- Palladium-Catalyzed C?H Functionalization of Phenyl 2-Pyridylsulfonates
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An efficient palladium(II)-catalyzed intermolecular direct ortho-alkenylation and acetoxylation of phenols has been developed. The reaction proceeded via a seven-membered cyclopalladated intermediate and showed complete regio- and diastereoselectivity. The approach also provided an efficient route for the synthesis of coumarins and benzofurans.
- Li, Bin,Guo, Dong-Dong,Guo, Shi-Huan,Pan, Gao-Fei,Gao, Ya-Ru,Wang, Yong-Qiang
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Read Online
- 1,4-Addition of an aryllithium reagent to diethyl ketomalonate. Scalable synthesis of ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate
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While optimizing the synthesis of pharmaceutical building block 3 [ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate], we encountered an unusual addition of an aryllithium reagent to the ketone oxygen atom of diethyl ketomalonate. Compound 3 was ultimately prepared on a large scale by a two-step sequence involving (1) annulation of a functionalized Grignard reagent with diethyl ketomalonate and (2) selective mono-reduction of a geminal diester using lithium tri-tert-butoxyaluminum hydride. 2012 Elsevier Ltd. All rights reserved.
- Rocke, Benjamin N.,Conn, Edward L.,Eisenbeis, Shane A.,Ruggeri, Roger B.
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Read Online
- Oxidative Cleavage of β -Keto Sulfones via Nitrous Acid
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The reaction of nitrous acid with 1-aryl-2-(arylsulfonyl)ethanones 3a-e afforded the unexpected arenecarboxylic acids 12a-e, formic acid 14, and benzene/4-toluenesulfinic acid 15a, b through oxidative cleavage reaction. 4-Chlorobenzoic acid (12a), [1,1′-biphenyl]-4-carboxylic acid (12b), 2-naphthoic acid (12c), 2-thiophenecarboxylic acid (12d), and 2-benzofurancarboxylic acid (12e) were isolated in 72%, 62%, 55%, 58%, and 62% yields, respectively. The reported mechanistic pathways proposed the production of 1-aryl-2-(phenyl/tolylsulfonyl)ethane-1,2-dione 7 instead of arenecarboxylic acids 12. A mechanistic pathway to explain the reaction of nitrous acid with 1-aryl-2-(arylsulfonyl)ethanones 3a-e was suggested. In this pathway, the intermediate 1,2-oxazete 10 lost benzene/4-toluenesulfinic acid 15 to produce 1,2-oxazet-3-one 11. Ring cleavage of the latter intermediate afforded the arenecarboxylic acids 12.
- Abdel-Aziz, Hatem A.
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Read Online
- Synthesis and biological evaluation of a series of novel benzofuran-2-carboxylate 1,2,3-triazoles
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A facile and efficient synthetic route has been developed to substituted benzofuran-2-carboxylate 1,2,3-triazoles for the first time by reacting prop-2-yn-1-yl benzofuran-2-carboxylate with a variety of substituted aryl/benzyl azides in DMF/H2O system employing standard click reaction. This new method has the lead of good yields, inexpensive reagents, easily available, easy work-up, mild reaction conditions, and environmentally friendly reaction conditions. All these compounds have been characterized by modern spectral techniques such as IR, 1H NMR, and mass spectroscopy, etc. Evaluation of synthesized compounds for antimicrobial activity against specific bacterial strains like Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa along with antifungal activity against Aspergillus Niger and Sclerotium rolfsii have been carried out.
- Bhaskar, K.,Yadav, J. S.
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p. 767 - 774
(2021/09/28)
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- Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
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Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
- Linciano, Pasquale,Benedetti, Rosaria,Pinzi, Luca,Russo, Fabiana,Chianese, Ugo,Sorbi, Claudia,Altucci, Lucia,Rastelli, Giulio,Brasili, Livio,Franchini, Silvia
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- Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site
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A novel series of shikonin-benzo[b]furan derivatives were designed and synthesized as tubulin polymerization inhibitors, and their biological activities were evaluated. Most compounds revealed the comparable anti-proliferation activities against the cancer cell lines to that of shikonin and simultaneously low cytotoxicity to non-cancer cells. Among them, compound 6c displayed powerful anti-cancer activity with the IC50 value of 0.18 μM against HT29 cells, which was significantly better than that of the reference drugs shikonin and CA-4. What's more, 6c could inhibit tubulin polymerization and compete with [3H] colchicine in binding to tubulin. Further biological studies depicted that 6c can induce cell apoptosis and cell mitochondria depolarize, regulate the expression of apoptosis related proteins in HT29 cells. Besides, 6c actuated the HT29 cell cycle arrest at G2/M phase, and influenced the expression of the cell-cycle related protein. Moreover, 6c displayed potent inhibition on cell migration and tube formation that contributes to the antiangiogenesis. These results prompt us to consider 6c as a potential tubulin polymerization inhibitor and is worthy for further study.
- Kong, Ling-Yi,Leng, Jia-Fu,Lian, Bao-Ping,Shao, Yu-Ying,Xia, Yuan-Zheng,Yin, Yong
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- Tandem Synthesis of 2-Carboxybenzofurans via Sequential Cu-Catalyzed C-O Coupling and Mo(CO)6-Mediated Carbonylation Reactions
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A modular tandem synthesis of 2-carboxybenzofurans from 2-gem-dibromovinylphenols has been established based on a sequence of Cu-catalyzed intramolecular C-O coupling and Mo(CO)6-mediated intermolecular carbonylation reactions. This protocol allowed one-step access to a broad variety of functionalized benzofuran-2-carboxylic acids, esters, and amides in good to excellent yields under Pd- and CO gas-free conditions.
- Mo, Qinliang,Sun, Nan,Jin, Liqun,Hu, Baoxiang,Shen, Zhenlu,Hu, Xinquan
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p. 11490 - 11500
(2020/10/12)
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- Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
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Six N-glycosyl benzofuran derivatives were synthesized by the catalysis of organic bases and condensation agents. The benzofuran derivatives were obtained by the reaction of various salicylaldehydes in acetone, and then hydrolyzed to the corresponding carboxylic acids. Finally, the target compounds were synthesized by acylation and the reaction conditions were optimized. The acetylcholinesterase (AChE) inhibitory activity of the desired compounds was tested using Ellman's method. Most of the compounds showed acetylcholinesterase-inhibition activity; N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzofuran-2-carbxamide (5a) showed the best acetylcholinesterase inhibition, with an inhibitory rate of 84%.
- Cao, Zhi-Ling,Liu, Shu-Hao,Liu, Wei-Wei,Liu, Xiu-Jian,Ren, Shu-Ting,Shi, Da-Hua,Wang, Lei,Wang, You-Xian,Wu, Yu-Ran
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p. 162 - 166
(2020/01/28)
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- A benzofuran -2 - preparation of formic acid method (by machine translation)
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A benzofuran - 2 - carboxylic acid, which belongs to the benzofuran - 2 - carboxylic acid technical field. Is to metallic iron porphyrin catalytic oxygen oxidation 2 - methyl benzofuran preparation of benzofuran - 2 - carboxylic acid, which belongs to the field of organic synthesis and green chemistry. The method uses 2 - methyl benzofuran as raw materials, in order to ethanol or ethanol aqueous solution as the solvent, metal porphyrin four (O - chlorophenyl) iron porphyrin as catalyst, oxygen as the oxidizing agent, sodium hydroxide or potassium hydroxide is used as the cocatalyst, for 80 - 130 °C reaction under 1 - 4 hours, after the reactant is acidified, filtration, recrystallization to obtain product benzofuran - 2 - carboxylic acid. The method of the invention catalyst the amount of raw material weight 0.02 - 0.05%, less catalyst levels and without the need of separation, clean oxygen as the oxidizing agent, and the pressure is 0.5 - 2.0 mpa, solvent environment friendly, the reaction temperature is lower, the reaction raw materials through a simple separation, but also can be recycled. (by machine translation)
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Paragraph 0019-0048
(2019/01/24)
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- Amide pyridine derivative and application thereof
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The invention belongs to the technical field of medicine and relates to an amide pyridine derivative which is shown as a general formula I. The invention further relates to stereoisomer and pharmaceutically-acceptable salt, hydrate, solvate or prodrug of the amide pyridine derivative. The definitions of substituent groups of Ar, M, R and Py are given out in an instruction book. The invention further relates to a method for preparing the compound shown in the general formula I, pharmaceutical composition containing the compound and application of the compound and the pharmaceutical compositionin preparing medicine for treating and preventing superficial-layer fungal diseases and deep-layer fungal diseases.
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Paragraph 0076; 0079; 0080
(2019/02/06)
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- A biocatalytic method for the chemoselective aerobic oxidation of aldehydes to carboxylic acids
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Herein, we present a study on the oxidation of aldehydes to carboxylic acids using three recombinant aldehyde dehydrogenases (ALDHs). The ALDHs were used in purified form with a nicotinamide oxidase (NOx), which recycles the catalytic NAD+ at the expense of dioxygen (air at atmospheric pressure). The reaction was studied also with lyophilised whole cell as well as resting cell biocatalysts for more convenient practical application. The optimised biocatalytic oxidation runs in phosphate buffer at pH 8.5 and at 40 °C. From a set of sixty-one aliphatic, aryl-Aliphatic, benzylic, hetero-Aromatic and bicyclic aldehydes, fifty were converted with elevated yield (up to >99%). The exceptions were a few ortho-substituted benzaldehydes, bicyclic heteroaromatic aldehydes and 2-phenylpropanal. In all cases, the expected carboxylic acid was shown to be the only product (>99% chemoselectivity). Other oxidisable functionalities within the same molecule (e.g. hydroxyl, alkene, and heteroaromatic nitrogen or sulphur atoms) remained untouched. The reaction was scaled for the oxidation of 5-(hydroxymethyl)furfural (2 g), a bio-based starting material, to afford 5-(hydroxymethyl)furoic acid in 61% isolated yield. The new biocatalytic method avoids the use of toxic or unsafe oxidants, strong acids or bases, or undesired solvents. It shows applicability across a wide range of substrates, and retains perfect chemoselectivity. Alternative oxidisable groups were not converted, and other classical side-reactions (e.g. halogenation of unsaturated functionalities, Dakin-Type oxidation) did not occur. In comparison to other established enzymatic methods such as the use of oxidases (where the concomitant oxidation of alcohols and aldehydes is common), ALDHs offer greatly improved selectivity.
- Knaus, Tanja,Tseliou, Vasilis,Humphreys, Luke D.,Scrutton, Nigel S.,Mutti, Francesco G.
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supporting information
p. 3931 - 3943
(2018/09/11)
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- Development of coumarin–benzofuran hybrids as versatile multitargeted compounds for the treatment of Alzheimer’s Disease
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Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. The evidenced multifactorial nature of AD has been considered the main reason for the absence of cure so far. Therefore, the development of novel hybrids to treat the disease is very much essential. Focusing on this, a novel series of coumarin–benzofuran hybrids have been designed and screened as anti-Alzheimer’s disease agents. The strategy is to obtain an effective mimetic of donepezil, which is acetylcholinesterase inhibitor. Herein, the two main scaffolds namely coumarin and benzofuran are known pharmacophore moieties and we have performed their molecular design, pharmacokinetic descriptor studies for drug-likeliness. Further, in vitro studies such as antioxidant capacity, acetylcholinesterase (AChE) inhibition and amyloid-β (Aβ) self-aggregation inhibition have also been performed. Most importantly, these studies revealed that the newly synthesized hybrids can be versatile and promising drug-like moieties as efficient anti-AD agents.
- Hiremathad, Asha,Chand, Karam,Keri, Rangappa S.
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p. 1497 - 1503
(2018/07/31)
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- Synthesis and cholinesterase inhibitory activity of new 2-benzofuran carboxamide-benzylpyridinum salts
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A series of benzofuran-2-carboxamide-N-benzyl pyridinium halide derivatives (6a-o) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N-((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N-((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds (6a-o). The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC50 values in the range of 0.054–2.7 μM. In addition, good inhibitory effects on Aβ self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 μM, respectively).
- Abedinifar, Fahimeh,Farnia, S. Morteza F.,Mahdavi, Mohammad,Nadri, Hamid,Moradi, Alireza,Ghasemi, Jahan B.,Kü?ükk?l?n?, Tuba Tüylü,Firoozpour, Loghman,Foroumadi, Alireza
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p. 180 - 188
(2018/06/26)
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- Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51
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To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC–MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.
- Zhao, Shizhen,Wei, Peng,Wu, Mengya,Zhang, Xiangqian,Zhao, Liyu,Jiang, Xiaolin,Hao, Chenzhou,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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p. 3242 - 3253
(2018/05/23)
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- Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis
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Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prepared as potential inhibitors of Schistosoma mansoni histone deacetylase 8 (SmHDAC8). The crystal structures of SmHDAC8 with four inhibitors provided insight into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Two of the compounds showed significant, dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
- Bayer, Theresa,Chakrabarti, Alokta,Lancelot, Julien,Shaik, Tajith B.,Hausmann, Kristin,Melesina, Jelena,Schmidtkunz, Karin,Marek, Martin,Erdmann, Frank,Schmidt, Matthias,Robaa, Dina,Romier, Christophe,Pierce, Raymond J.,Jung, Manfred,Sippl, Wolfgang
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p. 1517 - 1529
(2018/08/01)
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- Donepezil structure-based hybrids as potential multifunctional anti-Alzheimer’s drug candidates
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A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer’s disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC50=4.0–30.0?μΜ) and moderate ability for inhibition of Aβ1–42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ42 aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ1–42 induced toxicity. Structure–activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.
- Piemontese, Luca,Tomás, Daniel,Hiremathad, Asha,Capriati, Vito,Candeias, Emanuel,Cardoso, Sandra M.,Chaves, Sílvia,Santos, M. Amélia
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p. 1212 - 1224
(2018/09/12)
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- Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents
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Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the “Malaria Box”. After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.
- Pieroni, Marco,Azzali, Elisa,Basilico, Nicoletta,Parapini, Silvia,Zolkiewski, Michal,Beato, Claudia,Annunziato, Giannamaria,Bruno, Agostino,Vacondio, Federica,Costantino, Gabriele
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p. 1959 - 1970
(2017/03/17)
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- A Metal-Free Approach to Carboxylic Acids by Oxidation of Alkyl, Aryl, or Heteroaryl Alkyl Ketones or Arylalkynes
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The metal-free oxidation of dialkyl, alkyl aryl, or alkyl heteroaryl ketones or arylalkynes to the corresponding carboxylic acids is achieved using an oxidative mixture of Oxone and trifluoroacetic acid. This green method is a simple and mild protocol to obtain carboxylic derivatives in excellent yields.
- Aravinda Kumar,Venkateswarlu, Vunnam,Vishwakarma, Ram A.,Sawant, Sanghapal D.
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p. 3161 - 3168
(2015/10/19)
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- Method for preparing carboxylic acids
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The present invention discloses a method for the preparation of carboxylic acid comprising contacting β-ketosulfone of Formula (I) with nitrous acid.
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Page/Page column 5; 6
(2015/05/05)
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- Metal-free oxidative cleavage of the C-C bond in α-hydroxy-β-oxophosphonates
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The potential of TBHP to promote oxidative hydroxylation of α-hydroxy-β-oxophosphonates (HOPs) through C(CO)-C bond cleavage is described. This cleavage, as depicted in the mechanism is expected through an isomer of HOP that reacts with TBHP to generate acids.
- Battula, Satyanarayana,Kumar, Atul,Ahmed, Qazi Naveed
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supporting information
p. 9953 - 9956
(2015/10/12)
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- DMSO/I2 mediated C-C bond cleavage of α-ketoaldehydes followed by C-O bond formation: A metal-free approach for one-pot esterification
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A novel and efficient I2/DMSO mediated metal-free strategy is presented for the direct C-C bond cleavage of aryl-/heteroaryl- or aliphatic α-ketoaldehydes by C2-decarbonylation and C1-carbonyl oxidation to give the corresponding carboxylic acids followed by esterification in one pot, offering excellent yields in both the steps. Here, DMSO acts as the oxygen source/oxidant and this reaction works very well under both conventional heating and microwave irradiation. This is a very simple and convenient protocol.
- Venkateswarlu, Vunnam,Aravinda Kumar,Gupta, Sorav,Singh, Deepika,Vishwakarma, Ram A.,Sawant, Sanghapal D.
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p. 7973 - 7978
(2015/07/27)
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- Copper-catalyzed formal c-h carboxylation of aromatic compounds with carbon dioxide through arylaluminum intermediates
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The C-H bond carboxylation of various aromatic compounds with CO2 was achieved by the deprotonative alumination with a mixed alkyl amido lithium aluminate compound iBu3Al(TMP)Li followed by the NHC-copper-catalyzed carboxylation of the resulting arylaluminum species, which afforded the corresponding carboxylation products in high yield and high selectivity. In addition to benzene derivatives, heteroarenes such as benzofuran, benzothiophene, and indole derivatives are also suitable substrates. Functional groups such as Cl, Br, I, vinyl, amide, and CN could survive the reaction conditions. Some key reaction intermediates such as the copper aryl and isobutyl complexes and their carboxylation products were isolated and structurally characterized by X-ray crystallographic analyses, thus offering important information on the reaction mechanism.
- Ueno, Atsushi,Takimoto, Masanori,Wylie,Nishiura, Masayoshi,Ikariya, Takao,Hou, Zhaomin
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supporting information
p. 1010 - 1016
(2015/03/31)
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- Continuous flow synthesis of ketones from carbon dioxide and organolithium or grignard reagents
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We describe an efficient continuous flow synthesis of ketones from CO 2 and organolithium or Grignard reagents that exhibits significant advantages over conventional batch conditions in suppressing undesired symmetric ketone and tertiary alcohol byproducts. We observed an unprecedented solvent-dependence of the organolithium reactivity, the key factor in governing selectivity during the flow process. A facile, telescoped three-step-one-flow process for the preparation of ketones in a modular fashion through the in-line generation of organometallic reagents is also established.
- Wu, Jie,Yang, Xiaoqing,He, Zhi,Mao, Xianwen,Hatton, T. Alan,Jamison, Timothy F.
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supporting information
p. 8416 - 8420
(2014/08/18)
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- Copper/silver-mediated cascade reactions for the construction of 2-sulfonylbenzo[b]furans from trans-2-hydroxycinnamic acids and sodium sulfinates
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Efficient construction of 2-sulfonylbenzo[b]furans is achieved from readily available trans-2-hydroxycinnamic acids and sodium sulfinates mediated by the CuCl2.2H2O/AgTFA system under mild conditions. This unprecedented synthetic protocol provides expedient access to a series of products in one step via a protodecarboxylation/C-S bond formation/C-O bond formation cascade.
- Li, Hong-Shuang,Liu, Gang
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p. 509 - 516
(2014/04/03)
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- Discovery of aroyl piperazine derivatives as IKr & I Ks dual inhibitors for cardiac arrhythmia treatment
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Combined blockade of IKr and IKs potassium channels is considered to be a promising therapeutic strategy for arrhythmia. In this study, we designed and synthesized 15 derivatives through modifying the hit compound 7 that was discovered by screening in-house database by whole-patch clamp technique. All of the compounds were evaluated on CHO and HEK 293 cell lines stably expressing hERG (IKr) and hKCNQ1/KCNE1 (IKs) potassium channels, and half of them exhibited improved dual IKr and IKs inhibitory effects compared to the hit compound. Compounds 7a and 7b with potent dual inhibitory activities were selected for further in vivo evaluations. Due to the preferable pharmacological behaviors, compound 7a deserved further optimization as a promising lead compound.
- Guo, Xiaoke,Sun, Haopeng,Du, Lvpei,Huang, Lu,Xu, Jing,Zhu, Yingying,Yu, Peng,Zhang, Xiaojin,Tang, Yiqun,You, Qidong
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p. 497 - 505
(2014/06/23)
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- Potassium-alkyl magnesiates: Synthesis, structures and Mg-H exchange applications of aromatic and heterocyclic substrates
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Using structurally well-defined dipotassium-tetra(alkyl)magnesiates, a new straightforward methodology to promote regioselective Mg-H exchange reactions of a wide range of aromatic and heteroaromatic substrates is disclosed. Contacted ion pair intermediates are likely to be involved, with K being the key to facilitate the magnesiation processes. This journal is
- Baillie, Sharon E.,Bluemke, Tobias D.,Clegg, William,Kennedy, Alan R.,Klett, Jan,Russo, Luca,De Tullio, Marco,Hevia, Eva
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supporting information
p. 12859 - 12862
(2014/12/11)
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- Flash carboxylation: Fast lithiation-carboxylation sequence at room temperature in continuous flow
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A method for the direct lithiation of terminal alkynes and heterocycles with subsequent carboxylation in a continuous flow format was developed. This method provides carboxylic acids at ambient conditions within less than five seconds with only little excess of the organometallic base and CO2. This journal is the Partner Organisations 2014.
- Pieber, Bartholomaeus,Glasnov, Toma,Kappe
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p. 13430 - 13433
(2014/04/03)
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- Direct carboxylation of simple arenes with CO2 through a rhodium-catalyzed C-H bond activation
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Direct carboxylation of simple arenes under atmospheric pressure of CO2 is achieved through a rhodium-catalyzed C-H bond activation without the assistance of a directing group. Various arenes such as benzene, toluene, xylene, electron-rich or electron-deficient benzene derivatives, and heteroaromatics are directly carboxylated with high TONs. This journal is
- Suga, Takuya,Mizuno, Hajime,Takaya, Jun,Iwasawa, Nobuharu
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supporting information
p. 14360 - 14363
(2015/02/19)
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- Silver(i)-catalyzed carboxylation of arylboronic esters with CO2
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A variety of arylboronic esters were efficiently carboxylated with CO 2 using a simple AgOAc/PPh3 catalyst, affording the corresponding carboxylic acids in good yield. This simple and efficient silver(i) catalytic system showed wide functional group compatibility. The Royal Society of Chemistry 2012.
- Zhang, Xiao,Zhang, Wen-Zhen,Shi, Ling-Long,Guo, Chun-Xiao,Zhang, Ling-Ling,Lu, Xiao-Bing
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supporting information; experimental part
p. 6292 - 6294
(2012/07/16)
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- Heteroaryl hydroxycarbonylation: An efficient, robust, practically scalable approach using formyl acetate as the co source
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A simple, efficient, regioselective, and scalable palladium-catalyzed hydroxycarbonylation of heteroaryl halides to corresponding carboxylic acids using acetic-formic anhydride in presence of Pd(OAc)2, dppf, and diisopropylethyl amine in dimethyl formamide at 80-90 °C in excellent yields. Taylor & Francis Group, LLC.
- Gadakh, Amol V.,Chikanna, Dinesh,Rindhe, Sahebrao S.,Karale, Bhausaheb K.
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experimental part
p. 658 - 666
(2011/12/16)
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- Ruthenium-catalyzed oxidative C - H alkenylations of anilides and benzamides in water
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A cationic ruthenium(II) complex enabled efficient oxidative alkenylations of anilides in water as a green solvent and proved applicable to double C - H bond functionalizations of (hetero)aromatic amides with ample scope. Detailed studies provided strong support for a change of ruthenation mechanism in the two transformations, with an irreversible metalation as the key step in cross-dehydrogenative alkenylations of benzamides.
- Ackermann, Lutz,Wang, Lianhui,Wolfram, Ratnakancana,Lygin, Alexander V.
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supporting information; experimental part
p. 728 - 731
(2012/03/22)
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- Synthesis and CYP24A1 inhibitory activity of N-(2-(1H-imidazol-1-yl)-2- phenylethyl)arylamides
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A series of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides were prepared, using an efficient three- to five-step synthesis, and evaluated for their inhibitory activity against human cytochrome P450C24A1 (CYP24A1) hydroxylase. Inhibition ranged from IC50 0.3-72 μM compared with the standard ketoconazole IC50 0.52 μM, with the styryl derivative (11c) displaying enhanced activity (IC50 = 0.3 μM) compared with the standard, providing a useful preliminary lead for drug development.
- Aboraia, Ahmed S.,Yee, Sook Wah,Gomaa, Mohamed Sayed,Shah, Nikhil,Robotham, Anna C.,Makowski, Bart,Prosser, David,Brancale, Andrea,Jones, Glenville,Simons, Claire
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experimental part
p. 4939 - 4946
(2010/09/10)
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- Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid derivatives
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A series of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic acid (norfloxacin) derivatives were prepared according to the principle of combinating bioactive substructures and tested for their activities against five plant pathogenic bacteria and three fungi in vitro. The preliminary bioassays indicated that almost all synthesized target compounds retained the antibacterial activities of norfloxacin and had some antifungal activities as carboxylic acid amide compounds. The activities of compounds 1 and 22 against Xanthomonas oryzae were better than norfloxacin and all tested compounds had better antibacterial activities as compared to the agricultural streptomycin sulfate (a commercial bactericide) against X. oryzae, Xanthomonas axonopodis and Erwinia aroideae. Additionally, compounds 2 and 20 displayed good antifungal activities against Rhizoctonia solani and their inhibition of growth reached 83% and 94% respectively at the concentration of 200 mg/L.
- Yu, Zhiyi,Shi, Guanying,Sun, Qiu,Jin, Hong,Teng, Yun,Tao, Ke,Zhou, Guoping,Liu, Wei,Wen, Fang,Hou, Taiping
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scheme or table
p. 4726 - 4733
(2010/01/06)
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- Copper(I)-catalyzed carboxylation of aryl- and alkenylboronic esters
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(Chemical Equation Presented) The copper(I)-catalyzed carboxylation reaction of aryl- and alkenylboronic esters proceeded smoothly under CO 2 to give the corresponding carboxylic acid in good yield. This reaction showed wide generality with higher functional group tolerance compared to the corresponding Rh(I)-catalyzed reaction.
- Takaya, Jun,Tadami, Satoshi,Ukai, Kazutoshi,Iwasawa, Nobuharu
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supporting information; experimental part
p. 2697 - 2700
(2009/05/26)
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- Rhodium(I)-catalyzed carboxylation of aryl- and alkenylboronic esters with CO2
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When the esters of arylboronic acids with 2,2-dimethylpropan-1,3-diol were treated with a catalytic amount of [Rh(OH)(cod)]2 in the presence of 1,3-bis(diphenylphosphino)propane and CsF in dioxane at 60 °C under carbon dioxide atmosphere, the benzoic acid derivatives were obtained in good yields. Reactions of alkenylboronic esters also proceeded under similar conditions to give α,β-unsaturated carboxylic acids. As these boronic esters are now easily available through coupling or direct borylation reactions, this method would be a useful method for the preparation of various functionalized aryl- and alkenyl-carboxylic acids. Copyright
- Ukai, Kazutoshi,Aoki, Masao,Takaya, Jun,Iwasawa, Nobuharu
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p. 8706 - 8707
(2007/10/03)
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- Antioxidant properties of 3-hydroxycoumarin derivatives
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A series of hydroxylated 3-hydroxycoumarins was synthesised and evaluated for their antioxidant properties. The compounds substituted on the C-7 position were almost as antioxidant as quercetin or vitamin C. The antioxidant properties were related by an EPR study to their abilities to give stable semiquinonic or polyhydroxylated radicals. A series of hydroxylated 3-hydroxycoumarins was synthesised by the reaction of 3-aryl-2-hydroxypropenoic derivatives with boron tribromide. They were evaluated for their ability to scavenge the 2,2-diphenyl-1-picrylhydrazyl radical, the superoxide anion radical, the hydroxyl radical and the peroxynitrite anion and to inhibit copper-induced human LDL peroxidation. The physicochemical results were in accordance to establish the compounds hydroxylated on C-6 and C-7 positions as the most active of the series with antioxidant potencies comparable to those of quercetin and vitamin C. These compounds form o- and p-quinonoid derivatives upon radical scavenging and may serve as new lead compounds for pharmacological investigations.
- Bailly, Fabrice,Maurin, Cédric,Teissier, Elisabeth,Vezin, Hervé,Cotelle, Philippe
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p. 5611 - 5618
(2007/10/03)
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- Directed ortho-metalation, a new insight into organosodium chemistry
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Finely dispersed metallic sodium in combination with an alkyl chloride RCcan replace organolithium reagents in the ortho-metalation of aromatic compounds (see scheme). The in situ generated base is consumed as soon as it is formed, which avoids Wurtz coupling, the usual side reaction, and the handling and storage of highly reactive alkyl sodium bases. Reaction conditions are mild, the reaction is easy to scale up, and the reagents needed are inexpensive.
- Gissot, Arnaud,Becht, Jean-Michel,Desmurs, Jean Roger,Pevere, Virginie,Wagner, Alain,Mioskowski, Charles
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p. 340 - 343
(2007/10/03)
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- Reaction of aryl-2-hydroxypropenoic derivatives with boron tribromide
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(Z)-Mono, di or trimethoxyphenyl-2-hydroxypropenoic acids 1a-d gave mixtures of (E) and (Z) mono, di or trihydroxyphenyl-2-hydroxypropenoic acids 2a-d when treated with boron tibromide. The isomerisation proceeds during the work-up and depends on the duration of the hydrolysis and the number of oxygens on the aromatic ring. When the aromatic ring was substituted with a methoxy group at the ortho position, a cyclisation occurs, and 3-hydroxycoumarins 3 and benzofuran-2-carboxylic acids 4 can be obtained. 3-Hydroxycoumarin 3a can also be obtained almost quatitatively from the reaction of methyl 3-(2-methoxyphenyl)-2,3-epoxypropanoate with boron tribromide.
- Dupont, Romain,Cotelle, Philippe
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p. 597 - 600
(2007/10/03)
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- New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central α2-antagonistic activity as potential antidepressants
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The synthesis and biological activity of a series of benzofuro[3,2- c]pyridines and a benzothieno[3,2-c]pyridine are described. These compounds exhibit high affinity for the α2-adrenoceptor, with high selectivity versus the α1-receptor. Compound 1 also shows potent in vivo central activity and has been selected for further biological and clinical evaluation.
- Kennis, Ludo E.J.,Bischoff, Francois P.,Mertens, Carolus J.,Love, Christopher J.,Van den Keybus, Frans A.F.,Pieters, Serge,Braeken, Mirielle,Megens, Anton A.H.P.,Leysen, Josee E.
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- Palladium-catalysed heteroannulation with acetylenic compounds: Synthesis of benzofurans
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A detailed study of the heteroannulation of 0-iodophenol with acetylenic substrates through palladiumcopper catalysis leading to the synthesis of the 2-substituted benzofurans 21-29 is reported. An acylic compound 30 has been isolated and proved to be an intermediate in the synthesis of the benzofurans. Some of the benzofurans have been transformed into biologically active compounds.
- Kundu, Nitya G.,Pal, Manojit,Mahanty, Jyan S.,De, Mahuya
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p. 2815 - 2820
(2007/10/03)
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- Lithiation in Flavones, Chromones, Coumarins, and Benzofuran Derivatives
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Flavones are lithiated at position 3 by lithium di-isopropylamide in tetrahydrofuran at -78 deg C and the products are stable at that temperature.Appropriate reagents replace the lithium by carboxy, ethoxycarbonyl, mercapto, methylthio, trimethylsilyl, hydroxy, and other groups, sometimes giving products not previously available.Benzofurans are preferentially lithiated at position 2 if this is free, and may not be attacked if it is blocked, but if there is an activating group (i.e., one able to co-ordinate with the lithium cation) at position 2, then lithiation occurs at position 3.In the benzofuran series ring-opening is easier and lithiation often leads directly to acetylenic phenols.Chromones can be lithiated at positions 2 and 3 depending upon the substitution pattern and whether the substituents are activating.Aurones are not easily deprotonated, and only the acetylenic phenol arising from ring opening was found in the one successful case.Coumarins tend to behave simply as esters and give amides with the lithiating reagent, but 4-methoxycoumarin is readily lithiated at position 3.It is suggested that 3-deprotonation in ethers occurs easily only when there is an ether link antiperiplanar to the proton removed, and that the lithiated species are really unstable intermediates in trans-eliminations leading to alkyne derivatives.
- Costa, Ana M. B. S. R. C. S.,Dean, Francis M.,Jones, Michael A.,Varma, Rajender S.
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p. 799 - 808
(2007/10/02)
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- BENZOFURAN DERIVATIVES. I. ON THE EFFECTS OF SUBSTITUENTS IN BENZOFURAN SYNTHESES.
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The Roessing's reaction of 4-substituted 2-acylphenoxyacetic acids give a mixture of benzofurans and 2-benzofurancarboxylic acids. The relative yields of benzofurans and 2-benzofurancarboxylic acids depend on the substituents on the benzene ring of the 2-acylphenoxyacetic acids. Electron-withdrawing substituents such as nitro groups favor the formation of 2-benzofurancarboxylic acids. On the other hand, the formation of benzofurans is favored by the steric hindrance of 2-acyl groups in the reaction of 2-acyl-4-nitrophenoxyacetic acids with anhydrous sodium acetate and acetic anhydride.
- Suzuki,Horaguchi,Shimizu,Abe
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p. 2762 - 2767
(2007/10/02)
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- β-Deprotonation by Lithium Di-isopropylamide. Vinyl Carbanions from Oxygen Heterocycles in the Synthesis of Carboxylic Acids in the Benzofuran, Flavone, and Coumarin Series and in the Regiospecific Acylation of 2,6-Dimethylchromone
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Lithium di-isopropylamide at -70 deg C can remove the α-proton from benzofuran in the absence of activating groups and the β-proton if such groups are present; in flavone and 4-methoxycoumarin β-deprotonation occurs readily and the carbanions are easily carboxylated giving acids not previously accessible, while in 2,6-dimethylchromone β-deprotonation is kinetically favoured allowing 3-acylation to be achieved separately from the conventional acylation at the 2-methyl group.
- Costa, Ana M. B. S. R. C. S.,Dean, Francis M.,Jones, Michael A.,Smith, Dennis A.,Varma, Rajender S.
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p. 1224 - 1226
(2007/10/02)
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