- Novel furfurylidene N-acylhydrazones derived from natural safrole: Discovery of LASSBio-1215, a new potent antiplatelet prototype
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We describe herein the discovery of (E)-N-methyl-N'-((5-nitrofuran-2-yl) methylene)benzo[d]1,3 dioxole-5-carbohydrazide (9e), named LASSBio-1215, as a novel antiplatelet agent belonging to the N-methyl-N-acylhydrazone class, which exert their antiaggregating actions on human and rabbit platelets induced by different agonists, through cyclooxygenase-1 (COX-1) or thromboxane synthase inhibition. This compound was elected after screening of a series of functionalized furyl N-acylhydrazone derivatives, synthesized from natural safrole 10. In vitro assays showed that compound 9e presents platelet-aggregating activity in rabbit platelet-rich plasma (PRP) induced by arachidonic acid (IC50=0.7 M) and collagen (IC50=4.5 M). Moreover, LASSBio-1215 also inhibited almost completely the second wave of adenosine diphosphate-induced platelet aggregation in human PRP, and this effect was correlated with their ability to block the production of pro-aggregating autacoid thromboxane A2.
- Rodrigues, Ana Paula C.,Costa, Luciana M.M.,Santos, Bruna L.R.,Maia, Rodolfo C.,Miranda, Ana L.P.,Barreiro, Eliezer J.,Fraga, Carlos A.M.
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Read Online
- Design, synthesis, crystal structure, molecular docking studies of some diorganotin(IV) complexes derived from the piperonylic hydrazide Schiff base ligands as cytotoxic agents
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Inspired by the role of organotin(IV) complexes in inhibition of cancer cell growth and interaction with different target proteins, we have synthesized a series of new organotin(IV) complexes of Schiff base ligands of benzylidene benzohydrazide analogues. The structural elucidation of compounds was done by spectroscopic studies showing tridentate nature (NOO) of Schiff base ligands having pentacoordinated geometry around the central tin metal. The X-ray crystallographic study of complex 9 (Me2SnL2) revealed the distorted trigonal bipyramidal geometry (SnO2NC2). The cytotoxic activity of compounds was tested against human cancer cell lines A549, Hela, MCF7 and normal cell line L6 using MTT assay. Compound 12 (Ph2SnL2), 14 (Et2SnL3), 19 (Bu2SnL4) was found most active against tested cell lines having IC50 value 22.909–32.303 μM. Further, molecular docking study was performed for the active compounds 12, 14 and 20 at 3D space of enzymes Tyrosine kinase and EGFR kinase domain.
- Devi, Jai,Yadav, Jyoti,Lal, Kashmiri,Kumar, Nikhil,Paul, Avijit Kumar,Kumar, Deepak,Dutta, Partha P.,Jindal, Deepak Kumar
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Read Online
- Effect of s–se bioisosteric exchange on affinity and intrinsic efficacy of novel n-acylhydrazone derivatives at the adenosine a2a receptor
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In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3–8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1–8). However, the N-methylated compounds (2, 6–8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3–5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.
- Barreiro, Eliezer J.,No?l, Fran?ois G.,Pedreira, Júlia Galvez Bulh?es,Silva, Rafaela Ribeiro
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- AMINO ALCOHOL DERIVATIVE, PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF
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The present invention belongs to the field of medicine, and specifically discloses an amino alcohol derivative represented by Formula I, a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof. In addition, the present invention also discloses a pharmaceutical composition comprising the above substances, and a use of the substance in the preparation of a medicament for the prevention and treatment of an immune inflammatory disease, or a disease or condition associated with immunological competence such as multiple sclerosis, ALS, CIDP, systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, psoriasis, polymyositis, etc.
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Paragraph 0157; 0158
(2021/11/13)
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- Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction
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Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.
- Zhou, Wenjuan,Xu, Chenhao,Dong, Guanjun,Qiao, Hui,Yang, Jing,Liu, Hongmin,Ding, Lina,Sun, Kai,Zhao, Wen
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- Mild Copper-Catalyzed Addition of Arylboronic Esters to Di- tert -butyl Dicarbonate: An Easy Access to Methyl Arylcarboxylates
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An efficient copper-catalyzed addition of arylboronic esters to (Boc) 2O was developed. The reaction can be conducted under exceedingly mild conditions and is compatible with a variety of synthetically relevant functional groups. It therefore represents a useful alternative route for the synthesis of methyl arylcarboxylates. A preliminary mechanistic study indicated the involvement of an addition-elimination mechanism.
- Xu, Jin-Di,Su, Xiao-Bo,Wang, Cai,Yao, Li-Wei,Liu, Jing-Hui,Hu, Guo-Qin
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supporting information
p. 833 - 837
(2021/02/26)
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- ACTIVATORS OF THE RETINOIC ACID INDUCIBLE GENE "RIG-I' PATHWAY AND METHODS OF USE THEREOF
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The present invention is directed to compounds of Formula (I), which are activators of the RIG-I pathway.
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Page/Page column 86-87
(2020/03/05)
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- ACTIVATORS OF THE RETINOIC ACID INDUCIBLE GENE "RIG-I" PATHWAY AND METHODS OF USE THEREOF
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The present invention is directed to compounds of Formula (I), which are activators of the RIG-I pathway.
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Paragraph 0544
(2020/03/01)
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- Cobalt Nanoparticles-Catalyzed Widely Applicable Successive C?C Bond Cleavage in Alcohols to Access Esters
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Selective cleavage and functionalization of C?C bonds have important applications in organic synthesis and biomass utilization. However, functionalization of C?C bonds by controlled cleavage remains difficult and challenging because they are inert. Herein, we describe an unprecedented efficient protocol for the breaking of successive C?C bonds in alcohols to form esters with one or multiple carbon atoms less using heterogeneous cobalt nanoparticles as catalyst with dioxygen as the oxidant. A wide range of alcohols including inactive long-chain alkyl aryl alcohols undergo smoothly successive cleavage of adjacent ?(C?C)n? bonds to afford the corresponding esters. The catalyst was used for seven times without any decrease in activity. Characterization and control experiments disclose that cobalt nanoparticles are responsible for the successive cleavage of C?C bonds to achieve excellent catalytic activity, while the presence of Co-Nx has just the opposite effect. Preliminary mechanistic studies reveal that a tandem sequence reaction is involved in this process.
- Dai, Wen,Gao, Shuang,Li, Guosong,Luo, Huihui,Lv, Ying,Shang, Sensen,Wang, Lianyue
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supporting information
p. 19268 - 19274
(2020/08/26)
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- Design, synthesis and the structure-activity relationship of agonists targeting on the ALDH2 catalytic tunnel
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ALDH2, a key enzyme in the alcohol metabolism process, detoxifies several kinds of toxic small molecular aldehydes, which induce severe organ damages. The development of novel Alda-1 type ALDH2 activators was mostly relied on HTS but not rational design so far. To clarify the structure–activity relationship (SAR) of the skeleton of Alda-1 analogs by synthesis of the least number of analogs, we prepared 31 Alda-1 analogs and 3 isoflavone derivatives and evaluated for their ALDH2-activating activity. Among these, the ALDH2-activating activity of mono-halogen-substituted (Cl and Br) N-piperonylbenzamides 3b and 3 k, and non-aromatic amides 8a-8c, were 1.5–2.1 folds higher than that of Alda-1 at 20 μM. The relationship between binding affinity in computer aided molecular docking model and the ALDH2-activating activity assays were clarified as follows: for Alda-1 analogs, with the formation of halogen bonds, the enzyme-activating activity was found to follow a specific regression curve within the range between ?5 kcal/mol and ?4 kcal/mol. For isoflavone derivatives, the basic moiety on the B ring enhance the activating activity. These results provide a new direction of utilizing computer-aided modeling to design novel ALDH2 agonists in the future.
- Cheng, Ming-Che,Lo, Wei-Chi,Chang, Yu-Wen,Lee, Shoei-Sheng,Chang, Chia-Chuan
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- Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
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An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
- Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
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p. 17887 - 17896
(2020/08/19)
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- ACTIVATORS OF THE RETINOIC ACID INDUCIBLE GENE "RIG-1" PATHWAY AND METHODS OF USE THEREOF
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The present invention is directed to compounds of Formula (I), which are activators of the RIG-I pathway.
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Paragraph 0266
(2020/03/02)
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- Palladium-Catalyzed Visible-Light-Driven Carboxylation of Aryl and Alkenyl Triflates by Using Photoredox Catalysts
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A visible-light-driven carboxylation of aryl and alkenyl triflates with CO2 is developed by using a combination of Pd and photoredox catalysts. This reaction proceeds under mild conditions and can be applied to a wide range of substrates including acyclic alkenyl triflates.
- Shimomaki, Katsuya,Nakajima, Tomoya,Caner, Joaquim,Toriumi, Naoyuki,Iwasawa, Nobuharu
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p. 4486 - 4489
(2019/06/24)
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- Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases
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A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC50 values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide (3) was identified as a lead AChE inhibitor with IC50=0.052±0.006 μm. N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide (2) was the lead MAO-B inhibitor with IC50=0.034±0.007 μm, and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.
- Vishnu,Pavankumar,Kumar, Sandeep,Raja, A. Senthil
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p. 1359 - 1376
(2019/07/15)
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- Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents
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4-(Nitrophenyl)hydrazone derivatives of N-acylhydrazone were synthesized and screened for suppress lymphocyte proliferation and nitrite inhibition in macrophages. Compared to an unsubstituted N-acylhydrazone, active compounds were identified within initial series when hydroxyl, chloride and nitro substituents were employed. Structure-activity relationship was further developed by varying the position of these substituents as well as attaching structurally-related substituents. Changing substituent position revealed a more promising compound series of anti-inflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Anti-inflammatory activity of compounds is achieved by modulating IL-1β secretion and prostaglandin E2 synthesis in macrophages and by inhibiting calcineurin phosphatase activity in lymphocytes. Compound SintMed65 was advanced into an acute model of peritonitis in mice, where it inhibited the neutrophil infiltration after being orally administered. In summary, we demonstrated in great details the structural requirements and the underlying mechanism for anti-inflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the anti-inflammatory drug development in general.
- Meira, Cássio S.,dos Santos Filho, José Maurício,Sousa, Caroline C.,Anjos, Pamela S.,Cerqueira, Jéssica V.,Dias Neto, Humberto A.,da Silveira, Rafael G.,Russo, Helena M.,Wolfender, Jean-Luc,Queiroz, Emerson F.,Moreira, Diogo R.M.,Soares, Milena B.P.
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p. 1971 - 1985
(2018/03/12)
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- Comparison of Phenylacetates with Benzoates and Phenylpropanoates as Antifeedants for the Pine Weevil, Hylobius abietis
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This study concludes an extensive investigation of antifeedants for the pine weevil, Hylobius abietis (Coleoptera: Curculionidae), an economically important pest of planted conifer seedlings. Building on the previously reported antifeedant effects of benzoates and phenylpropanoids (aromatic compounds with one- or three-carbon-atom substituents on the benzene ring), we here report the antifeedant effects of compounds with two-carbon-atom side chains (i.e., phenylacetates). We also present new results; the best antifeedants from the benzoate class were tested at 10-fold lower concentrations in order to find the optimal antifeedants. Generally, for all three compound classes, efficient antifeedants were found to have one or two methyl, chloro, or methoxy substituents on the aromatic ring. For monosubstituted phenylpropanoids, the substituent preferably should be in the para-position. In the search for synergistic antifeedant effects among the three compound classes, combinations of compounds from the three classes were tested in binary and ternary mixtures.
- Unelius, C. Rikard,Bohman, Bj?rn,Nordlander, G?ran
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p. 11797 - 11805
(2018/11/21)
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- Superior performance of Co-N/m-C for direct oxidation of alcohols to esters under air
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A convenient, expeditious, and high-efficiency protocol for the transformation of alcohols into esters using a Co-modified N-doped mesoporous carbon material (Co-N/m-C) as the catalyst is proposed. The catalyst was prepared through direct pyrolysis of a macromolecular precursor. The catalyst prepared using a pyrolysis temperature of 900 °C (labeled Co-N/m-C-900) exhibited the best performance. The strong coordination between the ultra-dispersed cobalt species and the pyridine nitrogen as well as the large area of the mesoporous surface resulted in a high turnover frequency value (107.6 mol methyl benzoate mol?1 Co h?1) for the direct aerobic oxidation of benzyl alcohol to methyl benzoate. This value is much higher than those of state-of-the-art transition-metal-based nanocatalysts reported in the literature. Moreover, the catalyst exhibited general applicability to various structurally diverse alcohols, including benzylic, allylic, and heterocyclic alcohols, achieving the target esters in high yields. In addition, a preliminary evaluation revealed that Co-N/m-C-900 can be used six times without significant activity loss. In general, the process was rapid, simple, and cost-effective.
- Li, Ning,Shang, Sensen,Wang, Lianyue,Niu, Jingyang,Lv, Ying,Gao, Shuang
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p. 1249 - 1257
(2018/06/14)
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- Development of N-Doped Carbon-Supported Cobalt/Copper Bimetallic Nanoparticle Catalysts for Aerobic Oxidative Esterifications Based on Polymer Incarceration Methods
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Heterogeneous nitrogen-doped carbon-incarcerated cobalt/copper bimetallic nanoparticle (NP) catalysts, prepared from nitrogen-containing polymers, were developed, and an efficient catalytic process for aerobic oxidative esterification was achieved in the presence of a low loading (1 mol %) of catalyst that could be reused and easily reactivated. This protocol enabled diverse conditions for the bimetallic NP formation step to be screened, and significant rate acceleration by inclusion of a copper dopant was discovered. The catalytic activity of the bimetallic Co/Cu catalysts is much higher than that for cobalt catalysts reported to date and is even comparable with noble-metal NP catalysts.
- Yasukawa, Tomohiro,Yang, Xi,Kobayashi, Shu
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supporting information
p. 5172 - 5176
(2018/09/12)
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- Chemoselective and Metal-Free Synthesis of Aryl Esters from the Corresponding Benzylic Alcohols in Aqueous Medium Using TBHP/TBAI as an Efficient Catalytic System
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A novel and transition-metal-free strategy has been developed for the synthesis of aryl esters starting from corresponding benzylic primary alcohols as the exclusive substrates using tert -butyl hydroperoxide (TBHP) as a terminal oxidant in the presence of catalytic amount of tetrabutylammonium iodide (TBAI) and imidazole, where the aliphatic alcohols remained unaffected. These reactions are highly chemoselective and associated with high yield and wide applicability accommodating a wide range of substituents. Excellent chemoselectivity has also been demonstrated through intramolecular competition experiments. This protocol can be considered as an important analogue of Tishchenko reaction using benzylic alcohols as the substrates instead of benzaldehydes.
- Nandy, Sneha,Ghatak, Avishek,Das, Asit Kumar,Bhar, Sanjay
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p. 2208 - 2212
(2018/10/02)
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- As the PI3K/mTOR inhibitor tricyclic compound, its preparation and use
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The invention discloses a tricyclic compound as a PI3K/mTOR inhibitor. The tricyclic compound is a compound with the general formula (I) in the specification, wherein Ar is selected from aryl or heteroaryl; X, Y and Z are independently selected from O, CR2R3 and NR4 respectively; Q is selected from O, CR2R3 and NR4 or does not exists; R1 represents C1-C6 alkyl; n is selected from integers from 0 to 4; when n is more than or equal to 2, two R1 and a morpholine cycle can be combined into a combined cycle, a bridge cycle or a spiral cycle; R2 and R3 are selected from hydrogen and C1-C6 alkyl; R4 is selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclic radical, acyl and sulfonyl. The invention further discloses a perpetration method of the compound with the general formula (I) as well as a pharmaceutical composition and application of the compound with the general formula (I).
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Paragraph 0152; 0153
(2017/08/25)
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- Imidazole-containing condensed tricyclic compound and application thereof
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The invention discloses an imidazole-containing condensed tricyclic compound adopting the structure as shown in the formula (I) or pharmaceutically acceptable salts, stereisomers or prodrug molecules thereof. The imidazole-containing condensed tricyclic compound has the IDO1 activity regulation function, can enhance T-cell activation through blocking immune checkpoints IDO1, is used for treating IDO1-mediated immunosuppression, and therefore, can become an effective medicine for treating malignant tumors. When used together with checkpoint protein anti-body drugs or other anti-cancer drugs, the imidazole-containing condensed tricyclic compound can enhance the anti-cancer effect. Meanwhile, the imidazole-containing condensed tricyclic compound has the potential of effectively treating IDO1 abnormity related immunosuppressive diseases and has a high application value.
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Paragraph 0339
(2018/03/01)
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- Visible-Light-Driven Carboxylation of Aryl Halides by the Combined Use of Palladium and Photoredox Catalysts
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A highly useful, visible-light-driven carboxylation of aryl bromides and chlorides with CO2 was realized using a combination of Pd(OAc)2 as a carboxylation catalyst and Ir(ppy)2(dtbpy)(PF6) as a photoredox catalyst. This carboxylation reaction proceeded in high yields under 1 atm of CO2 with a variety of functionalized aryl bromides and chlorides without the necessity of using stoichiometric metallic reductants.
- Shimomaki, Katsuya,Murata, Kei,Martin, Ruben,Iwasawa, Nobuharu
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supporting information
p. 9467 - 9470
(2017/07/24)
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- 4-Alkyliden-azetidinones modified with plant derived polyphenols: Antibacterial and antioxidant properties
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Antimicrobial resistance is one of the major and growing concerns in hospital- and community acquired infections, and new antimicrobial agents are therefore urgently required. It was reported that oxidative stress could contribute to the selection of resistant bacterial strains, since reactive oxygen species (ROS) revealed to be an essential driving force. In the present work 4-alkylidene-azetidinones, a new class of antibacterial agents, were functionalized with phytochemical polyphenolic acids such as protocatechuic, piperonyl, caffeic, ferulic, or sinapic acids and investigated as dual target antibacterial-antioxidant compounds. The best candidates showed good activities against multidrug resistant clinical isolates of MRSA (MICs 2–8 μg/mL). Among the new compounds, two revealed the best antioxidant capacity with TEAC-DPPH and TEAC-ABTS being significantly more active than Trolox.
- Giacomini, Daria,Musumeci, Rosario,Galletti, Paola,Martelli, Giulia,Assennato, Lorenzo,Sacchetti, Gianni,Guerrini, Alessandra,Calaresu, Enrico,Martinelli, Marianna,Cocuzza, Clementina
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p. 604 - 614
(2017/10/10)
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- Heterogeneous cobalt catalysts for selective oxygenation of alcohols to aldehydes, esters and nitriles
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Efficient and green oxygenation of alcohols to the corresponding aldehydes, esters and nitriles was developed with high selectivity. Functional alcohols, including some heterocyclic and allylic alcohols can be oxygenated to the corresponding aldehydes, esters and nitriles respectively. Moreover, the catalyst can be recycled and reused without significant deactivation. Noteworthy, the Co@NC (800-2h) catalyzed oxygenation of alcohols can be regulated easily by changing the reaction conditions, and then the corresponding aldehydes, esters and nitriles can be obtained in high yields respectively.
- Mao, Fei,Qi, Zhengliang,Fan, Haipeng,Sui, Dejun,Chen, Rizhi,Huang, Jun
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p. 1498 - 1503
(2017/01/18)
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- Efficient and selective palladium-catalyzed direct oxidative esterification of benzylic alcohols under aerobic conditions
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A highly efficient palladium-catalyzed approach for the direct oxidative esterification of benzylic alcohols with methanol and long-chain aliphatic alcohols under mild conditions has been achieved. This practical catalyst system exhibits a broad substrate scope and good functional group tolerance. Catalytic amount of Bi(OTf)3 is used as co-catalyst to improve the activity and selectivity of the reactions. A variety of esters are obtained in yields of 43–96%.
- Hu, Yongke,Li, Bindong
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p. 7301 - 7307
(2017/11/29)
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- Conversion of alcohols to alkyl esters and carboxylic acids using heterogeneous palladium-based catalysts
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Disclosed are methods for synthesizing an ester or a carboxylic acid from an organic alcohol. To form the ester one reacts, in the presence of oxygen gas, the alcohol with methanol or ethanol. This reaction occurs in the presence of a catalyst comprising palladium and a co-catalyst comprising bismuth, tellurium, lead, cerium, titanium, zinc and/or niobium (most preferably at least bismuth and tellurium). Alternatively that catalyst can be used to generate an acid from that alcohol, when water is also added to the reaction mix.
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- Thermolysis of 2-diazo-3-aryl ketoesters: New route to α-aryl malonates and aromatic esters
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Thermochemical excitation enabled efficient α-aryl malonates synthesis from 2-diazo-3-aryl ketoesters and alcohols under transition metal-free reaction conditions. Furthermore, an unusual C[sbnd]C bond cleavage and C[sbnd]O/(N) bond formation occurred whe
- Zhang, Zhao,Tang, Mengyao,Zang, Lei,Zou, Liang-Hua,Li, Jie
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supporting information
p. 5681 - 5684
(2016/11/28)
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- Microwave-assisted synthesis and photophysical studies of novel fluorescent N-acylhydrazone and semicarbazone-7-OH-coumarin dyes
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A microwave-assisted synthesis of novel N-acylhydrazone and semicacarbazone-7-hidroxy-coumarins derivatives, starting from 3-acetyl-7-hydroxy-2H-chromen-2-one, is described. This optimized protocol led to higher yields and considerable reduction in reaction time from ～24 to ～1 hour. Aqueous solutions of these compounds showed bright blue to cyan emission and maximum quantum yields of 0.244. The stereoelectronic effects of the attached groups led to modulation of the spectral characteristics by favoring syn or anti amide conformers. The synthesized compounds showed pH dependent luminescence and a strong batochromic shift up to 65 nm in a low polarity medium (methanol) due to a better stabilization of the syn-conformer promoting this redshifted emission. These characteristics can be exploited for designing new luminescent probes for pH as well as polar microenvironments.
- Pereira, Thiago Moreira,Vitório, Felipe,Amaral, Ronaldo Costa,Zanoni, Kassio Papi Silva,Murakami Iha, Neyde Yukie,Kümmerle, Arthur Eugen
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p. 8846 - 8854
(2016/10/11)
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- Highly efficient dehydrogenative cross-coupling of aldehydes with amines and alcohols
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A common protocol for the synthesis of amides, esters and α-ketoesters via cross dehydrogenative coupling of aldehydes and amines/alcohols has been developed. The method is applicable to a wide variety of alcohols and amines as well as aliphatic and aromatic aldehydes. Also, the use of acetaldehyde for acetylation and ethyl glyoxalate to access 2-oxo-amino esters is presented for the first time.
- Deshidi, Ramesh,Rizvi, Masood Ahmad,Shah, Bhahwal Ali
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p. 90521 - 90524
(2015/11/11)
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- Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid
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The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic, electrophilic alkylating reagents. Although the Chan-Lam reaction has been widely applied in the arylation of heteroatom nucleophiles, O-alkylation with boronic acids is rare. We report a Cu-catalyzed nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds in air with no additional oxidant. An isotope-labeling study supports an oxidative cross-coupling mechanism, in analogy to that proposed for Chan-Lam arylation.
- Jacobson, Clare E.,Martinez-Mu?oz, Noelia,Gorin, David J.
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p. 7305 - 7310
(2015/07/28)
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- Divergent and concise total syntheses of dihydrochalcones and 5-deoxyflavones recently isolated from Tacca species and Mimosa diplotricha
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Dihydrochalcones and 5-deoxyflavones are types of compounds possessing various biologically interesting properties. Herein, we report the concise and divergent total syntheses of several naturally occurring dihydrochalcones and 5-deoxyflavones from readily available starting materials. The divergent strategy is based around manipulation of a common chalcone scaffold and features application of Algar-Flynn-Oyamada oxidation and benzoquinone C-H activation methodologies. These are the first reported total syntheses of these biologically interesting compounds and the concise and flexible route should be readily amenable to future analogue generation. Furthermore, this work provides an illustration of the utility of divergent synthesis for the expedient and step-economical preparation of natural product libraries.
- Sum, Tze Han,Sum, Tze Jing,Stokes, Jamie E.,Galloway, Warren R.J.D.,Spring, David R.
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p. 4557 - 4564
(2015/06/08)
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- Correlation of the rates of solvolysis of electron-rich benzoyl chloride using the extended Grunwald-Wistein equation
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The solvolysis rate constants of piperonyloyl chloride (1) in 27 different solvents are well correlated with the extended Grunwald-Winstein equation, using the NT solvent nucleophilicity scale, YCl solvent ionizing scale, and I aromatic ring parameter with sensitivity values of 0.30 ± 0.05, 0.71 ± 0.02, and 0.60 ± 0.04 for l, m, and h, respectively. The solvent kinetic isotope effect values (SKIE, kMeOH/kMeOD and k 50%MeOD-50%D2O) of 1.16 and 1.12 were also in accord with the values for the SN1 mechanism and/or the dissociative SN2 mechanism. The product selectivity values (S) for solvolysis of 1 in alcohol/water mixtures were in the range of 0.5 to 1.9, which is also consistent with the proposed unimolecular ionization mechanism.
- Oh, Hyunjung,Choi, Hojune,Park, Jong Keun,Yang, Kiyull,Koo, In Sun
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p. 2697 - 2701
(2013/10/22)
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- Structure-based optimization of oxadiazole-based GSK-3 inhibitors
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Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases β-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and β, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3β. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3β, with an IC 50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.
- Lo Monte, Fabio,Kramer, Thomas,Gu, Jiamin,Brodrecht, Martin,Pilakowski, Johannes,Fuertes, Ana,Dominguez, Juan Manuel,Plotkin, Batya,Eldar-Finkelman, Hagit,Schmidt, Boris
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- Catalytic methyl transfer from dimethylcarbonate to carboxylic acids
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Although methylation reactions are commonplace, currently used reagents are hazardous, toxic, and/or unstable. Dimethylcarbonate has been put forth as an inexpensive, nontoxic, and green potential methylating reagent. Herein we report a general, base-catalyzed methyl transfer from dimethylcarbonate to carboxylic acids. High selectivity for esterification is observed even in the presence of unprotected phenols, and the mild reaction conditions enable conservation of stereochemistry at epimerizable stereocenters. Isotope-labeling studies suggest a mechanism proceeding by direct methyl transfer from dimethylcarbonate to the substrate.
- Ji, Yuan,Sweeney, Jessica,Zoglio, Jillian,Gorin, David J.
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p. 11606 - 11611
(2013/12/04)
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- Aerobic oxidation of diverse primary alcohols to methyl esters with a readily accessible heterogeneous Pd/Bi/Te catalyst
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Efficient aerobic oxidative methyl esterification of primary alcohols has been achieved with a heterogeneous catalyst consisting of 1 mol % Pd/charcoal (5 wt %) in combination with bismuth(III) nitrate and tellurium metal. The Bi and Te additives significantly increase the reaction rate, selectivity, and overall product yields. This readily accessible catalyst system exhibits a broad substrate scope and is effective with both activated (benzylic) and unactivated (aliphatic) alcohols bearing diverse functional groups.
- Powell, Adam B.,Stahl, Shannon S.
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supporting information
p. 5072 - 5075
(2013/10/22)
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- Selective oxidation of alcohols to esters using heterogeneous Co 3O4-N@C catalysts under mild conditions
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Novel cobalt-based heterogeneous catalysts have been developed for the direct oxidative esterification of alcohols using molecular oxygen as benign oxidant. Pyrolysis of nitrogen-ligated cobalt(II) acetate supported on commercial carbon transforms typical homogeneous complexes to highly active and selective heterogeneous Co3O4-N@C materials. By applying these catalysts in the presence of oxygen, the cross and self-esterification of alcohols to esters proceeds in good to excellent yields.
- Jagadeesh, Rajenahally V.,Junge, Henrik,Pohl, Marga-Martina,Radnik, Joerg,Brueckner, Angelika,Beller, Matthias
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supporting information
p. 10776 - 10782
(2013/08/23)
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- Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors
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Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
- Kümmerle, Arthur E.,Schmitt, Martine,Cardozo, Suzana V. S.,Lugnier, Claire,Villa, Pascal,Lopes, Alexandra B.,Romeiro, Nelilma C.,Justiniano, Hélène,Martins, Marco A.,Fraga, Carlos A. M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
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p. 7525 - 7545
(2012/11/06)
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- Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-α
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The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-α and GSK-3β to AD pathology and AML is ongoing. Thus, the identification of potent GSK-α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-α inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK-α selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay.
- Lo Monte, Fabio,Kramer, Thomas,Gu, Jiamin,Anumala, Upendra Rao,Marinelli, Luciana,La Pietra, Valeria,Novellino, Ettore,Franco, Bénédicte,Demedts, David,Van Leuven, Fred,Fuertes, Ana,Dominguez, Juan Manuel,Plotkin, Batya,Eldar-Finkelman, Hagit,Schmidt, Boris
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experimental part
p. 4407 - 4424
(2012/08/13)
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- Influence of structure of benzodioxole derivatives on photoinitiation efficiency of benzophenone
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To investigate the influence of the substituents at the 5-position of the phenyl ring of benzodioxole on the reactivity of a benzophenone (BP)/benzodioxole-based photoinitiator system, three benzodioxole-based compounds were synthesized in this study. The structure was characterized by FT-IR, 1H NMR and 13C NMR. The kinetics were monitored by a real-time Fourier Transform near-IR (FT-NIR) spectrometer. The results showed that the introduction of the electron-donating substituents in the 5-position of the phenyl ring contributed to the increase in the reactivity of the BP/benzodioxole-based system. On the contrary, the electron-drawn substituents at the 5-position of the phenyl ring caused the opposite effect. Compared with the BP/ethyldimethylaminobenzoate (EDAB) photoinitiating system, the combination of BP/5-methoxy-1,3-benzodioxole (BDOOMe) led to almost the same Rp max and final double bond conversions. It indicated that BDOOMe had the potential to be used as a coinitiator in the place of an amine in current BP/amine initiating systems for practical applications to decrease cytotoxicity and yellowing.
- Yang, Jinliang,Xu, Fei,Shi, Suqing,Nie, Jun
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experimental part
p. 1377 - 1382
(2012/09/08)
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- Oxidative esterification of aldehydes with alcohols and phenols in air
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Nucleophilic carbene-catalysed oxidative esterification of aldehydes with alcohols and phenols without additional oxidant under an air atmosphere has been achieved, which provides a metal-free new methodology for the oxidative esterification of aldehydes.
- Cheng, Shuanghua,Chen, Jiuxi,Gao, Wenxia,Jin, Huile,Ding, Jinchang,Wu, Huayue
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experimental part
p. 130 - 132
(2010/06/19)
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- Design, synthesis, and DNA-binding of N-alkyl(anilino)quinazoline derivatives
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New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7- methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b, 22a,d), and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for their cytotoxic activities and as potential DNA intercalating agents. We studied the strength and mode of binding to DNA of these molecules by DNA melting temperature measurements, fluorescence emission, and circular dichroism. The results of various spectral and gel electrophoresis techniques obtained with the different compounds, in particular compounds 5g and 22f, revealed significant DNA interaction. These experiments confirm that the N-aminoalkyl(anilino)-6,7-dimethoxyquinazoline nucleus is an efficient pharmacophore to trigger binding to DNA, via an intercalative binding process.
- Garofalo, Antonio,Goossens, Laurence,Baldeyrou, Brigitte,Lemoine, Amélie,Ravez, Séverine,Six, Perrine,David-Cordonnier, Marie-Hélène,Bonte, Jean-Paul,Depreux, Patrick,Lansiaux, Amélie,Goossens, Jean-Fran?ois
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scheme or table
p. 8089 - 8103
(2011/03/17)
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- Synthesis of N-substituted benzo[c][1,7]- and benzo[c][1,8] phenanthrolin-(5H)-6-ones through a Pd-mediated Suzuki-Miyaura heteroaryl-aryl coupling reaction
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In the course of the search for non-camptothecin topoisomerase I inhibitors we have undertaken the synthesis of N-substituted benzo[c][1,7]- and benzo[c][1,8]phenanthrolinone derivatives. An intermolecular Suzuki-Miyaura heteroaryl-aryl coupling reaction was planned as the key step. Then a nitro reduction followed by a concomitant lactamization achieved the construction of the tetracycle structures. This methodology permitted a rapid and efficient elaboration of biologically potent compounds.
- Genès, Constance,Michel, Sylvie,Tillequin, Fran?ois,Porée, Fran?ois-Hugues
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experimental part
p. 10009 - 10015
(2010/02/27)
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- Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives
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In this report we disclose the synthesis, vasodilatory activity, and identification of bioactive conformation of new N-acylhydrazone and N-methyl-N-acylhydrazone derivatives, structurally designed by bioisosteric replacements of previously described cardioactive compounds LASSBio-294 and its N-methyl derivative LASSBio-785. Some of these novel derivatives presented improved vasorelaxant properties, being new cardiovascular drug candidates.
- Kuemmerle, Arthur E.,Raimundo, Juliana M.,Leal, Carla M.,da Silva, Givanildo S.,Balliano, Tatiane L.,Pereira, Mariano A.,de Simone, Carlos A.,Sudo, Roberto T.,Zapata-Sudo, Gisele,Fraga, Carlos A.M.,Barreiro, Eliezer J.
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experimental part
p. 4004 - 4009
(2009/12/04)
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- THIAZOLE AND OXAZOLE KINASE INHIBITORS
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The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 175
(2009/04/25)
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- Highly efficient cyanoimidation of aldehydes
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"Chemical Equation Presented" Cyanoimidation of aldehydes using cyanamide as a nitrogen source and using NBS as an oxidant was achieved in high yields without the addition of a catalyst. The method has several advantages, Including mild conditions, simple workflow, and inexpensive reagents. The reaction proceeds in a one-pot manner, giving rise to the formation of intermolecular C-N and C-O bonds. Subsequently, the substituted W-cyanobenimidate products may also undergo a cyclization reaction to give 1,2,4-triazole derivatives in high yields.
- Yin, Ping,Wen-Bo, Ma.,Chen, Yue,Huang, Wen-Cal,Deng, Yong,He, Ling
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scheme or table
p. 5482 - 5485
(2010/02/27)
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- Chemoenzymatic approaches to lycorine-type amaryllidaceae alkaloids: Total syntheses of enf-lycoricidine, 3-epi-ent-lycoricidine, and 4-deoxy-3-epi-ent- lycoricidine
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The readily available and enzymatically derived cis-1,2-dihydrocatechol 4 has been elaborated, over 11 steps including an Overman rearrangement, into the non-natural enantiomer, (-)-1, of the alkaloid lycoricidine [(+)-1]. Related chemistries have provided analogues 18, 19, and 26.
- Matveenko, Maria,Kokas, Okanya J.,Banwell, Martin G.,Willis, Anthony C.
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p. 3683 - 3685
(2008/02/13)
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- Thienylhydrazon with digitalis-like properties (positive inotropic effects)
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The invention discloses a compound having the formula (I) wherein R1 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, unsubstituted phenyl, and substituted phenyl; R2 is selected from the group consisting of H, alkene, un-substituted phenol, and substituted phenyl; and pharmaceutically acceptable salts thereof, having digitalis-like properties. The invention further discloses a novel method to synthesize 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294). LASSBio-294 produces positive inotropic effect on cardiac and skeletal muscle. The invention is useful for the treatment of congestive heart failure and muscle fatigue. It lacks toxic effects seen in digitalis glycosides.
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Page/Page column 7-8; 11-13
(2008/06/13)
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- Synthesis of benzofurans through coupling of dienylacetylenes with carbene complexes: Total synthesis of egonol
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The reaction of various carbene complexes with dienylacetylenes has been examined. The reaction has been used as the cornerstone for the preparation of the nor-neolignan natural product egonol in five steps from readily available components. In most examples of the carbene-alkyne coupling, the reaction proceeds to form benzofuran derivatives. In the case of one highly functionalized terminal alkyne, a competing rearrangement/cyclization process occurs in preference to the carbene coupling process. The use of silylated alkynes subverts this process.
- Zhang, Jianwei,Zhang, Yi,Zhang, Yanshi,Herndon, James W.
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p. 5609 - 5616
(2007/10/03)
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- A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle
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This study was designed to investigate the effects on single skeletal muscle fibers of a novel thienylhydrazone, referred to as LASSBio-294, which is a bioisoster of pyridazinone compounds that inhibit the cyclic AMP-specific phosphodiesterase (PDE) 4. Twitch and fatigue were analyzed in single skeletal muscle fibers isolated from either the semitendinous or the tibialis anterior muscles dissected from the frog Rana pipiens. LASSBio-294 (12.5-100 μM) increased twitch tension, accelerated the maximal rate of tension decay during relaxation, and had very little effect in the maximal rate of tension development of muscle fibers directly stimulated at ≤30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, reaching its maximum at 40 min and was inversely proportional to the frequency of stimulation, becoming negligible at 60 and 90 Hz. The concentration-response relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 μM. In addition, LASSBio-294 reduced development of fatigue induced by tetanic stimulation of the muscle fibers and reduced the time needed for 80% prefatigue tension recovery after fatigue had developed to 50% of the maximal pretetanic force. These effects of LASSBio-294 can be fully explained by stimulation of the sarcoplasmic reticulum Ca2+ pump and could be ascribed to an increase in cellular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditions in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure).
- Gonzalez-Serratos, Hugo,Chang, Ruzhang,Pereira, Edna F. R.,Castro, Newton G.,Aracava, Yasco,Melo, Paulo A.,Lima, Patricia C.,Fraga, Carlos A. M.,Barreiro, Eliezer J.,Albuquerque, Edson X.
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p. 558 - 566
(2007/10/03)
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- Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole
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A new series of antinociceptive compounds belonging to the N- acylarylhydrazone (NAH) class were synthesized from natural safrole (7). The most analgesic derivative represented by 10f, [(4'-N,N- dimethylaminobenzylidene-3-(3',4'-methylenedioxyphenyl)propionylhydrazine], was more potent than dipyrone and indomethacin, used as standards. The NAH compounds described herein were structurally planned by molecular hybridization and classical bioisosterism strategies on previously reported analgesic NAH in order to identify the pharmacophoric contribution of the N- acylarylhydrazone moiety and investigate the structure-activity relationship (SAR) in these series. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Lima, Patricia C.,Lima, Lidia M.,Da Silva, Kelli Cristine M.,Leda, Paulo Henrique O.,De Miranda, Ana Luisa P.,Fraga, Carlos A. M.,Barreiro, Eliezer J.
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p. 187 - 203
(2007/10/03)
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