937648-16-3Relevant academic research and scientific papers
Syntheses and biological evaluation of 2-amino-3-acyl- tetrahydrobenzothiophene derivatives; Antibacterial agents with antivirulence activity
The Dang, Hung,Chorell, Erik,Uvell, Hanna,Pinkner, Jerome S.,Hultgren, Scott J.,Almqvist, Fredrik
, p. 1942 - 1956 (2014/03/21)
Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.
Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors
Ekkati, Anil R.,Mandiyan, Valsan,Ravindranathan, Krishna P.,Bae, Jae H.,Schlessinger, Joseph,Jorgensen, William L.
, p. 2228 - 2231 (2011/05/05)
Optimization of thienopyrimidinone derivatives as FGFR1 kinase inhibitors is being pursued. The present results confirm predictions of computational modeling that an aryl substituent can be introduced at the 2-position in structure 3. The substituent is anticipated to project deeper into the binding site and provide opportunities for enhanced activity and selectivity. The most potent analog reported herein, 13, has a 4-hydroxyphenyl substituent and yields an IC50 of 6 μM for inhibition of phosphorylation by FGFR1 kinase. It was also found that the western anisole-containing substituent in 3 can be replaced by a propionic acid group with no loss in potency and with potentially significant gains in pharmacologically relevant properties.
Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode
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.
experimental part, p. 5336 - 5341 (2009/10/23)
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.
Activation of elemental sulfur by electrogenerated cyanomethyl anion: Synthesis of substituted 2-aminothiophenes by the Gewald reaction
Feroci, Marta,Chiarotto, Isabella,Rossi, Leucio,Inesi, Achille
supporting information; experimental part, p. 2740 - 2746 (2009/10/06)
The activation of elemental sulfur (S8) has been achieved by means of electrogenerated cyanomethyl anion [easily obtained by galvanostatic reduction from acetonitrile/tetraethylammonium hexafluorophosphate (MeCN-Et 4NPF4)]. The activated sulfur reacted with ylidenemalononitriles to give substituted 2-aminothiophenes in very high yields. This variation of the Gewald reaction has been carried out using only catalytic amounts of electricity and supporting electrolyte. A proposed mechanism for the interaction between S8 and cyanomethyl anion is described.
