- Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2
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Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold (43) with potent sBCL-2 activity (IC50 30 nM). Human BCL-XL potency (IC50 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.
- Nguyen, William,Lee, Erinna F.,Evangelista, Marco,Lee, Mihwa,Harris, Tiffany J.,Colman, Peter M.,Smith, Nicholas A.,Williams, Luke B.,Jarman, Kate E.,Lowes, Kym N.,Haeberli, Cécile,Keiser, Jennifer,Smith, Brian J.,Fairlie, W. Douglas,Sleebs, Brad E.
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p. 1143 - 1163
(2021/02/22)
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- Metal-free C–H mercaptalization of benzothiazoles and benzoxazoles using 1,3-propanedithiol as thiol source
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A facile and effective C–H functionalization strategy for the synthesis of 2-mercaptobenzothiazoles and 2-mercaptobenzoxazoles is described. 1,3-Propanedithiol was employed to convert benzothiazoles and benzoxazoles to the corresponding heteroarylthiols in the presence of potassium hydroxide and DMSO. This novel protocol is featured by direct C–H mercaptalization of heteroarenes and a simple reaction system.
- Xiao, Yan,Jing, Bing,Liu, Xiaoxia,Xue, Hongyu,Liu, Yajun
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supporting information
p. 279 - 284
(2019/02/20)
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- Preparation method of 2-mercaptobenzoxazole(thiazole) compounds taking 1,3-dimercaptopropane as mercapto source
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The invention belongs to the synthesis field of medicine chemical intermediate, and provides a preparation method of 2-mercaptobenzoxazole(thiazole) compounds taking 1,3-dimercaptopropane as a mercapto source. According to the preparation method, under inert gas protection, in dimethyl sulphoxide solvent, substituted benzoxazole(thiazole) and 1,3-dimercaptopropane are subjected to 120 to 140 DEG Cheating stirring in the presence of an alkali, after 12 to 24h of reaction, an obtained reaction solution is cooled to room temperature, and is subjected to acidifying post-treatment so as to obtaina product. The reaction conditions are simple; function group compatibility is excellent; yield is relatively high; the obtained 2-mercaptobenzoxazole(thiazole) compounds are important organic synthesis intermediates; application range in the field of chemical raw material, pesticide, and medicine is wide; and practical value and social and economic benefit are excellent.
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Paragraph 0026; 0027
(2018/10/02)
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- AlCl3-Promoted Synthesis of 2-Mercapto Benzoheterocycles by Using Sodium Dimethyldithiocarbamate as Thiocarbonyl Surrogate
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A simple, expeditious and high-efficiency synthetic method for the AlCl3-mediated one-pot preparation of 2-mercapto benzoheterocycles (2-mercapto benzothiazoles, benzoxazoles and benzimidazoles) is described. By the treatment of a series of S, O and N heteroatoms containing bifunctional molecules with sodium dimethyldithiocarbamate in AlCl3, the desired benzoheterocycles are obtained smoothly. The protocol can also be applied on the synthesis of a series of thiazolidine-2-thiones, imidazolidine-2-thiones. This novel synthetic approach has advantages such as ligand-free, high efficiency, short reaction time, readily available starting materials and simple experimental procedures.
- Liu, Xing,Zhang, Shi-Bo,Dong, Zhi-Bing
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p. 5406 - 5411
(2018/10/20)
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- Copper(I)-Catalyzed Tandem One-Pot Synthesis of 2-Arylthiobenzothiazoles and 2-Arylthiobenzoxazoles in Water
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An efficient tandem process for the preparation of 2-arylthiobenzothiazoles has been developed. By condensation of 2-aminobenzenethiol with tetramethylthiuram disulfide (TMTD), 2-mercaptobenzothiazoles was in situ generated, which susequently underwent coupling with iodobenzenes to give the desired 2-arylthiobenzothiazoles fluently in a one-pot manner. This method can also be used for the synthesis of 2-arylthiobenzoxazoles. Inexpensive metal catalyst and ligand, mild reaction temperature, and water as solvent make this protocol practically valuable and useful in organic synthesis.
- Liu, Xing,Zhang, Shi-Bo,Zhu, Hui,Dong, Zhi-Bing
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p. 11703 - 11711
(2018/10/02)
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- LEGO-Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4-Dihydroxyphenyl Moiety as Plasma Membrane H+-ATPase Inhibitors
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The fungal plasma membrane H+-ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure–activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO-inspired fragment assembly strategy for the design, synthesis, and discovery of benzo[d]thiazoles containing a 3,4-dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2-(benzo[d]thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanones was found to inhibit Pma1p, with the most potent IC50 value of 8 μm in an in vitro plasma membrane H+-ATPase assay. These compounds were also found to strongly inhibit the action of proton pumping when Pma1p was reconstituted into liposomes. 1-(3,4-Dihydroxyphenyl)-2-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)thio)ethan-1-one (compound 38) showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae, which could be correlated and substantiated with the ability to inhibit Pma1p in vitro.
- Tung, Truong-Thanh,Dao, Trong T.,Junyent, Marta G.,Palmgren, Michael,Günther-Pomorski, Thomas,Fuglsang, Anja T.,Christensen, S?ren B.,Nielsen, John
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- Synthesis, in vitro α-glucosidase inhibitory activity and molecular docking studies of novel benzothiazole-triazole derivatives
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Benzothiazole-triazole derivatives 6a–6s have been synthesized and characterized by1H-NMR and13C-NMR. All synthetic compounds were screened for their in vitro α-glucosidase inhibitory activity by using Baker’s yeast α-glucosidase enzyme. The majority of compounds exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 20.7 and 61.1 μM when compared with standard acarbose (IC50 = 817.38 μM). Among the series, compound 6s (IC50 = 20.7 μM) bearing a chlorine group at the 5-position of the benzothiazole ring and a tert-butyl group at the para position of the phenyl ring, was found to be the most active compound. Preliminary structure-activity relationships were established. Molecular docking studies were performed to predict the binding interaction of the compounds in the binding pocket of the enzyme.
- Gong, Zipeng,Peng, Yaping,Qiu, Jie,Cao, Anbai,Wang, Guangcheng,Peng, Zhiyun
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- An environmentally benign and efficient synthesis of substituted benzothiazole-2-thiols, benzoxazole-2-thiols, and benzimidazoline-2-thiones in water
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An efficient and practical method for the one-step synthesis of benzothiazole-2-thiols, benzoxazole-2-thiols and benzimidazoline-2-thiones by cyclization of 2-aminothiophenols, 2-aminophenols, and 1,2-phenylenediamines with tetramethylthiuram disulfide (TMTD) in water was described. The features of this method include metal/ligand-free, excellent yield, short reaction time and broad substrate scope. The method provides a facile and convenient preparation of some potentially biologically active compounds.
- Liu, Xing,Liu, Min,Xu, Wan,Zeng, Meng-Tian,Zhu, Hui,Chang, Cai-Zhu,Dong, Zhi-Bing
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p. 5591 - 5598
(2017/12/06)
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- Highly efficient synthesis of 2-mercaptobenzothiazole derivatives in water: Metal sulfide-disulfide dynamic interchange reaction
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A convenient and efficient method for the synthesis of 2-mercaptobenzothiazoles from disulfide and CS2 mediated by a metal sulfide in water is described. This synthetic methodology could be used to prepare diverse 2-mercaptobenzothiazole derivatives in good to excellent yields. In this paper, the concept of metal sulfide-disulfide dynamic interchange reaction was put forward. Then the intermediates of the interchange reaction between NaHS and a disulfide were detected by LC-MS, which demonstrated that the S-S bond of the disulfide could be broken by the metal sulfide through the dynamic interchange reaction. In addition, NaHS was eventually transformed into sulfur S8 by the dynamic interchange reaction. Moreover, the underlying mechanism of 2-mercaptobenzothiazole formation is proposed, in which NaHS not only acts as an S-S bond cleaving agent but also as an activator of CS2. As a result, a novel synthetic route for the preparation of sulfur-containing heterocycles from a disulfide is developed.
- Lou, Chunqing,Zhu, Ning,Fan, Ronghua,Hong, Hailong,Han, Limin,Zhang, Jianbin,Suo, Quanling
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p. 1102 - 1108
(2017/08/15)
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- Green synthesis method of 2-mercaptobenzothiazoles derivatives
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The invention provides a green synthesis method of 2-mercaptobenzothiazoles derivatives. The method comprises the step of enabling o-amino aromatic disulfide, CS2 and metal sulfide to be in contact with a solvent to obtain the 2-mercaptobenzothiazoles derivatives, wherein the solvent is at least one of water, low carbon alcohol, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), N-methyl pyrrolidone (NMP) and 1, 4-dioxane. Compared with the prior art, the method enables the o-amino aromatic disulfide to react with the CS2, thus rapidly and efficiently synthesizing the 2-mercaptobenzothiazoles derivatives; the raw materials used by the method are stable, easy to obtain and low in cost; the synthesis method is simple and convenient in operation, short in step, high in yield and easy in purification of a product.
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-
Paragraph 0095; 0096
(2018/02/04)
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- Copper-Catalyzed Three-Component Synthesis of Benzothiazolethiones from o-Iodoanilines, Isocyanide, and Potassium Sulfide
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An efficient copper catalyzed strategy for the synthesis of a variety of benzothiazolethione derivatives has been developed. In the presence of CuCl, the three-component reaction of o-iodoanilines and K2S with p-toluenesulfonylmethyl isocyanide proceeded smoothly to obtain the corresponding benzothiazolethiones in good to excellent isolated yields. Notably, isocyanide functioned as a carbon source and K2S functioned as a sulfur source in this reaction.
- Dang, Pan,Zeng, Weilan,Liang, Yun
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supporting information
p. 34 - 37
(2015/07/28)
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- COMPOUNDS USEFUL AS ANTIBIOTIC TOLERANCE INHIBITORS
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The disclosure provides compounds and pharmaceutical compositions of the compounds useful for treating chronic and acute bacterial infections. Certain of the compounds are compounds and salts of general Formula VIII Certain compounds of this disclosure are MvfR inhibitors. MvfR inhibitors reduce the formation of antibiotic tolerant bacterial strains and are useful for treating Gram-negative bacterial infections and reducing the virulence of Pseudomonas aeruginosa. Methods of treating bacterial infections in a patient, including Pseudomonas aeruginosa infections, are also provided by the disclosure.
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Page/Page column 29
(2014/11/13)
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- Lanthanide-catalyzed cyclocarbonylation and cyclothiocarbonylation: A facile synthesis of benzannulated 1,3-diheteroatom five- and six-membered heterocycles
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La[N(SiMe3)2]3 proves to be an efficient catalyst system for the cyclocarbonylation of 1,2-disubstituted benzenes with isocyanates. In this approach, aryl/alkyl isocyanates react with o-phenylenediamine, o-aminophenol, o-aminothiophenol, catechols and anilines ortho-substituted by CH2NH2 and CONH2 to form, respectively, the corresponding benzimidazolones, benzoxazolones, benzothiazolones, benzodioxolones, 3,4-dihydroquinazolin-2(1H)-one, and quinazolinediones. These results represent the first example of lanthanide-catalyzed carbonylation. This methodology is also applicable for the preparation of various benzannulated 1,3-diheteroatom cyclic thioketones starting from aryl/alkyl isothiocyanates or CS2 in good to excellent yields. Based on the results of experiments performed using an o-aminobenzamido dianion lanthanide complex, a general mechanism, involving the tandem reaction of two lanthanide-ligand bonds with one heterocumulene molecule, is proposed as well.
- Jing, Yufeng,Liu, Ruiting,Lin, Yanghui,Zhou, Xigeng
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p. 1117 - 1125
(2014/08/18)
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- AMINOPYRIMIDINONES AS INTERLEUKIN RECEPTOR-ASSOCIATED KINASE INHIBITORS
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This invention relates to aminopyrimidinone compounds of Formula (I) that are inhibitors of Interleukin receptor-associated kinases, in particular IRAK-4, and are useful in the treatment or prevention of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease.
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Page/Page column 222
(2013/05/22)
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- Analogues of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents
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The rhodacyanine, MKT-077, has antiproliferative activity against cancer cell lines through its ability to inhibit members of the heat shock protein 70 (Hsp70) family of molecular chaperones. However, MKT-077 is rapidly metabolized, which limits its use as either a chemical probe or potential therapeutic. We report the synthesis and characterization of MKT-077 analogues designed for greater stability. The most potent molecules, such as 30 (JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC50 values of 0.4 ± 0.03 and 0.7 ± 0.2 μM, respectively). The analogues modestly destabilized the chaperone clients, Akt1 and Raf1, and induced apoptosis in these cells. Further, the microsomal half-life of JG-98 was improved at least 7-fold (t1/2 = 37 min) compared to MKT-077 (t1/2 5 min). Finally, NMR titration experiments suggested that these analogues bind an allosteric site that is known to accommodate MKT-077. These studies advance MKT-077 analogues as chemical probes for studying Hsp70s roles in cancer.
- Li, Xiaokai,Srinivasan, Sharan R.,Connarn, Jamie,Ahmad, Atta,Young, Zapporah T.,Kabza, Adam M.,Zuiderweg, Erik. R. P.,Sun, Duxin,Gestwicki, Jason E.
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supporting information
p. 1042 - 1047
(2013/12/04)
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- Synthesis and antibacterial evaluation of a novel series of 2-(1,2-dihydro-3-oxo-3H-pyrazol-2-yl)benzothiazoles
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The 2-(1,2-dihydro-3-oxo-3H-pyrazol-2-yl)benzothiazole scaffold was selected as a central core structure for the discovery of novel antibacterial compounds. A systematic variation of the substituents on the oxo-pyrazole moiety, as well as on the benzo moiety, led to the creation of a small and focused library of benzothiazoles that was subjected to antibacterial screening. In a first round of screening, activity of the compounds against six representative microorganisms was established. For the most potent congeners, MIC values against S. aureus and P. aeruginosa were determined. The structure-activity relationship study clearly revealed that subtle structural variations influence the antibacterial activity to a large extent. The most potent congeners displayed MIC values of 3.30 μM.
- Stella, Alessandro,Segers, Kenneth,De Jonghe, Steven,Vanderhoydonck, Bart,Rozenski, Jef,Anne, Jozef,Herdewijn, Piet
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experimental part
p. 253 - 265
(2011/09/30)
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- Synthesis of chloro-substituted analogs of Thiazole orange - Fluorophores for flow cytometric analyses
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Synthesis, absorption and fluorescence properties of a series of asymmetrical monomethine cyanine dyes, chloro-containing analogs of Thiazole orange, are reported. Their staining ability was studied by flow cytometry. The saturating concentrations of each dye that gives a stable staining intensity have been determined. The ability of dyes B9, B11, B13 to stain live macrophages and apoptotic splenocytes was investigated. Positive signal in nucleus of adherent macrophages detected by fluorescent microscopy showed good specificity of B9, B11 and B13 dyes for DNA. In apoptotic assay cells positive for Annexin V were stained more brightly with the dyes B9, B11 and B13 than with propidium iodide. Despite that B13 showed high DNA selectivity it induces apoptosis of splenocytes and it is not suitable for detection of dead cells. The other synthesized chloro-containing analogs of Thiazole orange B9 and B11 can be successfully used for flow cytometric analyses of DNA content in live cells and for analyses of cell apoptosis.
- Kaloyanova,Ivanova,Tchorbanov,Dimitrova,Deligeorgiev
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experimental part
p. 215 - 221
(2012/03/11)
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- Improved synthesis of 2-(3H)benzothiazolethiones under microwave irradiation
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2-(3H)Benzothiazolethiones (2-mercaptobenzothiazole) are prepared by an improved method, which utilizes microwave-assisted cyclization of the corresponding ortho-haloanlines with potassium O-ethyl dithiocarbonate. By using microwave irradiation, the relative reactivity of 2-chloroanilines was greatly improved to the same level as that of 2-fluoroanilines and 2-bromoanilines. Copyright Taylor & Francis Group, LLC.
- Huang, Wei,Tan, Ying,Ding, Ming-Wu,Yang, Guang-Fu
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p. 369 - 376
(2007/10/03)
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- Process for the preparation of 2-mercaptobenzothiazoles
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The preparation of (optionally substituted) 2-mercaptobenzothiazole by reaction of corresponding 2-halogenoanilines with an alkali metal xanthate or alkaline earth metal xanthate or with CS2 in the presence of bases.
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