- Lead derivatization of ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate and 5-bromo-2-(thiophene-2-carboxamido) benzoic acid as FabG inhibitors targeting ESKAPE pathogens
-
Our previous studies on FabG have identified two compounds 5-bromo-2-(thiophene-2-carboxamido) benzoic acid (A) and ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate(B) as best hits with allosteric mode of inhibition. FabG is an integral part of bacterial fatty acid biosynthetic system FAS II shown to be an essential gene in most ESKAPE Pathogens. The current work is focussed on lead expansion of these two hit molecules which ended up with forty-three analogues (twenty-nine analogues from lead compound A and fourteen compounds from lead compound B). The enzyme inhibition studies revealed that compound 15 (effective against EcFabG, AbFabG, StFabG, MtFabG1) and 19 (inhibiting EcFabG and StFabG) had potency of broad-spectrum inhibition on FabG panel.
- Varakala, Saiprasad Dasugari,Reshma, Rudraraju Srilakshmi,Schnell, Robert,Dharmarajan, Sriram
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- Synthesis of Dichlorobenzamide Derivatives: Crystal Structures of 3,5-Dichloro-N-(2-chlorophenyl)benzamide and 3,5-Dichloro-N-(4-chlorophenyl)benzamide
-
Abstract: Reactions of 3,5-dichlorobenzoyl chloride and arylamine compounds in N,N′-dimethylformamidesolution at 60 °C afforded a series of dichlorobenzamidederivatives 4–14 in good yields. These new compounds and accompanyingintermediates were characterized and confirmed by nuclear magneticresonance and infrared spectroscopy, of which structures of compounds 4and 6 were established by X-ray crystallography. Compound 4 crystallizesin triclinic space group Pī, with a = 5.047 (18), b = 10.28 (4), c = 13.36 (5) ?, α =107.59 (5)°, β = 93.55 (5)°, γ = 98.34 (5)°, and Z = 2. The unit cell of 6 has a monoclinic Pn symmetry with the cell parameters a = 9.581 (3), b = 12.217 (4), c = 11.072 (3) ?, β = 92.584 (4)°, and Z = 4. Graphic Abstract: A series of 3,5-dichlorobenzamide compounds were synthesized from reactions of arylamine compounds with 3,5-dichlorobenzoyl chloride, which was prepared from 3,5-dichlorobenzonitrile.[Figure not available: see fulltext.]
- Zhang, Jun,Li, Yue,Wang, Bei,Jia, Ai-Quan,Zhang, Qian-Feng
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p. 108 - 115
(2020/02/18)
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- Synthetic method 3 and 5 - dichlorobenzoyl chloride
-
3-dichlorophthaloyl chloride is reacted under the action of a fibrous silica/ppd nano-particle catalyst to prepare the 5 -dichlorobenzoyl chloride, 5 - 5 -dichlorobenzoyl chloride is obtained 3. Therein, the reaction comprises the step of digesting a partial product while supplementing 5 - chloroisophthaloyl chloride. To the invention, a continuous production process is adopted, and a fibrous silica/ppd nano particle catalyst which is high in activity and resistant to use is compounded, raw materials are added while steaming the product, and the content and yield of the product 1, 3 and 5 - trichlorobenzene are reduced on the one hand. The synthesis method 3, 5 -dichlorobenzoyl chloride is high in production efficiency, good in economic benefit, low in cost, green and environment-friendly, and is particularly suitable for industrial production.
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Paragraph 0009; 0042; 0045-0046; 0047-0049; 0050-0051; ...
(2021/09/26)
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- IMPROVED PROCESS FOR THE PREPARATION OF 2-(3,5-DICHLOROPHENYL)-1,3-BENZOXAZOLE-6-CARBOXYLIC ACID OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS AND POLYMORPHS THEREOF
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The present invention relates to process for the preparation of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid of formula (I), its pharmaceutically acceptable salts and polymorphs thereof which are used in the treatment of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis
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Page/Page column 17; 18
(2021/01/23)
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- Staphylococcus aureus rnpa inhibitors: Computational-guided design, synthesis and initial biological evaluation
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Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus aureus, RnpA has been hypothesized to be one of the main players in these mech-anisms. S. aureus RnpA is able to modulate mRNA degradation and complex with a ribozyme (rnpB), facilitating ptRNA maturation. Corresponding small molecule screening campaigns have recently identified a few classes of RnpA inhibitors, and their structure activity relationship (SAR) has only been partially explored. Accordingly, in the present work, using computational modeling of S. aureus RnpA we identified putative crucial interactions of known RnpA inhibitors, and we used this information to design, synthesize, and biologically assess new potential RnpA inhibitors. The present results may be beneficial for the overall knowledge about RnpA inhibitors belonging to both RNPA2000-like thiosemicarbazides and JC-like piperidine carboxamides molecular classes. We evaluated the importance of the different key moieties, such as the dichlorophenyl and the piperidine of JC2, and the semithiocarbazide, the furan, and the i-propylphenyl ring of RNPA2000. Our efforts could provide a foundation for further computational-guided investigations.
- Suigo, Lorenzo,Chojnacki, Michaelle,Zanotto, Carlo,Sebastián-Pérez, Victor,Morghen, Carlo De Giuli,Casiraghi, Andrea,Dunman, Paul M.,Valoti, Ermanno,Straniero, Valentina
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- Synthesis and structure-activity relationship studies of n-monosubstituted aroylthioureas as urease inhibitors
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Background: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Results: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. Conclusion: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.
- Dawalamu,Fang, Hai-Lian,Fu, Zi-Juan,Li, Fang,Li, Ke,Li, Wei-Yi,Liu, Li,Ni, Wei-Wei,Ouyang, Hui,Xiao, Zhu-Ping,Ye, Ya-Xi,Zhu, Hai-Liang,Zhu, Wen-Yan,Zou, Xia
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p. 1046 - 1059
(2021/11/30)
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- Synthetic method of 3,5 -dichlorobenzoyl chloride
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The invention discloses a synthesis method of 3,5-dichlorobenzoyl chloride. The method is characterized in that trimesoyl chloride is taken as a raw material, and two carbon monoxides are directly removed under the action of nickel or a nickel-based catalyst, and thus the 3,5-dichlorobenzoyl chloride is obtained. Compared with the conventional preparation method, the synthesis method of the 3,5-dichlorobenzoyl chloride, disclosed by the invention, has the characteristics of short reaction flow, low catalyst price, few three wastes, no need of recovering and treating a large amount of dangerousby-products, lower production cost and the like; the synthesis method of the 3,5-dichlorobenzoyl chloride is suitable for industrial production.
- -
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Paragraph 0017-0024
(2020/12/31)
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- Preparation method of 2,4,6-trimethylbenzoyl chloride and acyl chloride co-production technology
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The invention relates to the field of new materials of fine chemicals, in particular to 2,4,6-trimethylbenzoyl chloride (also known as trimesoyl chloride) and an environment-friendly and economical novel preparation process technology for co-producing series acyl chloride products.
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Paragraph 0033-0035
(2020/11/25)
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- Rhodium-Catalyzed Electrooxidative C?H Olefination of Benzamides
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Metal-catalyzed chelation-assisted C?H olefinations have emerged as powerful tools for the construction of functionalized alkenes. Herein, we describe the rhoda-electrocatalyzed C?H activation/alkenylation of arenes. The olefinations of challenging electron-poor benzamides were thus accomplished in a fully dehydrogenative fashion under electrochemical conditions, avoiding stoichiometric chemical oxidants, and with H2 as the only byproduct. This versatile alkenylation reaction also features broad substrate scope and used electricity as a green oxidant.
- Ackermann, Lutz,Struwe, Julia,Zhang, Yan
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supporting information
p. 15076 - 15080
(2020/06/20)
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- Method for synthesizing 3.5-dichlorobenzene formyl chloride
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The invention provides a synthesis method of 3, 5-dichlorobenzene formyl chloride, relating to the technical field of fine chemical engineering. The synthesis method of 3.5-dichlorobenzene formyl chloride comprises the following steps: taking isophthalic acid and trichlorotoluene as raw material under the action of a catalyst reacting at 50-150 DEG C to obtain crude m-phthaloyl chloride; distilling crude m-phthaloyl chloride under reduced pressure at 0.098mpa to obtain refined m-phthaloyl chloride and catalyst; chlorine is introduced at 70-150 DEG C for 4 hours at the rate of 100 mL/min-200 mL/min to obtain 5-dichlorobenzene formyl chloride. The decarbonylation of distilled 5-chloroisophthaloyl chloride is carried out under the action of catalyst at 200-280 DEG C to obtain 3,5-dichlorobenzene formyl chloride. The synthesis method of 3,5-dichlorobenzene formyl chloride has the advantages of high conversion rate, simple operation, little pollution and the like.
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-
Paragraph 0018; 0028; 0033; 0034; 0039; 0040; 0045
(2019/04/30)
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- N-(Substituted sulfonyl)benzamide derivative and preparation method and pharmaceutical application thereof
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The invention relates to an N-(substituted sulfonyl)benzamide derivative and preparation method and pharmaceutical application thereof, in particular to an N-(substituted sulfonyl)benzamide derivativeshown as general formula (I), preparation method thereof, medicinal salts of the derivative, and their application as therapeutics, especially as Nav1.7 inhibitors, wherein substituents in the general formula (I) shown in the description are defined the same as in the description.
- -
-
Paragraph 0439; 0441-0444
(2019/04/17)
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- NEW POLYMORPHS AND NEW PATH TO SYNTHESIZE TAFAMIDIS
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The present invention relates to a new path to synthesize crystalline Tafamidis polymorphs starting from a Tafamidis acetic acid adduct. In addition, this invention relates to a process to synthesize Tafamidis (2-(3,5-dichlorophenyl)-1,3-benzoxazole- 6-carboxylic acid * (2R,3R,4R,5S)-6-(methyl-amino)-hexane-1,2,3,4,5-pentol), new Tafamidis crystalline polymorphs, a pharmaceutical compositions comprising the new crystalline polymorphs and to the therapeutic use of such new polymorphs.
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Page/Page column 21
(2019/10/04)
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- Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model
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Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50 = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole)were evaluated in comparison to MY 5445 (4b)in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.
- Bollenbach, Maud,Lugnier, Claire,Kremer, Mélanie,Salvat, Eric,Megat, Salim,Bihel, Frédéric,Bourguignon, Jean-Jacques,Barrot, Michel,Schmitt, Martine
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supporting information
p. 269 - 290
(2019/06/05)
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- A benzoyl chloride to the preparation of 3, 5 - dichloro benzoyl chloride (by machine translation)
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The invention provides a process for preparing to benzoyl chloride for 3, 5 - dichloro benzoyl chloride method, the method is carried out in three steps, the reaction conditions are in the 50 - 150 °C, benzoyl chloride as the starting material by sulfonation, chlorinated, desulfurization to obtain 3, 5 - dichloro formyl chlorine thick, can be obtained through the rectification after the content is more than 99.5% target product 3, 5 - dichloro benzoyl chloride. The method not only raw material is simple and easy to obtain, by adding amides with the metal salt catalyst after the catalyst reaction temperature is greatly reduced, the whole no waste water is produced, exhaust gas HCl adopts the water absorbed to prepare hydrochloric acid, sulfur dioxide using 30% liquid caustic soda absorbed to prepare sodium sulfite, rectification stage only produces a small amount of solid residue, it is easy to realize industrial. (by machine translation)
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- Preparation method of 3,5-dichlorobenzoyl
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The invention discloses a preparation method of 3,5-dichlorobenzoyl. The preparation method comprises the following steps of adding cyclooctatetraene iron tricarbonyl into a prepared mixture, after mixing uniformly, rising the temperature to 110-120 DEG C under protection of nitrogen gas, then introducing chlorine gas into the mixture, stirring to react for 2-3 hours, then stopping introducing thechlorine gas, carrying out distillation on prepared reactants, collecting fractions under the condition of 125-127 DEG C, and obtaining the 3,5-dichlorobenzoyl. The preparation method disclosed by the invention has the advantages that the side products are few, the conversion rate is high, the operation is simple and safe, the requirements for the environmental condition is mild and the product yield is higher.
- -
-
Paragraph 0018-0052
(2018/04/28)
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- Facile synthesis of 3(2H)-furanones
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Abstract: A practical method for the synthesis of 3(2H)-furanones including the bullatenone was described. Intramolecular cyclization of 4-hydroxyalkynones in the presence of KOH affords the biologically potent furanones in moderate-to-good yield at room temperature. Synthesis of 4-hydroxyalkynones from the reaction of acid chloride and terminal alkyne in the presence of copper iodide at room temperature was also reported.
- Panda, Niranjan,Nayak, Dinesh K.
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p. 1093 - 1100
(2018/02/22)
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- Synthesis and structure–activity relationship studies of MI-2 analogues as MALT1 inhibitors
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Recent studies revealed that MALT1 is a promising therapeutic target for the treatment of ABC-DLBCL. Among several reported MALT1 inhibitors, MI-2 as an irreversible inhibitor represents a new class of ABC-DLBCL therapeutics. Due to its inherent potential cross-reactivity, further structure–activity relationship (SAR) study is imperative. In this work, five focused compound libraries based on the chemical structure of MI-2 are designed and synthesized. The systematic SARs revealed that the side chain of 2-methoxyethoxy has little impact on the activity and can be replaced by other functionalized groups, providing new MI-2 analogues with retained or enhanced potency. Compounds 81–83 with terminal hydroxyl group as side chain displayed enhanced activities against MALT1. Replacement of triazole core with pyrazole is also tolerant, while structural modifications on other sites are detrimental. These findings will facilitate further development of small-molecule MALT1 inhibitors.
- Wu, Guolin,Wang, Haixia,Zhou, Wenhui,Zeng, Bihua,Mo, Wenhui,Zhu, Kejie,Liu, Rong,Zhou, Jia,Chen, Ceshi,Chen, Haijun
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supporting information
p. 3321 - 3344
(2018/05/23)
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- Pharmaceutical-Oriented Methoxylation of Aryl C(sp 2)-H Bonds using Copper Catalysts
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A pharmaceutical-oriented, copper(II)-catalyzed methoxylation of aryl C(sp 2)-H bonds has been developed. This simple and environmentally benign reaction system occurs efficiently using oxygen as oxidant with broad substrate scope and high functional group tolerance.
- Zhang, Guofu,Zhu, Jianfei,Tong, Chaolai,Ding, Chengrong
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supporting information
p. 1451 - 1454
(2018/05/14)
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- Design, synthesis and docking study of 4-arylpiperazine carboxamides as monoamine neurotransmitters reuptake inhibitors
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Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.
- Paudel, Suresh,Sun, Ningning,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon
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p. 4127 - 4135
(2018/07/21)
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- Preparation method of 3,5-dichlorobenzoyl chloride
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The invention discloses a preparation method of 3,5-dichlorobenzoyl chloride. The preparation method includes subjecting benzoic acid and a sulfonating agent to sulfonation reaction to obtain 3,5-disulphonatobenzoate; enabling the 3,5-disulphonatobenzoate to react with a chlorinating agent to obtain 5-chloroformyl m-benzenedisulfonyl chloride; subjecting the 5-chloroformyl m-benzenedisulfonyl chloride to sulfur dioxide removal so as to obtain the 3,5-dichlorobenzoyl chloride. The preparation method has the advantages of high product yield, high product purity, environment friendliness and low production cost.
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-
Paragraph 0046; 0048; 0050; 0052; 0054; 0055; 0056
(2017/08/27)
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- Novel carboxamide derivates salt and use of the same
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The present invention relates to a novel carboxamide derivative salt having mental disorder remedial effects, and uses thereof. The salt as a compound represented by chemical formula 1 or a pharmaceutically allowable salt thereof can treat or prevent mental disorders such as depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, phobias, attention deficit hyperactivity disorder, etc., can increase a remission rate, has fewer side effects and can effectively inhibit reabsorption of serotonin, norepinephrine or dopamine.COPYRIGHT KIPO 2017
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Paragraph 0139-0143
(2018/02/10)
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- Application of the Huisgen cycloaddition and ‘click’ reaction toward various 1,2,3-triazoles as HIV non-nucleoside reverse transcriptase inhibitors
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The development of novel anti-HIV agents remains an important medicinal chemistry challenge given that no cure for the disease is imminent, and the continued use of current NNRTIs inevitably leads to problems associated with resistance. Inspired by the pyrazole-containing NNRTI lersivirine (LSV), we embarked upon a study to establish whether 1,2,3-triazole heterocycles could be used as a new scaffold for the creation of novel NNRTIs. An especially attractive feature of triazoles used for this purpose is the versatility in accessing variously functionalised systems using either the thermally regulated Huisgen cycloaddition, or the related ‘click’ reaction. Employing three alternative forms of these reactions, we were able to synthesise a range of triazole compounds and evaluate their efficacy in a phenotypic HIV assay. To our astonishment, even compounds closely mimicking LSV were only moderately effective against HIV.
- Pribut, Nicole,Veale, Clinton G.L.,Basson, Adriaan E.,van Otterlo, Willem A.L.,Pelly, Stephen C.
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supporting information
p. 3700 - 3704
(2016/07/21)
-
- Anion conductive aromatic copolymers from dimethylaminomethylated monomers: Synthesis, properties, and applications in alkaline fuel cells
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A novel series of anion conductive aromatic copolymers were synthesized from preaminated monomers (2,5-, 3,5-, or 2,4-dichloro-N,N-dimethylbenzylamine), and their properties were investigated for alkaline fuel cell applications. The targeted copolymers (QPE-bl-11a, -11b, and -11c) were synthesized via nickel-mediated Ullmann coupling polymerization, followed by quaternization and ion exchange reactions. Unlike the conventional method involving chloromethylation or bromination, this method provided copolymers with well-defined chemical structure. The hydrophilic components of the copolymers were composed of chemically stable phenylene main chain modified with high-density ammonium groups. Oligo(arylene ether sulfone ketone)s were employed as a hydrophobic block. QPE-bl-11a gave tough and bendable membranes by solution casting. The obtained membrane with the highest ion exchange capacity value (IEC = 2.47 mequiv g-1) showed high hydroxide ion conductivity (130 mS cm-1) in water at 80 °C. The QPE-bl-11a membrane showed reasonable alkaline stability in 1 M KOH aqueous solution for 1000 h at 60 °C. A platinum-free fuel cell was successfully operated with hydrazine as a fuel, the QPE-bl-11a as a membrane, and an electrode binder. The maximum power density of 380 mW cm-2 was achieved at a current density of 1020 mA cm-2 with O2.
- Akiyama, Ryo,Yokota, Naoki,Nishino, Eriko,Asazawa, Koichiro,Miyatake, Kenji
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p. 4480 - 4489
(2016/07/07)
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- Acid Chloride Synthesis by the Palladium-Catalyzed Chlorocarbonylation of Aryl Bromides
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We report a palladium-catalyzed method to synthesize acid chlorides by the chlorocarbonylation of aryl bromides. Mechanistic studies suggest the combination of sterically encumbered PtBu3 and CO coordination to palladium can rapidly equilibrate the oxidative addition/reductive elimination of carbon-halogen bonds. This provides a useful method to assemble highly reactive acid chlorides from stable and available reagents, and can be coupled with subsequent nucleophilic reactions to generate new classes of carbonylated products. The Good, the Bad and the Bulky! By employing a sterically encumbered phosphine ligand, tri-tert-butyl phosphine, under palladium catalysis inert aryl bromides are chlorocarbonylated to create reactive acid chlorides by reversible carbon-halogen bond reductive elimination. This general platform allows for an expanded scope of the Heck carbonylation reaction to include previously incompatible nucleophiles.
- Quesnel, Jeffrey S.,Kayser, Laure V.,Fabrikant, Alexander,Arndtsen, Bruce A.
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supporting information
p. 9550 - 9555
(2015/06/30)
-
- A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N -[3-[(Benzimidazol-2-yl)amino]propyl]amides
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Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group. (Graph Presented).
- Keurulainen, Leena,Vahermo, Mikko,Puente-Felipe, Margarita,Sandoval-Izquierdo, Elena,Crespo-Fernández, Benigno,Guijarro-López, Laura,Huertas-Valentín, Leticia,De Las Heras-Due?a, Laura,Leino, Teppo O.,Siiskonen, Antti,Ballell-Pages, Lluís,Sanz, Laura M.,Casta?eda-Casado, Pablo,Jiménez-Díaz, M. Belén,Martínez-Martínez, María S.,Viera, Sara,Kiuru, Paula,Calderón, Félix,Yli-Kauhaluoma, Jari
-
supporting information
p. 4573 - 4580
(2015/06/25)
-
- Design and synthesis of 4-benzylpiperidine carboxamides as dual serotonin and norepinephrine reuptake inhibitors
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A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their dual (serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine HCl.
- Paudel, Suresh,Cao, Yongkai,Guo, Shuohan,An, Byeongkwan,Kim, Kyeong-Man,Cheon, Seung Hoon
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p. 6418 - 6426
(2015/10/05)
-
- Re/Mg bimetallic tandem catalysis for [4+2] annulation of benzamides and alkynes via C-H/N-H functionalization
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A rhenium-magnesium cocatalyzed [4+2] annulation of benzamides and alkynes via C-H/N-H functionalization is described. The reaction features a divergent and high level of diastereoselectivities, which are readily switchable by subtle tuning of reaction conditions. Thus, a wide range of both cis- and trans-3,4-dihydroisoquinolinones is expediently synthesized in a highly atom-economical manner. Moreover, mechanistic studies unraveled a tandem mode of action between rhenium and magnesium in the catalytic cycles.
- Tang, Qiuzheng,Xia, Dexin,Jin, Xiqing,Zhang, Qing,Sun, Xiao-Qiang,Wang, Congyang
-
supporting information
p. 4628 - 4631
(2013/05/21)
-
- Structure-activity evaluation of new uracil-based non-nucleoside inhibitors of HIV reverse transcriptase
-
A new series of potential nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) based on the carbocyclic 5′-nor-uracil scaffold were designed and synthesized. Three different aspects of the scaffold were investigated: the effects of adding a linker between the carbocyclic and phenyl fragments, introduction of different substituents on the benzoyl residue and replacing the central carbocyclic ring with a benzyl group. Analogues of 2′,3′-dideoxy-2′,3′-didehydro-5′-nor-uridine, bearing 3,5-dichloro- or 3,5-dimethylbenzoyl groups, showed inhibitory activity against HIV-RT wild-type (IC50 5-10 μM) and mutants L100I (IC 50 1.2-2.1 μM) and K103N (IC50 8-17 μM).
- Matyugina, Elena S.,Valuev-Elliston, Vladimir T.,Geisman, Alexander N.,Novikov, Mikhail S.,Chizhov, Alexander O.,Kochetkov, Sergey N.,Seley-Radtke, Katherine L.,Khandazhinskaya, Anastasia L.
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p. 1443 - 1451
(2013/11/19)
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- Discovery and characterization of AZD9272 and AZD6538 - Two novel mGluR5 negative allosteric modulators selected for clinical development
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AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
- Raboisson, Patrick,Breitholtz-Emanuelsson, Anna,Dahlloef, Henrik,Kers, Annika,Minidis, Alexander B. E.,Nordmark, Anna,Stroem, Peter,Terelius, Ylva,Wensbo, David,Edwards, Louise,Isaac, Methvin,Jarvie, Keith,Slassi, Abdelmalik,Wilson, Julie M.,Xin, Tao,Heaton, William L.,Sheehan, Susan M.,McLeod, Donald A.
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p. 6974 - 6979,6
(2020/09/02)
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- Synthesis and bioactivity of N-tert-butyl-N′-acyl-5-methyl-1,2,3- thiadiazole-4-carbohydrazides
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A series of novel N-tert-butyl-N′-acyl-5-methyl-1,2,3-thiadiazole-4- carbohydrazides were designed and synthesized. Their structures were characterized by melting points, 1H NMR, IR, ESI-MS, and elemental analysis. The bioassay tests indicated that compound 7o exhibited excellent direct anti-TMV activity and induction activity in vivo at 50 μg/mL, which was better than that of Ninamycin and tiadinial. Our studies indicated that 1,2,3-thiadiazole was an active substructure for novel pesticide development.
- Mao, Wu Tao,Zhao, Hui,Fan, Zhi Jin,Ji, Xiao Tian,Hua, Xue Wen,Kalinina, Tatiana,Yury, Yu. Morzherin,Vasiliy, A. Bakulev
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p. 1233 - 1236,4
(2020/10/15)
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- Synthesis and antimicrobial evaluation of new benzofuran derivatives
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Thirteen compounds, based on benzofuran skeleton bearing aryl substituents at its C-3 position through methanone linker, were synthesized and screened for their antibacterial and antifungal activities against four bacteria Escherichia coli, Staphylococcus aureus, Methicillin-resistant S. aureus, Bacillus subtilis, and a fungus Candida albicans. Four hydrophobic benzofuran analogs were found to exhibit favorable antibacterial activities (MIC80 = 0.39-3.12 μg/mL), which were better than the control drugs.
- Jiang, Xizhen,Liu, Wenlu,Zhang, Wei,Jiang, Faqin,Gao, Zhe,Zhuang, Hao,Fu, Lei
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experimental part
p. 3526 - 3530
(2011/07/31)
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- Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
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The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.
- Steffen, Jamin D.,Coyle, Donna L.,Damodaran, Komath,Beroza, Paul,Jacobson, Myron K.
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experimental part
p. 5403 - 5413
(2011/10/02)
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- Design and synthesis of 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and pyrazolo[3,4-b]pyridines for Aurora-A kinase inhibitors
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Two series of 3-aminopyrazole compounds including 24 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and 16 pyrazolo[3,4-b]pyridines were synthesized and evaluated against HCT116, A549, and A2780 tumor cell lines. Among them, three compounds were found to have the ideal anti-proliferative activities in vitro. Docking experiments showed that the novel pyrazolo[3,4-b]pyridines share the similar interaction mode with Aurora-A kinase as PHA739358.
- Shi, Jianyou,Xu, Guobin,Zhu, Wei,Ye, Haoyu,Yang, Shengyong,Luo, Youfu,Han, Jing,Yang, Jincheng,Li, Rui,Wei, Yuquan,Chen, Lijuan
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supporting information; experimental part
p. 4273 - 4278
(2010/09/04)
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- Synthesis and pharmacological screening of several aroyl and heteroaroyl selenylacetic acid derivatives as cytotoxic and antiproliferative agents
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The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH2-COOH or Heterar-CO-Se-CH2-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with --bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3) and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7) and one mammary gland-derived non-malignant cell line (184B5). Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar=phenyl, 3,5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 -M. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 -M. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7.
- Sanmartin, Carmen,Plano, Daniel,Dominguez, Enrique,Font, Maria,Calvo, Alfonso,Prior, Celia,Encio, Ignacio,Palop, Juan Antonio
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scheme or table
p. 3313 - 3338
(2010/03/04)
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- SEROTONIN 5-HT3 RECEPTOR AGONIST
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A serotonin 5-HT3 receptor agonist containing a compound represented by the general formula (1) [R1, R3 and R5 represent hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogen atom, hydroxyl group, amino group, a lower alkoxy group, carboxyl group, carbamoyl group, or nitro group, R2 and R4 represent a halogen atom, hydroxyl group, or amino group, R6 represents hydrogen atom, a lower alkyl group, or a lower alkenyl group, R7 represents hydrogen atom, a lower alkyl group, a lower alkenyl group, or an aralkyl group, and m and n are integers of 1 to 3] or a physiologically acceptable salt thereof as an active ingredient and having both a serotonin 5-HT3 receptor antagonistic action and a serotonin 5-HT3 receptor activating action.
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Page/Page column 12-13
(2008/06/13)
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- SUBSTITUTED 5, 6, 7, 8-TETRAHYDRO-PYRIDO[4, 3-D]PYRIMIDINE-2-YL COMPOUNDS AND 5, 6, 7, 8-TETRAHYDRO-QUINAZOLINE-2-YL COMPOUNDS
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The invention relates to substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine-2-yl compounds and 5,6,7,8-tetrahydro-quinazoline-2-yl compounds, methods for the production thereof, medicaments containing said compounds, and the use thereof for producing medicaments.
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Page/Page column 81-82
(2008/06/13)
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- N-Aroyloxylthioxo-naphthalimides as DNA photocleavers of aroyloxyl oxygen radicals: Synthesis, evaluation, and substituents' effect
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Novel N-Aroyloxylthioxo-naphthalimides as highly efficient 'time-resolved' DNA photocleavers of aroyloxyl radicals type were designed and synthesized. The substituents at the aroyloxyl moiety have an important and unusual influence on the DNA photocleavage, and DNA photodamages of the compounds were unusually not depended on the electronic effects of substituents on the corresponding oxygen-centered radicals. With AM1 semi-empirical quantum calculation, it was found that their photocleaving activities were correlated with the densities of electron clouds on the N-O bonds in the triplet state. N-(m-Dichloro-benzoyloxy) -thioxo-naphthalimide could photodamage DNA effectively at less than the concentration of 2μM.
- Xu, Yufang,Huang, Xiayu,Qian, Xuhong,Yao, Wei
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p. 2335 - 2341
(2007/10/03)
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- Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents
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A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Young, Jonathan R.,Huang, Song X.,Chen, Irene,Walsh, Thomas F.,DeVita, Robert J.,Wyvratt Jr., Matthew J.,Goulet, Mark T.,Ren, Ning,Lo, Jane,Yang, Yi Tien,Yudkovitz, Joel B.,Cheng, Kang,Smith, Roy G.
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p. 1723 - 1727
(2007/10/03)
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- Antineoplastic agents. 379. Synthesis of phenstatin phosphate
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A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A- 4 (1b) directed at maintaining the (Z)stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c → 3a), and the parent phenstatin (3b) was later synthesized (6a → 3a → 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b → 3c → 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseria gonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A- 4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.
- Pettit, George R.,Toki, Brian,Herald, Delbert L.,Verdier-Pinard, Pascal,Boyd, Michael R.,Hamel, Ernest,Pettit, Robin K.
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p. 1688 - 1695
(2007/10/03)
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- Synthesis and anticonvulsant activity of a series of benzamides
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A series of benzamides containing N,N,2-trimethyl-1,2-propane diamine as the amide moiety was synthesized. The compounds were evaluated in the maximal electroshock (MES) and pentylenetetrazol (metrazole, MET) screens for anticonvulsant activity. The 3,5-trifluoromethyl, 3,5-dichloro, and 3-bromo analogues proved to be either equipotent with or more potent than phenytoin.
- Musso,Boswell,Mehta,Soroko,Burchall
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p. 331 - 334
(2007/10/03)
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- Allosteric Modifiers of Hemoglobin. 1. Design, Synthesis, Testing, and Structure-Allosteric Activity Relationship of Novel Hemoglobin Oxygen Affinity Decreasing Agents
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Three isomeric series of 2-(aryloxy)-2-methylpropionic acids were prepared and studied for their ability to decrease the oxygen affinity of human hemoglobin A.The isomeric aryloxy groups included 4-methyl>phenoxy, 4-(arylacetamido)phenoxy, and 4-methyl>phenoxy.A total of 20 compounds were synthesized and tested.Structure-activity relationships are presented.Several of the new compounds were found to be strong allosteric effectors of hemoglobin.The two most active compounds are 2-methyl>phenoxy>-2-methylpropionic acid and the corresponding 3,5-dimethyl derivative.The latter two compounds have been compared to other known potent allosteric effectors in the same assay and show greater activity.Both compounds also exhibit a right shift in the oxygen equilibrium curve when incubated with whole blood.The new compounds may be of interest in clinical or biological areas that require or would benefit from a reversal of depleted oxygen supply (i.e., ischemia, stroke, tumor radiotherapy, blood storage, blood substitutes, etc.).They are also structurally related to several marketed antilipidemic agents.
- Randad, Ramnarayan S.,Mahran, Mona A.,Mehanna, Ahmed S.,Abraham, Donald J.
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p. 752 - 757
(2007/10/02)
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- Substituted benzofurans and benzothiophenes
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The compounds are benzoyl benzofurans and benzothiophenes having pharmacological activity, in particular, coronary vasodilator activity useful for the treatment of angina pectoris and intermediates for the preparation thereof.
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