- Synthesis and pharmacological activity of benzo[b]thiophene-3-carboxylic acid derivatives
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Several dialkylaminoethyl benzo[b]thiophene-3-carboxylates, N-(2-dialkylaminoethyl)benzo[b]thiophene-3-carboxamides, 2-dialkylaminoethyl benzo[b]thiophene-3-carbamates, and substituted ureas with benzo[b]thiophene moiety, were prepared and tested for local anesthetic, anticholinergic, and antihistaminic activities. Several of the compoundds showed significant activity.
- Shafiee,Hedayati,Salimi,Faghihi
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- Formal Lossen Rearrangement/Alkenylation or Annulation Cascade of Heterole Carboxamides with Alkynes Catalyzed by CpRhIII Complexes with Pendant Amides
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It has been established that a cyclopentadienyl (Cp) RhIII complex with two aryl groups and a pendant amide moiety catalyzes the formal Lossen rearrangement/alkenylation cascade of N-pivaloyl heterole carboxamides with internal alkynes, leading to alkenylheteroles. Interestingly, the use of sterically demanding internal alkynes afforded not the alkenylation but the [3+2] annulation products ([5,5]-fused heteroles). In these reactions, the pendant amide moiety of the CpRhIII complex may accelerate the formal Lossen rearrangement. The use of five-membered heteroles may deter reductive elimination to form strained [5,5]-fused heteroles; instead, protonation proceeds to give the alkenylation products. Bulky alkyne substituents accelerate the reductive elimination to allow the formation of the [5,5]-fused heteroles.
- Yamada, Takayuki,Shibata, Yu,Tanaka, Ken
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- Development of a Library of Thiophene-Based Drug-Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity
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The anion-binding and transport properties of an extensive library of thiophene-based molecules are reported. Seventeen bis-urea positional isomers, with different binding conformations and lipophilicities, have been synthesized by appending α- or β-thiophene or α-, β-, or γ-benzo[b]thiophene moieties to an ortho-phenylenediamine central core, yielding six subsets of positional isomers. Through 1H NMR, X-ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre-organized binding conformation capable of promoting the recognition of chloride, using urea and C?H binding groups in a cooperative fashion. Additional large unilamellar vesicle-based assays, carried out under electroneutral and electrogenic conditions, together with N-methyl-d-glucamine chloride assays, have indicated that anion efflux occurs mainly through an H+/Cl? symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.
- Vieira, Paulo,Miranda, Margarida Q.,Marques, Igor,Carvalho, Sílvia,Chen, Li-Jun,Howe, Ethan N. W.,Zhen, Carl,Leung, Claudia Y.,Spooner, Michael J.,Morgado, Bárbara,da Cruz e Silva, Odete A. B.,Moiteiro, Cristina,Gale, Philip A.,Félix, Vítor
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Read Online
- Binding and Transport Properties of a Benzo[b]thiophene-Based Mono-(thio)urea Library
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Using the chemical versatility of the benzo[b]thiophene motif, an extensive library of 24 (thio)urea receptors, with different binding properties and lipophilicities, was prepared and included α,α-, α,β-, β,β-, β,γ-, α,γ-, and γ,γ-benzo[b]thiophene positional isomers, as well as β- or γ-benzo[b]thiophene-based molecules decorated with aliphatic chains or aryl moieties with different fluorination degrees. 1H NMR titrations, X-ray crystallographic studies, and DFT calculations were used to study the chloride binding affinities between receptors and substrates. Experimental efflux studies suggested that the anion transmembrane transport activity is dependent on the receptors′ lipophilicity and hydrogen bonding ability. Moreover, LUV based assays indicated that anion efflux occurs mainly through an uniport mechanism. Further MD simulations showed that anion transport is highly dependent on the orientation and interactions of the receptors at the water/lipid interface.
- Cachatra, Vasco,Carvalho, Sílvia,Chen, Li-Jun,Félix, Vítor,Gale, Philip A.,Goodfellow, Brian J.,Marques, Igor,Moiteiro, Cristina,Ryder, William G.
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supporting information
(2022/02/02)
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- Heterocyclic compound and preparation and application thereof
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The invention relates to bromodomain inhibitors, and provides a compound represented by a general formula I, a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method thereof, a pharmaceutical composition containing the same, and applicationthereof in pharmacy.
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Paragraph 0297-0299
(2020/07/24)
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- Design and synthesis of heteroaromatic-based benzenesulfonamide derivatives as potent inhibitors of H5N1 influenza A virus
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Influenza A virus is an enveloped negative single-stranded RNA virus that causes febrile respiratory infection and represents a clinically challenging threat to human health and even lives worldwide. Even more alarming is the emergence of highly pathogenic avian influenza (HPAI) strains such as H5N1, which possess much higher mortality rate (60%) than seasonal influenza strains in human infection. In this study, a novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as M2 proton channel inhibitors. A systematic investigation of the structure-activity relationships and a molecular docking study demonstrated that the sulfonamide moiety and 2,5-dimethyl-substituted thiophene as the core structure played significant roles in the anti-influenza activity. Among the derivatives, compound 11k exhibited excellent antiviral activity against H5N1 virus with an EC50 value of 0.47 μM and selectivity index of 119.9, which are comparable to those of the reference drug amantadine.
- Yu, Yongshi,Tazeem,Xu, Zhichao,Du, Liaoqi,Jin, Mengyu,Dong, Chune,Zhou, Hai-Bing,Wu, Shuwen
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- Benzene sulfonamide compound and application of compound in preparing anti-influenza A virus drug
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The invention discloses a benzene sulfonamide compound and an application of the compound in preparing an anti-influenza A virus drug and belongs to the technical field of pharmaceuticals. A structural formula of the benzene sulfonamide compound is shown as formula (I) as shown in the specification, and the benzene sulfonamide compound is prepared by preparing a corresponding furoyl chloride compound, a thiophenecarbonyl chloride compound and a benzothiophene formyl chloride compound from a furoic acid compound, a thiophenic acid compound or a thionaphthencarboxylic acid compound under the backflow conditions of thionyl chloride and methylbenzene, further performing amination reaction to form a corresponding furoylamide compound, a thiophenecarboxamide compound and a benzothiophene formamide compound, reducing to a corresponding furylmethylamine compound, a thienylmethylamine compound and a benzothiophene methylamine compound under the condition of lithium aluminium hydride, and performing sulfonylation reaction under the conditions of taking triethylamine as an acid-binding agent and dichloromethane as a solvent. The benzene sulfonamide compound can effectively inhibit activity ofan influenza A virus, is low in cytotoxicity and can be used for preparing the anti-influenza A virus drug.
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Paragraph 0027; 0031
(2018/07/06)
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- Dehydrative Nazarov-type electrocyclizations of alkenyl (hetero)aryl carbinols via calcium catalysis: Access to cyclopenta[b]thiophenes and indene derivatives
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A general approach to the understudied cyclopenta[b]thiophenes is reported. The products were directly generated from calcium-catalyzed, dehydrative, Nazarov-type electrocyclizations of alkenyl thienyl carbinols in up to 82% yield. The thienyl carbinols demonstrated good tolerance for aryl and heteroaryl substituents on the alkene. Aryl carbinols were also amenable to the calcium-catalyzed conditions and afforded indene derivatives in good yields. In most cases, the reaction was selective for the thermodynamic alkene isomer; however, substituent effects played a role in determining product outcomes. Mechanistically, the calcium catalyst initiated formation of alkenyl (hetero)aryl carbinyl cations which subsequently underwent a 4π electrocyclization and elimination that is reminiscent of the Nazarov reaction. This transformation is significant for two main reasons: 1) it represents one of the only examples of catalysis for dehydrative, Nazarov-type electrocyclizations in which thiophene was compatible; 2) it allowed for the direct formation of cyclopenta[b]thiophenes while circumventing the need for cyclopenta[b]thiophenones as precursors.
- Martin, M. Cynthia,Sandridge, Matthew J.,Williams, Corey W.,Francis, Zola A.,France, Stefan
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p. 4093 - 4108
(2017/06/29)
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- Synthesis and preliminary biological evaluation of new heterocyclic carboxamide models
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The heterocyclic system is a promising core nucleus in many bioactive compounds. This work describes our effort to synthesize and characterize a set of new biphenyl, benzofuran and benzothiophene carboxamide derivatives. Our biological studies showed that
- Sweidan, Kamal,Engelmann, J?rn,Rayyan, Walid Abu,Sabbah, Dima,Zarga, Musa Abu,Al-Qirim, Tariq,Al-Hiari, Yusuf,Sheikha, Ghassan Abu,Shattat, Ghassan
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p. 417 - 429
(2015/06/22)
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- Dual role of Rh(III) catalyst enables regioselective halogenation of (electron-rich) heterocycles
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The Rh(III)-catalyzed selective bromination and iodination of electron-rich heterocycles is reported. Kinetic investigations show that Rh plays a dual role in the bromination, catalyzing the directed halogenation and preventing the inherent halogenation of these substrates. As a result, this method gives highly selective access to valuable halogenated heterocycles with regiochemistry complementary to those obtained using uncatalyzed approaches, which rely on the inherent reactivity of these classes of substrates. Furans, thiophenes, benzothiophenes, pyrazoles, quinolones, and chromones can be applied.
- Schr?der, Nils,Lied, Fabian,Glorius, Frank
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supporting information
p. 1448 - 1451
(2015/02/19)
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- Facile oxidation of electron-poor benzo[b]thiophenes to the corresponding sulfones with an aqueous solution of H2O2 and P 2O5
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A facile oxidation for the clean conversion of benzo[b]thiophenes to their corresponding sulfones is described employing an aqueous solution of H 2O2 and P2O5; the solution can be prepared and stored on a multi-
- Antonow, Dyeison,Marrafa, Teresa,Dawood, Irfaan,Ahmed, Tauheed,Haque, Mohammad R.,Thurston, David E.,Zinzalla, Giovanna
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supporting information; experimental part
p. 2289 - 2291
(2010/07/08)
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- The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38α MAP kinase
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A novel pyrrole-2-carboxamide series of p38α inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies.
- Down, Kenneth,Bamborough, Paul,Alder, Catherine,Campbell, Amanda,Christopher, John A.,Gerelle, Maria,Ludbrook, Steve,Mallett, Dave,Mellor, Geoff,Miller, David D.,Pearson, Rosannah,Ray, Keith,Solanke, Yemisi,Somers, Don
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scheme or table
p. 3936 - 3940
(2010/08/19)
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- Design and synthesis of 2-(3-benzo[b]thienyl)-6,7-methylenedioxyquinolin-4- one analogues as potent antitumor agents that inhibit tubulin assembly
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As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7- methylenedioxyquinolin-4-one analogues was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4- one (CHM-1), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones, identified by CoMFA models. The newly synthesized analogues were evaluated for cytotoxicity against seven human cancer cell lines, and structure -activity relationship (SAR) correlations were established. Analogues 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07 and 0.19 μM. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents.
- Chang, Yu-Hsun,Hsu, Mei-Hua,Wang, Sheng-Hung,Huang, Li-Jiau,Qian, Keduo,Morris-Natschke, Susan L.,Hamel, Ernest,Kuo, Sheng-Chu,Lee, Kuo-Hsiung
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experimental part
p. 4883 - 4891
(2010/02/28)
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- NEW COMPOUNDS
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The present invention relates to compounds of formula (I) [Chemical formula should be inserted here. Please see paper copy] as well as pharmaceutically acceptable salts and pharmaceutical compositions including the compounds are prepared or thereof: wherein, A1, A2, R1, R2, R3, R4, and R5 and n are as defined in the specification. The compounds of formula (I) are useful in therapy.
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Page/Page column 103
(2008/06/13)
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- The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction
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Two new heterocyclic diphenylphosphinooxazolines derived from thiophene and benzothiophene were prepared in moderate to good yield and these, and a range of related HETPHOX ligands, were applied in the intermolecular asymmetric Heck reaction. Phenylation of 2,3-dihydrofuran with the t-butyl-substituted thiophene-oxazoline ligand gave (R)-2-phenyl-2,3-dihydrofuran highly regioselectively with excellent enantioselectivity (91-95% ee) and in good yields (70-97%). In addition, cyclohexenylation of 2,3-dihydrofuran proceeded with enantioselectivities of up to 97% ee in excellent (97%) yields, again with the t-butyl-substituted thiophene-oxazoline ligand proving optimal over a range of reaction conditions investigated.
- Kilroy, Tim G.,Cozzi, Pier Giorgio,End, Nicole,Guiry, Patrick J.
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p. 106 - 110
(2007/10/03)
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- Synthesis of novel chiral thiophene-, benzothiophene- and benzofuran-oxazoline ligands and their use in the enantioselective Pd-catalyzed allylation
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Novel thiophene, benzothiophene and benzofuran-oxazoline ligands 6-11 containing a diphenylphosphino group at different positions of the heterocyclic skeleton have been prepared and used in the enantioselective allylation. The advantage of these new ligands is their easy accessibility and their high reactivity. The best results were obtained with ligand 9 to give the product 13 in 97.0% ee with 92% yield in 2 hours at 0°C.
- Tietze, Lutz F.,Lohmann, J. Klaas
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p. 2083 - 2085
(2007/10/03)
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- Further structure-activity relationships in the series of tropanyl esters endowed with potent antinociceptive activity
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Several analogs of the α-tropanyl esters of 2-(4-chlorophenoxy)butyric acid (SM21) and 2-phenylthiobutyric acid (SM32), endowed with potent antinociceptive and cognition enhancing activity, were synthesized, aimed at obtaining more potent and safe drug candidates. Variation of the acyl moiety, as well as the conformational restriction of atropine to give the α-tropanyl ester of 2,3-dihydrobenzofurane-3-carboxylic acid (18), practically abolished activity. In the case of 18, the antimuscarinic activity was also severely affected by the conformation restrain. On the contrary, conformational restriction of phenoxybutyric and phenylthiobutyric acid derivatives to give the α-tropanyl ester of 2,3-dihydro-benzofurane-2-carboxylic acid and 2,3-dihydro-benzothiophene-2-carboxylic acid, afforded potent analgesic drugs that unfortunately were too toxic to be reliable drug candidates. A series of related esters of benzofurane-3-carboxylic acid and benzothiophene-3-carboxylic acid were also studied and found to be potent but toxic analgesics.
- Scapecchi, Serena,Giorgi, Antonella,Bellucci, Cristina,Dei, Silvia,Ghelardini, Carla,Manetti, Dina,Romanelli, M. Novella,Teodori, Elisabetta
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p. 764 - 772
(2007/10/03)
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