes were devised and optimized to generate methylbithiazole analogs in four steps. Corrector potency and efficacy were assayed using epithelial cells expressing human ΔF508-CFTR. These structure-activity data establish that the bithiazole substructure plays a critical function; eight novel methylbithiazole correctors were identified with low micromolar potencies.
- Yoo, Choong Leol,Yu, Gui Jun,Yang, Baoxue,Robins, Lori I.,Verkman,Kurth, Mark J.
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p. 2610 - 2614
(2008/12/21)
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- Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells
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Ten cytoselective compounds have been identified from 372 thiazolidinone analogues by applying iterative library approaches. These compounds selectively killed both non-small cell lung cancer cell line H460 and its paclitaxel-resistant variant H460taxR at an IC50 between 0.21 and 2.93 μM while showing much less toxicity to normal human fibroblasts at concentrations up to 195 μM. Structure-activity relationship studies revealed that (1) the nitrogen atom on the 4-thiazolidinone ring (ring B in Figure 1) cannot be substituted, (2) several substitutions on ring A are tolerated at various positions, and (3) the substitution on ring C is restricted to the -NMe2 group at the 4-position. A pharmacophore derived from active molecules suggested that two hydrogen bond acceptors and three hydrophobic regions were common features. Activities against P-gp-overexpressing and paclitaxel-resistant cell line H460taxR and modeling using a previously validated P-gp substrate pharmacophore suggested that active compounds were not likely P-gp substrates.
- Zhou, Hongyu,Wu, Shuhong,Zhai, Shumei,Liu, Aifeng,Sun, Ying,Li, Rongshi,Zhang, Ying,Ekins, Sean,Swaan, Peter W.,Fang, Bingliang,Zhang, Bin,Yan, Bing
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p. 1242 - 1251
(2008/12/23)
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- Synthesis of carbon-11 labeled fluorinated 2-arylbenzothiazoles as novel potential PET cancer imaging agents
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Fluorinated 2-arylbenzothiazoles are new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes for positron emission tomography (PET) to image tyrosine kinase in cancers. The preparation of 4-fluorinated 2-arylbenzothiazoles 4-fluoro-2-(3-benzloxy-4-methoxyphenyl)benzothiazole (6a) and 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole (6b) was achieved by a modification of Jacobson thioanilide radical cyclization chemistry. Hydrogenolytic cleavage of the benzyl ether group of compound 6a using H2/Pd-C provided the precursor 4-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole (7) for radiolabeling. Synthesis of radiolabeling precursors and the reference standards 5- and 6-fluorinated arylbenzothiazoles (11c-n) was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. The target radiotracers carbon-11 labeled 4-, 5-, and 6-fluorinated arylbenzothiazoles (3-[11C]6b, 4-[11C]11c, 3-[11C]11c, 5-[11C]11f, 4-[11C]11f, 4-[11C]11i, 3-[11C]11i, 5-[11C]11l, and 4-[11C]11l) were prepared by O-[11C]methylation of the phenolic hydroxyl precursors (7, 11d, 11e, 11g, 11h, 11j, 11k, 11m, and 11n) with [11C]methyl triflate and isolated by solid-phase extraction (SPE) purification in 30-55% radiochemical yields.
- Wang, Min,Gao, Mingzhang,Mock, Bruce H.,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.,Zheng, Qi-Huang
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p. 8599 - 8607
(2008/02/07)
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- Novel 1,4-benzothiazephine and 1,5-benzothiazepine compounds as inhibitors of apical sodium co-dependent bile acid transport and taurocholate uptake
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Compounds, pharmaceutical compositions, and methods for the treatment of a hyperlipidemic condition in a subject. The compounds of the present invention are apical sodium co-dependent bile acid transport inhibitors and are 1,4-benzothiazepine and 1,5-benzothiazepine compounds corresponding to Formula I: wherein j, m, Y, Z, R1A, R1B, R2A, R2B and R6 are as defined in the specification.
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- Histamine H1 receptor ligands - Part II. Synthesis and in vitro pharmacology of 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives
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New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA2 : 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38-6.15; at the para-position pA2: 6.04-5.87).
- Walczynski, Krzysztof,Guryn, Roman,Zuiderveld, Obbe P.,Zhang, Ming-Qiang,Timmerman, Henk
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p. 569 - 574
(2007/10/03)
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- New herbicidal fluorobenzothiazolyloxyacetamides
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Novel herbicidal fluorobenzothiazolyloxyacetamides of the formula STR1 in which R1 represents hydrogen or an optionally substituted radical from the group consisting of alkyl, alkenyl, alkinyl and aralkyl, R2 represents an optionally
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- N-(5-Fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxamide. A Novel, Systemically Active Antitumor Agent Effective against 3LL Lewis Lung Carcinoma
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N-(5-Fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxamide (1) is a member of a series of amides found to substantially increase lifespan in mice bearing established micrometastatic 3LL Lewis lung carcinoma.Amide 1 is effective after either oral or i
- Schnur, Rodney C.,Fliri, Anton F. J.,Kajiji, Shama,Pollack, Vincent A.
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p. 914 - 918
(2007/10/02)
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- Synthesis & Pharmacological Evaluation of Ethyl 3-Substituted-phenyl-2-methylmercapto/ phenyl/ methyl-4(3H)-pyrimidone-5-carboxylates
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A number of ethyl 3-substituted-phenyl-2-methylmercapto/ phenyl/ methyl-4(3H)-pyrimidone-5-carboxylates (V) have been prepared by the reaction of amidines (III) with diethyl ethoxymethylenemalonate.In order to confirm the structure (V), ethyl 3-(2'-methylphenyl)-2-methylmercapto-4(3H)pyrimidone-5-carboxylate (103) has been transformed into the earlier synthesised 3-(2'-methylphenyl)-2-methylmercapto-4(3H)-pyrimidone (115) by decarboxylation of 3-(2'-methylphenyl)-2-methylmercapto-4(3H)-pyrimidone-5-carboxylic acid (114), obtained by the alkaline hydrolysis of 103.Someof these compounds have shown antiinflammatory, diuretic and antipassive cutaneous anaphylaxis activities.
- Gupta, K. A.,Saxena, Anil K.,Jain, Padam C.
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p. 228 - 233
(2007/10/02)
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