- Uses of 1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]-thiophen-2-yl)-3-dodecanoylthiourea as a building block in the synthesis of fused pyrimidine and thiazine systems
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The reaction of lauroyl isothiocyanate and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was used to synthesize the title compound 2. Compound 2 could serve as the main building block in the synthesis of many target heterocyclic systems. Various fused pyrimidines were synthesized in the reactions of compound 2 with sodium ethoxide, hydrazine hydrate, phenyl hydrazine, ethyl carbazate, thiourea, and/or 2-aminothiophenol. The structures of the synthesized compounds were confirmed by microanalytical and spectral data.
- Hemdan, Magdy Mohamed,El-Mawgoude, Heba Kamal Abd
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Read Online
- Identification of small-molecule inhibitors of USP2a
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USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
- Tomala, Marcin D.,Magiera-Mularz, Katarzyna,Kubica, Katarzyna,Krzanik, Sylwia,Zieba, Bartosz,Musielak, Bogdan,Pustula, Marcin,Popowicz, Grzegorz M.,Sattler, Michael,Dubin, Grzegorz,Skalniak, Lukasz,Holak, Tad A.
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Read Online
- Design, synthesis, and biological evaluation of new thieno[2,3-d] pyrimidine derivatives as targeted therapy for PI3K with molecular modelling study
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Cancer is one of the most aggressive diseases characterised by abnormal growth and uncontrolled cell division. PI3K is a lipid kinase involved in cancer progression which makes it fruitful target for cancer control. 28 new morpholine based thieno[2,3-d] p
- Elmenier, Fatma M.,Lasheen, Deena S.,Abouzid, Khaled A. M.
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p. 315 - 332
(2022/01/04)
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- Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase
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Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on
- Massari, Serena,Bertagnin, Chiara,Pismataro, Maria Chiara,Donnadio, Anna,Nannetti, Giulio,Felicetti, Tommaso,Di Bona, Stefano,Nizi, Maria Giulia,Tensi, Leonardo,Manfroni, Giuseppe,Loza, Maria Isabel,Sabatini, Stefano,Cecchetti, Violetta,Brea, Jose,Goracci, Laura,Loregian, Arianna,Tabarrini, Oriana
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- Design, molecular modeling and synthesis of metal-free sensitizers of thieno pyridine dyes as light-harvesting materials with efficiency improvement using plasmonic nanoparticles
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Considering the thiophene unit as an electron-rich heterocycle, it is investigated with the aim of elucidating its potential efficiency for solar cell application. With the introduction of active substituents such as COOEt, CONH2 and CN into the thiophene segment, three novel thieno pyridine sensitizers (6a–c), based on donor-acceptor D-π-A construction, are designed and synthesized. The effect of the anchoring groups is investigated based on their molecular orbital’s (MO’s) energy gap (Eg). The electrostatic interaction between the synthesized dyes and metal nanoparticles, namely gold, silver and ruthenium, is believed to improve their performance as organic sensitizers. The dye-sensitized solar cells (DSSCs) are manufactured using the novel diazenyl pyridothiophene dyes, along with their metal nanoparticles conjugates as sensitizers, and were examined for efficiency improvement. Accordingly, using this modification, the photovoltaic performance was significantly improved. The promising results of conjugate (6b/AgNPs), compared with reported organic and natural sensitizers (JSC (1.136 × 10–1 mA/cm2), VOC (0.436 V), FF (0.57) and η (2.82 × 10–2%)), are attributed to the good interaction between the amide, methyl, amino and cyano groups attached to the thiophene pyridyl scaffolds and the surface of TiO2 porous film. Implementation of a molecular modeling study is performed to predict the ability of the thiophene moiety to be used in solar cell applications.
- Almalki, Abdulraheem S. A.,Khalifa, Mohamed E.,Merazga, Amar,Mersal, Gaber A. M.
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- 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
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Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
- Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
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supporting information
p. 179 - 192
(2019/01/04)
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- Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity
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During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure–activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.
- Saleeb, Michael,Sundin, Charlotta,Aglar, ?znur,Pinto, Ana Filipa,Ebrahimi, Mahsa,Forsberg, ?ke,Schüler, Herwig,Elofsson, Mikael
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supporting information
p. 568 - 576
(2017/12/07)
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- New thiophene–acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies
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In this study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT01 and ACS01-ACS07). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS01 and ACS02 derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC50 values of 9.60?±?3.19 and 10.95?±?3.96?μm. Additionally, these two derivatives were effective against antimony-resistant Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS01 is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 104?m?1. In partial least-squares studies, it was observed that the most active compounds (ACS01 and ACS02) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene–acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene–acridine derivatives are promising molecules as potential drug candidates.
- de Lima Serafim, Vanessa,Félix, Mayara Barbalho,Frade Silva, Daiana Karla,Rodrigues, Klinger Ant?nio da Franca,Andrade, Patrícia Néris,de Almeida, Sinara M?nica Vitalino,de Albuquerque dos Santos, Sanderssonilo,de Oliveira, Jamerson Ferreira,de Lima, Maria do Carmo Alves,Mendon?a-Junior, Francisco Jaime Bezerra,Scotti, Marcus Tullius,de Oliveira, Márcia Rosa,de Moura, Ricardo Olímpio
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p. 1141 - 1155
(2018/03/28)
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- ZnO-CeO2 nanocomposite: Efficient catalyst for the preparation of thieno[2,3-d]pyrimidin-4(3H)-one derivatives
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The Zinc oxide-cerium oxide (ZnO-CeO2) nanocomposite was prepared by a coprecipitation method and characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), and particle size distribution analysis. The XRD p
- Ghayour, Farzaneh,Mohammad Shafiee, Mohammad Reza,Ghashang, Majid
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- Tetrahydro benzothiophene derivative and application thereof to preparation of glycogen synthase kinase 3 beta inhibitor
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The invention discloses a tetrahydro benzothiophene derivative and the application thereof to the preparation of a glycogen synthase kinase 3 beta inhibitor. The tetrahydro benzothiophene derivative, pharmaceutically acceptable salt, optical active body or racemate thereof has a chemical structure as shown in a formula I. Experiments show that the compound has good GSK-3 beta inhibitory activity. In addition, the invention further provides a method for preparing a tetrahydro benzothiophene compound. The method is short in synthesis route, simple in preparation process and easy to operate, and can meet the requirements of large-scale industrial production.
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- Design, synthesis, and biological evaluation of C-2 substituted 3H-thieno[2,3-d]pyrimidin-4-one derivatives as novel FGFR1 inhibitors
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Background: Thienopyrimidinone is a newly designed, selective fibroblast growth factor receptor 1 (FGFR1) inhibitor with an excellent anticancer effect. Objective: The goal of the present study was to design and synthesize better FGFR1 inhibitors through modifications of the lead compound thienopyrimidinone. Methods: In the present study, a series of C-2 substituted derivatives of thienopyrimidinone, namely L1–L16, were synthesized, and their inhibitory effects on FGFR1 were evaluated. The anti-proliferative activities of these compounds were assessed by MTT assay. Results: Among the novel derivatives, L11 was found to exert remarkable FGFR1 inhibitory activity (79.93% at 10 M) and anti-proliferative activity, with IC50 values of 2.1, 2.5, and 3.5 M in the FGFR1-overexpressing cell lines, H460, HT-1197, and B16F10, respectively. Conclusion: Our newly synthesized thienopyrimidinone derivatives may be candidate FGFR1 inhibitors for future development as novel anticancer agents.
- Guo, Ping,Xie, Zixin,Zhang, Huan,Zhang, Zaikui,Han, Chao,Cheng, Donghua,Lin, Dan,Zhang, Yuan,Wang, Xuebao,Guo, Xin,Ye, Faqing
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p. 753 - 760
(2017/12/28)
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- Thienopyrimidine derivatives exert their anticancer efficacy via apoptosis induction, oxidative stress and mitotic catastrophe
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In this study, a series of 13 structural variants of thieno[2,3d]pyrimidine derivatives (6a-6m) were synthesized and screened for cytotoxicity in a panel of colorectal, ovarian, and brain cancer cell lines. The selectivity of the compounds was assessed by
- Amawi, Haneen,Karthikeyan, Chandrabose,Pathak, Rekha,Hussein, Noor,Christman, Ryann,Robey, Robert,Ashby, Charles R.,Trivedi, Piyush,Malhotra, Ashim,Tiwari, Amit K.
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p. 1053 - 1065
(2017/08/02)
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- Containing amide four tetrahydrobenz [4, 5] thieno [2, 3 - d] pyrimidine compound and use thereof
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The invention belongs to the technical field of medicine, and relates to a tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidines compound containing amide, an application of the compound as an epidermal growth factor receptor tyrosine kinase inhibitor and a pr
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Paragraph 0017-0018; 0021-0023
(2017/08/16)
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- Tetrahydrobenzothiophene carboxamides: Beyond the kinase domain and into the fatty acid realm
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A series of tetrahydrobenzothiophene carboxamides, inspired by structural features present in kinase and SCD1 inhibitors, are presented here. Prototype compound 8 (MMDD13) modulates fatty acid elongase and desaturase indexes, lipid accumulation, while pre
- Llona-Minguez, Sabin,Fayezi, Shabnam,Alihemmati, Alireza,Juárez-Jiménez, Jordi,Piedrafita, F. Javier,Helleday, Thomas
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supporting information
p. 4462 - 4466
(2017/09/12)
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- Anti-tubercular activities of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues endowed with high activity toward non-replicative Mycobacterium tuberculosis
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Thirty three derivatives of 2-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues were synthesized by molecular modification of a reported antimycobacterial molecule (GSK163574A). Compounds were evaluated in vitro against actively replicative and nutrient starved non-replicative Mycobacterium tuberculosis (MTB), enzymatic screening and cytotoxicity against RAW 264.7 cell line. Among the compounds, 2-ethyl-N-phenethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (5c) was found to be the most active compound against non-replicative MTB with 2.7 log reduction of bacteria at 10?μg/mL and was more potent than isoniazid (1.2 log reduction) and rifampicin (2.0 log reduction) at same dose level. Compound 5c also showed activity against MTB alanine dehydrogenase enzyme with IC50of 1.82?±?0.42?μM and showed 25% cytotoxicity against RAW 264.7 cell line at 50?μg/mL.
- Samala, Ganesh,Brindha Devi, Parthiban,Saxena, Shalini,Gunda, Saritha,Yogeeswari, Perumal,Sriram, Dharmarajan
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p. 5556 - 5564
(2016/10/24)
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- Novel thiazole-thiophene conjugates as adenosine receptor antagonists: Synthesis, biological evaluation and docking studies
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Here we report novel thiazole-thiophene conjugates as adenosine receptor antagonists. All the molecules were evaluated for their binding affinity for adenosine receptors. Most of the molecules were found to interact with the A1, A2A and A3 adenosine receptor subtypes with good affinity values. The most potent and selective compound 8n showed an A3 Ki value of 0.33 μM with selectivity ratios of >90 versus the A1 and >30 versus the A2 subtypes. For compound 8n docking studies into the binding site of the A3 adenosine receptor are provided to visualize its binding mode.
- Pandya, Dhaivat H.,Sharma, Jayesh A.,Jalani, Hitesh B.,Pandya, Amit N.,Sudarsanam,Kachler, Sonja,Klotz, Karl Norbert,Vasu, Kamala K.
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p. 1306 - 1309
(2015/03/14)
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- Optimization of small-molecule inhibitors of influenza virus polymerase: From thiophene-3-carboxamide to polyamido scaffolds
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Influenza virus infections represent a serious concern to public health, being characterized by high morbidity and significant mortality. To date, compounds targeting the viral ion-channel M2 or the viral neuraminidase are the drugs available for treatment of influenza, but the emergence of drug-resistant viral mutants renders the search for novel targets and their possible inhibitors a major priority. Recently, we demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein-protein disruption by small molecules, with thiophene-3-carboxamide derivatives emerging as promising candidates for the development of new anti-influenza drugs with broad-spectrum activity. Here, we report a further dissection of the thiophene-3-carboxamide structure. By using a GRID molecular interaction field (MIF)-based scaffold-hopping approach, more potent and nontoxic polyamido derivatives were identified, highlighting a new space in the chemical variability of RdRP inhibitors. Finally, a possible pharmacophoric model highlighting the key features required for RdRP inhibition is proposed.
- Lepri, Susan,Nannetti, Giulio,Muratore, Giulia,Cruciani, Gabriele,Ruzziconi, Renzo,Mercorelli, Beatrice,Palù, Giorgio,Loregian, Arianna,Goracci, Laura
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p. 4337 - 4350
(2014/06/09)
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- Synthesis and biological activity of new fluorinated thieno[2,3-d] pyrimidinyl hydrazone derivatives
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A series of new fluorinated thieno[2,3-d]pyrimidine derivatives containing hydrazone substructure was synthesized by a five-step procedure, including trifluoroacetylation, cyclization, chlorination, substitution by hydrazine, and condensation reaction. The structures of these newly synthesized compounds were confirmed by IR, NMR, EI-MS, elemental analysis and single-crystal X-ray diffraction. The preliminary bioassay result showed that some title compounds exhibited relatively good fungicidal activity against Fusarium oxysporium f.sp.vasinfectum at the concentration of 50 μg·mL-1, especially the inhibition rate of compound 6b reached above 90%.
- Song, Xin-Jian,Yang, Ping,Wang, Dai-Fu,Tan, Zhi-Dou
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p. 380 - 385
(2014/05/20)
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- Exploiting drug-resistant enzymes as tools to identify thienopyrimidinone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H
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The thienopyrimidinone 5,6-dimethyl-2-(4-nitrophenyl)thieno[2,3-d] pyrimidin-4(3H)-one (DNTP) occupies the interface between the p66 ribonuclease H (RNase H) domain and p51 thumb of human immunodeficiency virus reverse transcriptase (HIV RT), thereby indu
- Masaoka, Takashi,Chung, Suhman,Caboni, Pierluigi,Rausch, Jason W.,Wilson, Jennifer A.,Taskent-Sezgin, Humeyra,Beutler, John A.,Tocco, Graziella,Le Grice, Stuart F. J.
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supporting information
p. 5436 - 5445
(2013/07/26)
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- Rational design and synthesis of new PARP1 inhibitors
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A preliminary simulation of bioactive compounds followed by their synthesis have been carried out: a set of new fragment PARP1 inhibitors - 3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one derivatives - have been obtained. Molecular simulation has shown that binding is characterized by correlated hydrogen bonds with PARP1 and displacement of the highly-conservative water molecule by a polar group.
- Romashov, Leonid V.,Zeifman, Alexey A.,Zakharenko, Alexandra L.,Novikov, Fedor N.,Stroilov, Viktor S.,Stroganov, Oleg V.,Chilov, Germes G.,Khodyreva, Svetlana N.,Lavrik, Olga I.,Titov, Ilya Yu.,Svitan'Ko, Igor V.
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scheme or table
p. 15 - 17
(2012/05/19)
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- Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors
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A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl) piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.
- Ismail, Mohamed M.,Kamel, Mona M.,Mohamed, Lamia W.,Faggal, Samar I.,Galal, Mai A.
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scheme or table
p. 7217 - 7231
(2012/09/22)
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- Thiophene inhibitors of PDE4: Crystal structures show a second binding mode at the catalytic domain of PDE4D2
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PDE4 inhibitors have been identified as therapeutic targets for a variety of conditions, particularly inflammatory diseases. We have serendipitously identified a novel class of phosphodiesterase 4 (PDE4) inhibitor during a study to discover antagonists of the parathyroid hormone receptor. X-ray crystallographic studies of PDE4D2 complexed to four potent inhibitors reveal the atomic details of how they inhibit the enzyme and a notable contrast to another recently reported thiophene-based inhibitor.
- Nankervis, Jacob L.,Feil, Susanne C.,Hancock, Nancy C.,Zheng, Zhaohua,Ng, Hooi-Ling,Morton, Craig J.,Holien, Jessica K.,Ho, Patricia W.M.,Frazzetto, Mark M.,Jennings, Ian G.,Manallack, David T.,John Martin,Thompson, Philip E.,Parker, Michael W.
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supporting information; experimental part
p. 7089 - 7093
(2012/01/06)
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- Synthesis of some 3-substituted amino-4,5-tetramethylene thieno[2,3-d][ 1,2,3]-triazin-4(3H)-ones as potential antimicrobial agents
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A series of 3-Substituted amino-4,5-tetramethylene thieno[2,3-d] [1,2,3]-triazine-4(3H)-ones have been synthesized and characterized by UV,IR, 1H NMR, elemental and mass spectral analysis. The title compounds were evaluated for their antimicrobial activit
- Saravanan, Janardhanan,Mohan, Shamanna,Roy, Jay Jyoti
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experimental part
p. 4365 - 4369
(2010/10/02)
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- Substituted 2-Aminothiopen-derivatives: A potential new class of GluR6-Antagonists
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In the course of search for new therapeutic agents against epilepsy new inhibitors for the kainate receptor subtypes GluR5 and GluR6 were synthesized. We were able to synthesize new substituted thieno[2,3-d]pyrimidines 3a,b, 4a,b, 5a,b as well as thiophene-3-carboxamides 2a-d and a multitude of substituted 4-methyl-5-phenylthiophene-3-carboxylic acids. All compounds described herein were tested for their antagonistic effect towards the kainate receptor subtypes GluR5 and GluR6. The highest activity was observed for ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate 1c with an IC50 = 0.75 μM at the GluR6 receptor.
- Briel,Rybak,Kronbach,Unverferth
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experimental part
p. 69 - 77
(2010/03/24)
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- A novel series of positive modulators of the AMPA receptor: Discovery and structure based hit-to-lead studies
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Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
- Jamieson, Craig,Basten, Stephanie,Campbell, Robert A.,Cumming, Iain A.,Gillen, Kevin J.,Gillespie, Jonathan,Kazemier, Bert,Kiczun, Michael,Lamont, Yvonne,Lyons, Amanda J.,MacLean, John K.F.,Moir, Elizabeth M.,Morrow, John A.,Papakosta, Marianthi,Rankovic, Zoran,Smith, Lynn
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scheme or table
p. 5753 - 5756
(2010/12/18)
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- Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode
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A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1-2 A. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design.
- Kranz, Michael,Wall, Michael,Evans, Brian,Miah, Afjal,Ballantine, Stuart,Delves, Chris,Dombroski, Brian,Gross, Jeffrey,Schneck, Jessica,Villa, James P.,Neu, Margarete,Somers, Don O.
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experimental part
p. 5336 - 5341
(2009/10/23)
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- HETEROCYCLIC COMPOUNDS AS SEROTONERGIC AND DOPAMINERGIC AGENTS AND USES THEREOF
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Novel heterocyclic compounds, which exhibit a dopamine receptor (preferably a D4 receptor) and/or a serotonine receptor (preferably 5HTA1 agonistic activity), processes of preparing same, pharmaceutical compositions containing same and uses the
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Page/Page column 47
(2008/12/04)
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- Reactions of some anellated 2-aminothiophenes with electron poor acetylenes
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The reactivity of 2-aminothiophenes in two different anellations: (a) [b]-anellation to a saturated carbocycle and (b) [3,4-c]-anellation to benzopyrans, towards typical acetylenic dienophiles has been investigated. Because of the absence of conjugation, the thiophenes of type (a) do not undergo [4+2]-cycloaddition with acetylenic dienophiles. Instead, the N-vinylated products 2 and 3 were obtained with dimethyl acetylene dicarboxylate (DMAD). Electron poor alkynes react with the thiophenes of type (b) in three main ways: DMAD reacts in a [4+2]-mode in dioxane to give the products 7, 8 and 14; a Michael addition type reaction also takes place at the doubly vinylene homologous carbon atoms (C-1 in the starting materials 4, 9 and 10) in dioxane, methanol or ethanol. Methyl propiolate reacts in a similar way. The doubly N-vinylated product 26 was obtained from 10 in toluene and the C-1 vinylated products 24B and 27 were obtained from 9 in dioxane and 10 in methanol. The reaction of 10 with phenyl ethyl propiolate in dimethylformamide gave no addition product, instead a dimer of the acetylenic reagent was the isolated product. The accuracy of the assigned structures 5, 12 and 13a could be achieved on the basis of a single-crystal X-ray structure analysis of compound 13a. The reaction mechanism and the nature of the isolated products are dependent on the nature of the solvent. No addition reaction was observed between 17 and DMAD. The influence of the N-substitution on the nature of the addition (Michael or Diels-Alder) could be settled through the reactions of 18 and 21 with DMAD, which gave 19 and 14 (via 22), respectively as the only isolable products.
- Sopbué Fondjo, Emmanuel,D?pp, Dietrich,Henkel, Gerald
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p. 7121 - 7131
(2007/10/03)
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- HETEROBICYCLIC COMPOUNDS AS PHARMACEUTICALLY ACTIVE AGENTS
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Described are heterobicyclic compounds such as 4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amides, 4,7-dihydro-5H-thieno[2,3-c]thiopyran- 3-carboxylic acid amides, 4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid amides, or benzo[b]thiophene
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Page/Page column 112
(2010/02/11)
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- FUNGICIDES
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A method of combating phytopathogenic diseases on plants and harvested food crops which comprises applying to a plant, to the seed of a plant, to the locus of the plant or seed or to a harvested crop a fungicidally effective amount of 2-aminothiophene derivatives of formula (1). The invention further relates to fungicidal compositions containing these compounds, processes for preparing these compounds and to some of the compounds themselves.
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Page/Page column 105-106
(2010/02/11)
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- Thienopyrimidines as hetryl moiety in 2-azetidinones: Synthesis of 4-hetryl-2-azetidinones
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A Facile and efficient method for the synthesis of 4-hetryl substituted β-lactams 1 have been reported from substituted thienopyrimidinone 2b, which in turn was prepared from appropriately substituted 2-amino-3-carboxamido thiophene 10. The structures of
- Kanwar, Seema,Sharma
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p. 2367 - 2371
(2007/10/03)
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- Microwave-assisted synthesis of 2-amino-thiophene-3-carboxylic derivatives under solvent-free conditions
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Under microwave irradiation and solvent-free conditions, cyanoacetates (cyanoacetamides) react with ketones and sulphur in the presence of a small amount of morpholine to give 2-amino-thiophene-3-carboxylic derivatives. In particular, tetrahydro-benzo[b]thiophene-3-carboxylic acid N-aryl amides were synthesized in high yields of 84-95%. Copyright Taylor & Francis, Inc.
- Huang, Wei,Li, Jian,Tang, Jing,Liu, Hong,Shen, Jianhua,Jiang, Hualiang
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p. 1351 - 1357
(2007/10/03)
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- Inhibition of tumor cell proliferation by thieno[2,3-d]pyrimidin-4(1H)-one- based analogs
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On the basis of a screening lead from an assay using a pair of p21 isogenic cell lines (p21-proficient cells and p21-deficient cells) to identify chemoselective agents, a series of novel thieno[2,3-d]pyrimidin-4(1H)-one-based analogs was prepared. Some an
- Wang, Yanong D.,Johnson, Steven,Powell, Dennis,McGinnis, John P.,Miranda, Miriam,Rabindran, Sridhar K.
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p. 3763 - 3766
(2007/10/03)
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- Parallel synthesis and biological evaluation of 5,6,7,8- tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one cytotoxic agents selective for p21-deficient cells
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A novel series of inhibitors of cancer cell proliferation, selective against p21 cell cycle checkpoint-disrupted cells vs. cells with intact p21 checkpoint, were identified by high-throughput screening. Optimization of both ends of the lead molecule to improve potency, using parallel synthesis and iterative design, is described. The 2-(1,4-dibenzodioxane)-substituted derivative 14 was identified as a highly selective and potent agent displaying an IC50 of 91 nM in the p21-deficient cell line.
- Jennings, Lee D.,Kincaid, Scott L.,Wang, Yanong D.,Krishnamurthy, Girija,Beyer, Carl F.,McGinnis, John P.,Miranda, Miriam,Discafani, Carolyn M.,Rabindran, Sridhar K.
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p. 4731 - 4735
(2007/10/03)
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