- Tulobuterol crystal form and preparation method thereof
-
The invention provides a tulobuterol crystal form and a preparation method thereof. The preparation method comprises the following steps of: dissolving tulobuterol in ethyl acetate and other good solvents, dropwisely adding n-heptane and other poor solvents into the system, filtering, taking the filter cake, and drying the filter cake to obtain the tulobuterol crystal form crystal. The crystal form is high in purity and good in stability, has superiority in process production, and is suitable for long-term storage in the preparation process.
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Paragraph 0036-0038
(2021/04/28)
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- Synthesis and anti-methicillin-resistant Staphylococcus aureus activity of 5,7-dibromo-2-benzoylbenzofurans alone and in combination with antibiotics
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A series of 5,7-dibromo-2-benzoylbenzofurans were synthesized by the Rap–Stoermer condensation of 5,7-dibromosalicylaldehyde with diverse phenacyl bromides and evaluated for in-vitro antibacterial activities against methicillin-sensitive Staphylococcus aureus (MSSA) ATCC 29213, methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, and MRSA ATCC 33591 by agar dilution method. The synergistic effects were determined by using the agar dilution checkerboard assay. The derivatives bearing carboxylic acid functional groups exhibited reasonable activity against MRSA strains with the best MIC = 32 μg/mL (9b, 9d). Moreover, the additive or synergistic interactions against MRSA strains was observed in six combinations (1b + cefuroxime/gentamicin, 1c + ciprofloxacin/gentamicin, 9b + gentamicin, and 9c + ciprofloxacin) with the fractional inhibitory concentration index (FICI) values in the range of 0.375–1.0. Significantly, the MICs of these antibiotics were reduced 2–4-fold. The results of the MTT assay illustrated the low mammalian cell cytotoxicity of these potent compounds.
- Phan, Phuong-Thuy T.,Nguyen, Hong-Nhung T.,Kim, Son N.,Pham, Tuan-Anh N.
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supporting information
p. 786 - 796
(2020/12/09)
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- Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies
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In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
- Zhou, You,Lu, Xin,Du, Chenxi,Liu, Yijun,Wang, Yifan,Hong, Kwon Ho,Chen, Yao,Sun, Haopeng
-
-
- Design and synthesis of 7-O-1,2,3-triazole hesperetin derivatives to relieve inflammation of acute liver injury in mice
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Based on the previous research results of our research group, to further improve the anti-inflammatory activity of hesperetin, we substituted triazole at the 7-OH branch of hesperetin. We also evaluated the anti-inflammatory activity of 39 new hesperetin derivatives. All compounds showed inhibitory effects on nitric oxide (NO) and inflammatory factors in lipopolysaccharide-induced RAW264.7 cells. Compound d5 showed a strong inhibitory effect on NO (half maximal inhibitory concentration = 2.34 ± 0.7 μM) and tumor necrosis factor-α, interleukin (IL)-1β, and (IL-6). Structure–activity relationships indicate that 7-O-triazole is buried in a medium-sized hydrophobic cavity that binds to the receptor. Compound d5 can also reduce the reactive oxygen species production and significantly inhibit the expression of inducible NO synthase and cyclooxygenase-2 through the nuclear factor-κB signaling pathway. In vivo results indicate that d5 can reduce liver inflammation in mice with acute liver injury (ALI) induced by CCI4. In conclusion, d5 may be a candidate drug for treating inflammation associated with ALI.
- Zheng, Yan,Zhang, Yi-long,Li, Zeng,Shi, Wen,Ji, Ya-ru,Guo, Ya-Hui,Huang, Cheng,Sun, Guo-ping,Li, Jun
-
-
- Ru-Tethered (R,R)-TsDPEN with DMAB as an efficient catalytic system for high enantioselective one-pot synthesis of chiral β-aminolviaasymmetric transfer hydrogenation
-
This work reflects Ru-tethered-TsDPEN as an active chiral catalyst for one pot selective synthesis of optically active α-substituted alcohols and its derivatives from α-bromo ketones in the presence of dimethylamine borane (DMAB) as the hydrogen source. Various Ru-chiral catalysts have been screened and the methodology proceededviaa (R,R) Ru-tethered TsDPEN catalyst through asymmetric transfer hydrogenation (ATH) of the in-situ formed ketones to the corresponding chiral β-aminol product. Thus, the Ru-tethered TsDPEN-DMAB catalytic system works efficiently with higher yield and high enantiomeric excess over others for the ATH process. Based on a study ofortho,metaandparasubstituted α-bromo acetophenone derivatives, effective enantioselectivity has been observed fororthosubstituted β-aminol. The mechanism has been optimized depending on product analysis with the help of its kinetic AT-IR study. This work also focusses on the synthesis of various β-amino alcohol derivatives where the effect of an EWG and EDG on enantio-selectivity has been studied.
- Mishra, Ashish A.,Bhanage, Bhalchandra M.
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supporting information
p. 5357 - 5362
(2021/04/06)
-
- An umpolung oxa-[2,3] sigmatropic rearrangement employing arynes for the synthesis of functionalized enol ethers
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An oxa-[2,3] sigmatropic rearrangement involving arynes is reported featuring the umpolung of ketones, where the C=O bond polarity is reversed. The in situ-generated sulfur ylides from β-keto thioethers and arynes undergo efficient rearrangement allowing the facile and robust synthesis of functionalized enol ethers in high yields and excellent functional group compatibility. Preliminary mechanistic studies rule out the possibility of Pummerer-type rearrangement operating in this case.
- Gaykar, Rahul N.,George, Malini,Guin, Avishek,Bhattacharjee, Subrata,Biju, Akkattu T.
-
supporting information
p. 3447 - 3452
(2021/05/04)
-
- BuChE-IDO1 inhibitor as well as preparation method and application thereof
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The invention relates to the field of medicines, and particularly discloses a BuChE-IDO1 inhibitor as well as a preparation method and application thereof. The 7-chlorine-3-substituted benzothiophene part of sertaconazole is chemically modified, the influence of the 7-chlorine-3-substituted benzothiophene part of sertaconazole on the in-vitro inhibitory activity of AChE, BuChE and IDO1 is explored, the target compound is further optimized, and the technical problems that an existing BuChE-IDO1 inhibitor is poor in pertinence and safety are solved. What is explored is that an appropriate substituent group introduced to a 2-benzothiazole ring can form additional interaction with surrounding amino acids and heme iron, so that the binding affinity of the analogue with BuChE and IDO1 is increased, and a new idea is broadened for more efficient and targeted treatment of advanced AD diseases.
- -
-
Paragraph 0070-0072; 0114-0115
(2021/04/26)
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- Chiral Bidentate Phosphoramidite-Pd Catalyzed Asymmetric Decarboxylative Dipolar Cycloaddition for Multistereogenic Tetrahydrofurans with Cyclic N-Sulfonyl Ketimine Moieties
-
An asymmetric [3 + 2] cycloaddition of vinyl ethylenecarbonates (VECs) and (E)-3-arylvinyl substituted benzo[d] isothiazole 1,1-dioxides has been developed using the Pd complex of a bidentate phosphoramidite (Me-BIPAM) as the catalyst, providing a wide variety of chiral multistereogenic vinyltetrahydrofurans in good yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, 99% ee).
- Lv, Hao-Peng,Yang, Xiao-Peng,Wang, Bai-Lin,Yang, Hao-Di,Wang, Xing-Wang,Wang, Zheng
-
supporting information
p. 4715 - 4720
(2021/06/28)
-
- Microwave-assisted synthesis and luminescent activity of imidazo[1,2-a]pyridine derivatives
-
In this work, a series of phenacyl bromide derivatives was synthesized and employed as key intermediate for the synthesis of substituted imidazo[1,2-a]pyridines. First, phenacyl bromide molecules were obtained from the bromination reaction of acetophenones assisted by microwave irradiation, obtaining the products 4a-v in a 15 minutes reaction with yields in the range of 50% to 99%. Subsequently, the conjugation of these molecules with 2-aminopyridine conduced to the production of imidazo[1,2-a]pyridine derivatives (7a-v) in a 60-second reaction with yields of 24% to 99%. Improved yields were determined with respect to those obtained with more tedious methodologies like thermally and mechanically assisted routes. Intense luminescence emissions in the purple and blue regions of the electromagnetic spectra were observed under UV excitation according to the nature of the substituents. This environmentally friendly methodology is expected to constitute an important class of organic compounds for the development of biomarkers, photochemical sensors, and medicinal applications.
- Rodríguez, Juan C.,Maldonado, Rony A.,Ramírez-García, Gonzalo,Díaz Cervantes, Erik,de la Cruz, Fabiola N.
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p. 2279 - 2287
(2020/03/16)
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- Nickel-Catalyzed Asymmetric Addition of Aromatic Halides to Ketones: Highly Enantioselective Synthesis of Chiral 2,3-Dihydrobenzofurans Containing a Tertiary Alcohol
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A highly enantioselective and straightforward synthetic procedure to chiral 3-hydroxy-2,3-dihydrobenzofurans has been developed by nickel/bisoxazoline-catalyzed intramolecular asymmetric addition of aryl halides to unactivated ketones, giving 2,3-dihydrobenzofurans with a chiral tertiary alcohol at the C-3 position in good yields and excellent enantioselectivities (up to 92percent yield and 98percent ee). The gram-scale reaction also proceeded smoothly without a loss of yield and enantioselectivity.
- Li, Ying,Li, Wendian,Tian, Jiangyan,Huang, Guozheng,Lv, Hui
-
supporting information
p. 5353 - 5357
(2020/07/14)
-
- Facile Synthesis of α-Haloketones by Aerobic Oxidation of Olefins Using KX as Nonhazardous Halogen Source
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An operationally simple and safe synthesis of α-haloketones using KBr and KCl as nonhazardous halogen sources is reported. It involves an iron-catalysed reaction of alkenes with KBr/KCl using O2 as terminal oxidant under the irradiation of visible-light. This strategy avoids the risks associated with handling halo-contained electrophiles (Cl2, Br2, NCS, NBS). The process is tolerant to several functional groups, and extended to a range of substituted styrenes in up to 89% yield. A radical reaction pathway is proposed based on control experiments and spectroscopy studies.
- Luo, Zhibin,Meng, Yunge,Gong, Xinchi,Wu, Jie,Zhang, Yulan,Ye, Long-Wu,Zhu, Chunyin
-
supporting information
p. 173 - 177
(2020/01/02)
-
- Structure-Based Design of N-(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors
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Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC50 = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy.
- Dai, Weiyang,Samanta, Soma,Xue, Ding,Petrunak, Elyse M.,Stuckey, Jeanne A.,Han, Yanyan,Sun, Duxin,Wu, Yong,Neamati, Nouri
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p. 3068 - 3087
(2019/03/07)
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- Application of poly(vinylphenyltrimethylammonium tribromide) resin as an efficient polymeric brominating agent in the α-bromination and α-bromoacetalization of acetophenones
-
The applications of a new supported tribromide reagent based on poly(vinylbenzyltrimethylammonium hydroxide) resin (Amberlite 717) were reported. This supported tribromide resin was used directly in α-bromination and α-bromoacetalization of acetophenones without any other catalyst under mild conditions. The effects of solvents and the amount of the supported tribromide resin on the reactions were investigated. Under the optimal conditions, most of α-bromo and α-bromoacetal of acetophenones were selectively obtained in excellent yields.
- Han, Bingbing,Zheng, Zubiao,Zheng, Dongcheng,Zhang, Lei,Cui, Peng,Shi, Jianjun,Li, Changjiang
-
supporting information
p. 2512 - 2520
(2019/07/04)
-
- Diaryl-containing imidazole compound and preparation method and medical application thereof
-
The invention discloses a diaryl-containing imidazole compound. The invention further discloses application of the diaryl-containing imidazole compound to preparation of drugs for preventing or treating Alzheimer's disease. The inventor screens butyrylcholine esterase and IDO1 as carriers for inhibiting the activity to evaluate the effect of the diaryl imidazole compound to treat Alzheimer's disease, and finds that the diaryl imidazole compound has good in vitro activity, and can be further developed as a precursor substance for performing the Alzheimer's disease resistant effect by inhibitingthe activity of cholinesterase. (The formula is shown in the description).
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Paragraph 0093; 0094; 0095
(2019/02/21)
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- Method of utilizing micro channel reactor to prepare pentafluorophenoxyl ketones continuously
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The invention discloses a method of utilizing a micro channel reactor to prepare pentafluorophenoxyl ketones continuously. Cheap and easily available styrene and pentafluorophenol are taken as the primary raw materials, two step continuous reactions are carried out in a micro channel reactor to obtain pentafluorophenoxyl ketones, the reaction time is shortened to several minutes from several hours; the product yield is high, the reaction efficiency is obviously enhanced, no any pricy organic catalyst or metal catalyst is needed, the operation is simple, the cost is low, the preparation technology is easy to control, the safety is high, the reaction conditions are mild, and the method can be applied to industrial production.
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-
Paragraph 0044-0045
(2019/06/30)
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- Method for synthesizing tulobuterol
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The invention discloses a method for synthesizing tulobuterol. According to the method, 1-(2-chlorophenyl)-2-bromoethanone (compound 3) and 1-(2-chlorophenyl)-2,2-dibromoethanone (compound 10) can besimultaneously utilized to synthesize the tulobuterol. In an original route, the compound 10 is a by-product of synthesis of the compound 3, and about 10-15% of the compound 10 is not fully utilized.The method provided by the invention can improve the synthesis yield of the tulobuterol, is simple to operate, is environmentally friendly, is low in cost and is suitable for industrial production.
- -
-
Paragraph 0015; 0031-0032
(2020/01/03)
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- Stable isotope tag R-clorprenaline and preparation method thereof
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The invention relates to a stable isotope tag R-clorprenaline and a preparation method thereof. The preparation method comprises the following steps: utilizing an organic synthesis method, taking a stable isotope tag chlorobenzene as a raw material and carrying out riedel-Crafts reaction to generate a stable isotope tag chloroacetophenone; carrying out bromination to obtain a stable isotope tag alpha-bromochloroacetophenone; then carrying out one-pot reaction on the stable isotope tag alpha-bromochloroacetophenone, a stable isotope tag isopropylamine and a reducing agent to obtain the stable isotope tag R-clorprenaline. Compared with the prior art, the stable isotope tag R-clorprenaline prepared by the preparation method has the advantages that the chemical purity reaches 99 percent or more and the isotope abundance is 99 percent or more; the stable isotope tag R-clorprenaline can be used for researching a metabolic mechanism of a medicine clorprenaline and detecting the residue of a prohibited veterinary drug clorprenaline in the field of food safety.
- -
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Paragraph 0062; 0066; 0067; 0082; 0086; 0087
(2019/01/07)
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- Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives
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Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.
- Sahin, Zafer,Ertas, Merve,Berk, Bark?n,Biltekin, Sevde Nur,Yurttas, Leyla,Demirayak, Seref
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p. 1986 - 1995
(2018/03/12)
-
- NOVEL DITHIOLANE COMPOUND OR A SALT OR AN N-OXIDE AND USE THEREOF
-
An object of the present invention is to provide a dithiolane compound or a salt or an N-oxide thereof that controls diseases. The present invention provides a dithiolane compound represented by Formula (1) or a salt or an N-oxide thereof, wherein R1 represents hydrogen, halogen, C1-6 alkyl or a substituent as defined herein; R2 represents hydrogen, halogen, C1-6 alkyl or a substituent as defined herein; R3 represents hydrogen, halogen, C1-6 alkyl or a substituent as defined herein; Y1 represents optionally substituted aryl, optionally substituted pyridyl or a substituent as defined herein; Y2 represents optionally substituted aryl, optionally substituted pyridyl or a substituent as defined herein; Q represents cyano or a substituent as defined herein.
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Page/Page column 64
(2018/10/19)
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- A H2O2/HBr system-several directions but one choice: oxidation-bromination of secondary alcohols into mono- or dibromo ketones
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In this work we found that a H2O2-HBr(aq) system allows synthesis of α-monobromo ketones and α,α′-dibromo ketones from aliphatic and secondary benzylic alcohols with yields up to 91%. It is possible to selectively direct the process toward the formation of mono- or dibromo ketones by varying the amount of hydrogen peroxide and hydrobromic acid. The convenience of application, simple equipment, multifaceted reactivity, and compliance with green chemistry principles make the application of the H2O2-HBr(aq) system very attractive in laboratories and industry. The proposed oxidation-bromination process is selective in spite of known properties of ketones to be oxidized by the Baeyer-Villiger reaction or peroxidated with the formation of compounds with the O-O moiety in the presence of hydrogen peroxide and Bronsted acids.
- Nikishin, Gennady I.,Kapustina, Nadezhda I.,Sokova, Liubov L.,Bityukov, Oleg V.,Terent'ev, Alexander O.
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p. 28632 - 28636
(2018/08/31)
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- α-Ketothioamide Derivatives: A Promising Tool to Interrogate Phosphoglycerate Dehydrogenase (PHGDH)
-
Given the putative role of PHGDH in cancer, development of inhibitors is required to explore its function. In this context, we established and validated a straightforward enzymatic assay suitable for high-throughput screening and we identified inhibitors with similar chemical scaffolds. Through a convergent pharmacophore approach, we synthesized α-ketothioamides that exhibit interesting in vitro PHGDH inhibition and encouraging cellular results. These novel probes may be used to understand the emerging biology of this metabolic target.
- Ravez, Séverine,Corbet, Cyril,Spillier, Quentin,Dutu, Alice,Robin, Anita D.,Mullarky, Edouard,Cantley, Lewis C.,Feron, Olivier,Frédérick, Rapha?l
-
supporting information
p. 1591 - 1597
(2017/03/08)
-
- Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors
-
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.
- Usui, Yoshihiro,Uehara, Fumiaki,Hiki, Shinsuke,Watanabe, Kazutoshi,Tanaka, Hiroshi,Shouda, Aya,Yokoshima, Satoshi,Aritomo, Keiichi,Adachi, Takashi,Fukunaga, Kenji,Sunada, Shinji,Nabeno, Mika,Saito, Ken-Ichi,Eguchi, Jun-ichi,Yamagami, Keiji,Asano, Shouichi,Tanaka, Shinji,Yuki, Satoshi,Yoshii, Narihiko,Fujimura, Masatake,Horikawa, Takashi
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p. 3726 - 3732
(2017/07/27)
-
- 1,3-Dibromo-5,5-dimethylhydantoin mediated oxidative amidation of terminal alkenes in water
-
A variety of terminal alkenes were converted to the corresponding amides in yields of 25 to 86% in water via treatment with 1,3-dibromo-5,5-dimethylhydantoin, followed by reaction with molecular iodine and aq. NH3 (or amine) in one pot. This metal- and organic solvent-free protocol is not only suitable for styrene derivatives, but also, for the first time, works well on terminal aliphatic alkenes.
- Ma, Chunhua,Fan, Guojie,Wu, Ping,Li, Zhi,Zhou, Yang,Ding, Qingjie,Zhang, Wei
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p. 9889 - 9894
(2017/12/12)
-
- Citric Acid-catalyzed Synthesis of 2,4-Disubstituted Thiazoles from Ketones via C–Br, C–S, and C–N Bond Formations in One Pot: A Green Approach
-
An improved and greener protocol has been developed for the synthesis of 2,4-disubstituted thiazoles via C–Br, C–S, and, C–N bond formations in a single step from readily available ketones, N-bromosuccinimide (NBS), and thiourea catalyzed by citric acid in a mixture of ethanol and water (3:1) under reflux conditions. This method has the advantages of freedom from the isolation of lachrymatory α-bromoketones, ease of carrying out, cleaner reaction profile, broad substrate scope, freedom from chromatographic purification, and suitability for large-scale synthesis.
- Gundala, Trivikram Reddy,Godugu, Kumar,Nallagondu, Chinna Gangi Reddy
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p. 1408 - 1416
(2017/10/23)
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- Water-controlled selective preparation of α-mono or α,α′-dihalo ketones: Via catalytic cascade reaction of unactivated alkynes with 1,3-dihalo-5,5-dimethylhydantoin
-
The control of a reaction that can produce multiple products from the same starting material is a highly attractive and challenging concept in organic synthesis. An efficient protocol for the selective synthesis of α-mono or α,α′-dihalo ketones via a water-controlled three-component thiourea-catalyzed cascade reaction of unactivated alkynes, 1,3-dihalo-5,5-dimethylhydantoin and water has been developed. α-Monohaloketones were obtained in aqueous acetone at 45 °C; conversely, α,α′-dihalo ketones were formed with pure water as the sole solvent at room temperature.
- Wu, Chao,Xin, Xiu,Fu, Zhi-Min,Xie, Long-Yong,Liu, Kai-Jian,Wang, Zheng,Li, Wenyi,Yuan, Zhi-Hui,He, Wei-Min
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p. 1983 - 1989
(2017/06/09)
-
- AuIII-Catalyzed Formation of α-Halomethyl Ketones from Terminal Alkynes
-
A AuIII-catalyzed synthesis of α-halomethyl ketones from terminal alkynes was developed. This approach features excellent functional group compatibility and good yields for both aromatic and aliphatic terminal alkynes. The resulting α-halomethyl ketones were used to prepare heterocyclic indolizine structures. The plausible mechanism of the one-pot reaction is proposed.
- Xing, Yalan,Zhang, Ming,Ciccarelli, Sarah,Lee, John,Catano, Bryant
-
supporting information
p. 781 - 785
(2017/02/15)
-
- In(OTf)3/acid co-catalyzed hydration of 1-haloalkynes to α-halomethyl ketones
-
A novel and efficient In(OTf)3and HOAc cooperatively catalyzed hydration of 1-haloalkynes is described. This method provides ready access to α-chloromethyl ketones, α-bromomethyl ketones and α-iodomethyl ketones in moderate to high yields from simple, inexpensive starting materials. A broad substrate scope is achieved, and the reaction is compatible with various functional groups, including alkoxy, trifluoromethyl, halide, hydroxyl, cyclohexyl, and heterocyclic groups.
- Zeng, Ming,Huang, Rui-Xue,Li, Wen-Yi,Liu, Xiao-Wen,He, Fu-Ling,Zhang, Yi-Yuan,Xiao, Fang
-
p. 3818 - 3822
(2016/07/06)
-
- Metal-free hydration of aromatic haloalkynes to α-halomethyl ketones
-
A highly regioselective and efficient metal-free hydration of aromatic haloalkynes to α-halomethyl ketones using cheap tetrafluoroboric acid as catalyst is described. The protocol is conducted under convenient conditions and affords products in good to excellent yields, with broad substrate scope, including a variety of aromatic alkynyl chlorides, alkynyl bromides, and alkynyl iodides.
- Ye, Min,Wen, Yuelu,Li, Huifang,Fu, Yejuan,Wang, Qinghao
-
supporting information
p. 4983 - 4986
(2016/10/21)
-
- Copper nitrate-catalyzed α -bromination of aryl ketones with hydrobromic acid
-
An efficient method for α-bromination of aryl ketones, using the combination of molecular oxygen and aqueous hydrobromic acid as a brominating agent in the presence of the copper nitrate, has been developed. This catalytic system, which uses cheap and readily available reactants, shows good atom economy with water as the only by-product.
- Wang, Jianqiang,Wang, Xiaolei,Niu, Zong-Qiang,Wang, Jian,Zhang, Man,Li, Jing-Hua
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p. 165 - 168
(2016/02/23)
-
- Synthesis, activity, and docking study of phenylthiazole acids as potential agonists of PPARγ
-
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-mediated transcription factor playing key roles in glucose and lipid homeostasis, and PPARγ ligands possess therapeutic potential in these as well as other areas. In this study, a series of phenylthiazole acids have been synthesized and evaluated for agonistic activity by a convenient fluorescence polarization-based PPARγ ligand screening assay. Compound 4t, as a potential PPARγ agonist with half maximal effective concentration (EC50) 0.75±0.20 μM, exhibited in vitro potency comparable with a 0.83±0.14 μM of the positive control rosiglitazone. Molecular docking and molecular dynamics simulations indicated that phenylthiazole acid 4t interacted with the amino acid residues of the active site of the PPARγ complex in a stable manner, consistent with the result of the in vitro ligand assay.
- Ma, Liang,Wang, Taijin,Shi, Min,Ye, Haoyu
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p. 1807 - 1815
(2016/06/09)
-
- Structure-based design of potent human dihydroorotate dehydrogenase inhibitors as anticancer agents
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It has been proven that inhibiting human dihydroorotate dehydrogenase (hDHODH) restricts the growth of rapidly proliferating cells, thus hDHODH can be developed as a promising target for the treatment of immunological disease and cancer. Here, a succession of substituted hydrazino-thiazole derivatives were designed, synthesized, and biologically evaluated through structure-based optimization, of which compound 22 was the most potent inhibitor of hDHODH with an IC50 value of 1.8 nM. Furthermore, 22 exhibited much better antiproliferative activity than brequinar, both in HCT-116 and BxPC-3 cancer cell lines. Flow cytometry analysis revealed that 22 induced S phase cell cycle arrest and promoted induction of apoptosis. All results established a proof that blocking the pyrimidine de novo synthesis pathway by inhibiting the rate-limiting enzyme hDHODH is an attractive therapy for cancer.
- Song, Wenlin,Li, Shiliang,Tong, Yi,Wang, Jiawei,Quan, Lina,Chen, Zhuo,Zhao, Zhenjiang,Xu, Yufang,Zhu, Lili,Qian, Xuhong,Li, Honglin
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p. 1441 - 1448
(2016/07/21)
-
- Synthesis and antimicrobial activity evaluation of new dithiocarbamate derivatives bearing thiazole/benzothiazole rings
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The synthesis of 2-(substituted phenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A1-A24) derivatives and 2-(4-substituted thiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B1-B14) derivatives was undertaken starting from the potassium salt of 4-(2-pyrimidinyl)piperazine dithiocarbamate. The structures of the obtained compounds were elucidated by1H NMR,13C NMR, MS spectral data, and elemental analysis. The antimicrobial activity of the thirty eight newly synthesized compounds were tested against 12 microorganism strains using the microdilution technique. Compounds 2-(4-ethoxycarbonylthiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B12), 2-(3-fluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A18) and 2-(3,4-difluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A21) were determined to possess high antimicrobial activity.
- Yurtta?, Leyla,?zkay, Yusuf,Duran, Murat,Turan-Zitouni, Gülhan,?zdemir, Ahmet,Cantürk, Zerrin,Kü?üko?lu, Kaan,Kaplanc?kl?, Zafer As?m
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p. 1166 - 1173
(2016/07/27)
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- Azabicyclo derivative and preparation method therefor and application thereof
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The invention relates to an azabicyclo derivative and a preparation method therefor and an application thereof. Specifically, the invention discloses a compound with a structure represented by a formula (A) or salts acceptable in pesticide science thereof, wherein the compound represented by the formula (A) is as shown in the description. The compound has an excellent killing effect on nematodes.
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Paragraph 0148
(2016/10/08)
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- NOVEL FUNCTIONALIZED 5-(PHENOXYMETHYL)-1,3-DIOXANE ANALOGS EXHIBITNG CYTOCHROME P450 INHIBITION
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Pharmaceutical compositions described in this document comprise 5-(phenoxymethyl)-1,3-dioxane analogs having a disease-modifying action in the treatment of diseases associated with the production of cortisol that include metabolic syndrome, obesity, headache, depression, hypertension, diabetes mellitus, Cushing's Syndrome, pseudo-Cushing syndrome, cognitive impairment, dementia, heart failure, renal failure, psoriasis, glaucoma, cardiovascular disease, cancer, stroke, incidentalomas, or any diseases involving the overproduction of cortisol.
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Paragraph 0191; 0192; 0194; 0195
(2015/04/15)
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- AgF/TFA-promoted highly efficient synthesis of α-haloketones from haloalkynes
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A AgF/TFA-promoted highly efficient synthesis of a wide range of α-haloketones from haloalkynes is described. The reactions are conducted under convenient conditions and provide products in moderate to excellent yields, with broad substrate scope, including a variety of aromatic chloroalkynes and bromoalkynes.
- Chen, Zheng-Wang,Ye, Dong-Nai,Ye, Min,Zhou, Zhong-Gao,Li, Shen-Huan,Liu, Liang-Xian
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supporting information
p. 1373 - 1375
(2014/03/21)
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- Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors
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Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
- Wang, Yonghui,Cai, Wei,Zhang, Guifeng,Yang, Ting,Liu, Qian,Cheng, Yaobang,Zhou, Ling,Ma, Yingli,Cheng, Ziqiang,Lu, Sijie,Zhao, Yong-Gang,Zhang, Wei,Xiang, Zhijun,Wang, Shuai,Yang, Liuqing,Wu, Qianqian,Orband-Miller, Lisa A.,Xu, Yan,Zhang, Jing,Gao, Ruina,Huxdorf, Melanie,Xiang, Jia-Ning,Zhong, Zhong,Elliott, John D.,Leung, Stewart,Lin, Xichen
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p. 692 - 702
(2014/01/23)
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- De novo design of non-coordinating indolones as potential inhibitors for lanosterol 14-α-demethylase (CYP51)
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The development of antifungal drugs that inhibit lanosterol 14-α-demethylase (CYP51) via non-covalent ligand interactions is a strategy that is gaining importance. A series of novel tetraindol-4-one derivatives with 1- and 2-(2,4-substituted phenyl) side chains were designed and synthesized based on the structure of CYP51 and fluconazole. The antifungal activities of these derivatives against eight human pathogenic filamentous fungi and yeast strains were evaluated in vitro by measuring the minimal inhibitory concentrations. Nearly all tested compounds 8a-g displayed activity against Candida tropicalis, Candida guilliermondii and Candida parapsilosis with a minimum inhibitory concentration (MIC) value until 8 μg mL-1, on the other hand compounds 7a-g showed activity against Aspergillus fumigatus with a MIC value of 31.25 μg mL-1. A molecular modeling study of the binding interactions between compounds 6, 7d, 8g and the active site of MtCYP51 was conducted based on the computational docking results.
- Gonzalez-Chavez, Rodolfo,Martinez, Roberto,Torre-Bouscoulet, Maria Eugenia,Gallo, Marco,Gonzalez-Chavez, Marco Martin
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- Base-catalyzed synthesis of substituted indazoles under mild, transition-metal-free conditions
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Back to basics: A transition-metal-free method developed for the synthesis of indazoles involves an inexpensive catalytic system composed of a diamine and K2CO3. Various (Z)-2-bromoacetophenone tosylhydrazones were converted into indazoles at room temperature in excellent yields (see example; Ts=p-toluenesulfonyl). The yield was improved by photoisomerization with UV light when E/Z isomeric mixtures of the starting material were used. Copyright
- Thome, Isabelle,Besson, Claire,Kleine, Tillmann,Bolm, Carsten
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supporting information
p. 7509 - 7513
(2013/07/26)
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- Optimization of inhibitors of the tyrosine kinase EphB4. 2. Cellular potency improvement and binding mode validation by X-ray crystallography
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Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.
- Lafleur, Karine,Dong, Jing,Huang, Danzhi,Caflisch, Amedeo,Nevado, Cristina
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- An organocatalyst bearing stereogenic carbon and sulfur centers as an efficient promoter for enantioselective hydrosilylation of 1,4-benzooxazines
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The efficient and enantioselective hydrosilylation of 3-aryl-1,4- benzooxazines was achieved using an l-phenyl alanine derived new Lewis base catalyst bearing stereogenic carbon and sulfur centers. In the presence of 2 mol % of catalyst, a broad range of 3-aryl-1,4-benzooxazines were hydrosilylated to afford the corresponding chiral 3-aryl-3,4-dihydro-2H-1,4-benzooxazine products with good to high yields (66-98%) and enantioselectivities (70-99% ee). This method provides an alternative approach with great practical application potential to access chiral 3-aryl-3,4-dihydro-2H-1,4-benzooxazines.
- Liu, Xiang-Wei,Wang, Chao,Yan, Yan,Wang, Yong-Qiang,Sun, Jian
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p. 6276 - 6280
(2013/07/26)
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- Palladium-catalyzed asymmetric hydrogenation of α-acyloxy-1- arylethanones
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First hand: The first example of a palladium-catalyzed asymmetric hydrogenation of α-acyloxy ketones (1) was accomplished to give the hydrogenated products 2 with by far the highest catalytic efficiency in up to quantitative conversions and excellent enantioselectivities. The hydrogenated products could serve as important intermediates for the preparation of many drug candidates. TFE=2,2,2-trifluoroethanol. Copyright
- Chen, Jianzhong,Liu, Delong,Butt, Nicholas,Li, Chao,Fan, Dongyang,Liu, Yangang,Zhang, Wanbin
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supporting information
p. 11632 - 11636
(2013/11/06)
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- Oxidative bromination of ketones using ammonium bromide and oxone
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A highly efficient, environmentally safe and economic method for selective α-monobromination of aralkyl, cyclic, acyclic, 1,3-diketones and β-keto esters and α,α-dibromination of 1,3-diketones and β-keto esters without catalyst is reported using ammonium bromide as a bromine source and oxone as an oxidant. The reaction proceeds at ambient temperature and yields range from moderate to excellent. Bromination of unsymmetrical ketones takes place at the less substituted α-position predominantly. Aromatisation of tetralones is also carried out with this reagent system.
- MacHarla, Arun Kumar,Chozhiyath Nappunni, Rohitha,Marri, Mahender Reddy,Peraka, Swamy,Nama, Narender
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supporting information; experimental part
p. 191 - 195
(2012/01/17)
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- NOVEL COMPOUNDS
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Disclosed are retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.
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Page/Page column 18
(2012/03/26)
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- Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes
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Present studies have shown that the lipid carrier has a significant role in several aspects of metabolic syndrome in A-FABP/ap2-deficient mice, including type 2 diabetes and atherosclerosis. 38 Thiazole- and indole-based derivatives were synthesized and investigated for their inhibitory effects on the production of LPS-stimulated TNF-α. Among them, 12b exhibited an excellent inhibitory efficiency compared to BMS309403 (95% vs. 85%) at the concentration of 10 μM and a binding affinity for ap2 with the apparent Ki values 33 nM. Oral administration of 12b at a dosage of 50 mg/kg effectively reduced the levels of plasma blood glucose, triglycerides, insulin, total cholesterol and alanine aminotransferase in high-fat/diet-induced obesity model. The results highlighted that 12b was a potent anti-diabetic agent.
- Xu, Qinyuan,Huang, Li,Liu, Juan,Ma, Liang,Chen, Tao,Chen, Jinying,Peng, Fei,Cao, Dong,Yang, Zhuang,Qiu, Neng,Qiu, Jingxiang,Wang, Guangcheng,Liang, Xiaolin,Peng, Aihua,Xiang, Mingli,Wei, Yuquan,Chen, Lijuan
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experimental part
p. 70 - 81
(2012/07/30)
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- Lewis base organocatalyzed enantioselective hydrosilylation of 1,4-benzoxazines
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A chiral Lewis base organocatalyzed enantioselective hydrosilylation of 1,4-benzoxazines is presented. The reactions afforded various enantioenriched 3-substituted dihydro-2H-1,4-benzoxazines with high yields (up to 98%) in moderate enantioselectivities (up to 87% ee).
- Jiang, Yan,Liu, Li-Xin,Yuan, Wei-Cheng,Zhang, Xiao-Mei
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supporting information; experimental part
p. 1797 - 1800
(2012/08/29)
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- Synthesis and bioactivity evaluation of rhodanine derivatives as potential anti-bacterial agents
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Five series of (Z)-5-(4-(2-oxo-2-phenylethoxy)benzylidene)-2- thioxothiazolidin-4-one derivatives (I-V) were synthesized, characterized, and evaluated for their anti-bacterial activity. Most of the synthesized compounds showed potent inhibition against several Gram-positive bacteria (including multidrug-resistant clinical isolates) with MIC values in the range of 1-32 μg/mL. Compounds IIIi, Vb and Vc presented the most potent activity, showing four-fold more potency than norfloxacin (MIC = 8 μg/mL and 4 μg/mL) and 64-fold more activity than oxacillin (MIC > 64 μg/mL) against MRSA CCARM 3167 and 3506 strains with MIC values of 1 μg/mL, and 64-fold more potency than norfloxacin (MIC > 64 μg/mL) and comparable activity to oxacillin (MIC = 1 μg/mL) against the QRSA CCARM 3505 and 3519 strains. None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL.
- Song, Ming-Xia,Zheng, Chang-Ji,Deng, Xian-Qing,Wang, Qing,Hou, Shao-Pu,Liu, Ting-Ting,Xing, Xiao-Lan,Piao, Hu-Ri
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experimental part
p. 403 - 412
(2012/10/08)
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- Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis
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Efficient and rapid synthesis of 1,2,3-triazole derivatives has been achieved via Huisgen's 1,3-dipolar cycloaddition between alkyl/arylazides and diethyl/dimethyl acetylenedicarboxylate in excellent yields under solvent-free conditions. The environmentally friendly solvent-free protocol overcomes the limitations associated with the prevailing time-consuming solution phase protocols and affords the triazoles just in 1-3 min. In vitro antitubercular activity of these triazoles was screened against Mycobacterium tuberculosis H37Rv strain. Four of the compounds showed MIC in the range of 1.56-3.13 μg/mL proving their potential activity.
- Shanmugavelan, Poovan,Nagarajan, Sangaraiah,Sathishkumar, Murugan,Ponnuswamy, Alagusundaram,Yogeeswari, Perumal,Sriram, Dharmarajan
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supporting information; experimental part
p. 7273 - 7276
(2012/02/04)
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- Substituent effects on the reaction of β-benzoylalanines with Pseudomonas fluorescens kynureninase
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Kynureninase is a pyridoxal 5′-phosphate-dependent enzyme that catalyzes the hydrolytic cleavage of l-kynurenine to give l-alanine and anthranilic acid. β-Benzoyl-l-alanine, the analogue of l-kynurenine lacking the aromatic amino group, was shown to a good substrate for kynureninase from Pseudomonas fluorescens, and the rate-determining step changes from release of the second product, l-Ala, to formation of the first product, benzoate [Gawandi, V. B., et al. (2004) Biochemistry 43, 3230-3237]. In this work, a series of aryl-substituted β-benzoyl-dl-alanines was synthesized and evaluated for substrate activity with kynureninase from P. fluorescens. Hammett analysis of kcat and kcat/Km for 4-substituted β-benzoyl-dl-alanines with electron-withdrawing and electron-donating substituents is nonlinear, with a concave downward curvature. This suggests that there is a change in rate-determining step for benzoate formation with different substituents, from gem-diol formation for electron-donating substituents to Cβ-Cγ bond cleavage for electron-withdrawing substituents. Rapid-scanning stopped-flow kinetic experiments demonstrated that substituents have relatively minor effects on formation of the quinonoid and 348 nm intermediates but have a much greater effect on the formation of the aldol product from reaction of benzaldehyde with the 348 nm intermediate. Since there is a kinetic isotope effect on its formation from β,β-dideuterio-β-(4-trifluoromethylbenzoyl)-dl- alanine, the 348 nm intermediate is proposed to be a vinylogous amide derived from abortive β-deprotonation of the ketimine intermediate. These results provide additional evidence for a gem-diol intermediate in the catalytic mechanism of kynureninase.
- Kumar, Sunil,Gawandi, Vijay B.,Capito, Nicholas,Phillips, Robert S.
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experimental part
p. 7913 - 7919
(2011/11/06)
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- δ3- SUBSTITUTED QUINOLINE OR QUINOXALINE DERIVATIVES AND THEIR USE AS PHOSPHATIDYLINOSITOL 3-KINASE ( PI3K) INHIBITORS
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Substituted bicyclic heteroaryls having the structure: (I) or any pharmaceutically-acceptable salt thereof, wherein: X1 is C(R9) or N; X2 is C(R10) or N; Y is N(R11), O or S; which are useful to inhibit the biological activity of human PI3KH and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110H activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myeloproliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia ( T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer
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Page/Page column 49
(2008/12/04)
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- Synthesis, structure, and biological activity of novel 1H-1,2,4-triazol-1- yl-thiazole derivatives
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2-Amino-4-aryl-5-(1H-1,2,4-triazol-1-yl)thiazole derivatives were synthesized from the reaction of α-bromo substituted acetophenone and thiourea. The structures were confirmed by elemental analysis, 1H NMR and single crystal X-ray diffraction analysis. Biological evaluation showed that some of them possess antifungal and plant growth regulatory activities. Copyright Taylor & Francis Group, LLC.
- Ling, Shao,Xin, Zhou,Qing, Zhang,Jian-Bing, Liu,Zhong, Jin,Jian-Xin, Fang
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p. 199 - 207
(2007/10/03)
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