Synthesis and combinatorial approach of the reactivity of 6- and 7-arylthieno[3,2-d][1,3]oxazine-2,4-diones

Foulon, François-Xavier Le; Braud, Emmanuelle; Fabis, Frédéric; Lancelot, Jean‐Charles; Rault, Syl­vain

doi:10.1016/j.tet.2003.10.028

Cited by 20 publications

(12 citation statements)

References 14 publications

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“…The latter reacted with the appropriate amines in water followed by acidic workup to yield the desired 5-aryl-3-ureidothiophene-2-carboxylic acids 6–11 . 17,20,21 The compounds of classes II and III were synthesized by a straightforward procedures via Gewald reaction of the arylacetaldehydes 12a,b or the acetophenones 1a,b (Scheme 1) with ethyl cyanoacetate and elemental sulfur under basic conditions in a one-pot reaction to afford the ethyl esters 13a,b and 22a,b 22,23 respectively. After saponification, synthesis of both the 5- and 4-aryl-2-ureidothiophene-3-carboxylic acids 16–21 and 25–30 via the thiaisatoic anhydrides 15a,b and 24a,b was also successfully employed as described for the class I derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…White solid; mp 214–216 °C (lit., 20 245 °C, lit., 55 > 260 °C); δ H (300 MHz, DMSO-d 6 ) 7.49 (2H, d, J = 8.8 Hz, 3′,5′Ar-H), 7.54 (2H, d, J = 8.8 Hz, 2′,6′Ar-H), 8.25 (1H, s, C6–H), 11.86 (1H, br s, NH); δ C (75 MHz, DMSO-d 6 ) 107.66 (C4a), 129.20 (C2′, C6′), 129.35 (C7), 130.97 (C3′, C5′), 131.03 (C1′), 133.66 (C4′), 136.87 (C6), 147.24 (C7a), 149.41 (C2), 156.06 (C4); m / z (ESI+) 279 (24%, M + ), 251 (100, M − CO); t R = 10.18 min.…”

Section: Methodsmentioning

confidence: 99%

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Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids

et al. 2014

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The emergence of bacterial resistance requires the development of new antibiotics with an alternative mode of action. Based on class I, developed in our previous study, a new series of RNA polymerase (RNAP) inhibitors targeting the switch region was designed. Feasible synthetic procedures for the aryl-ureido-heterocyclic-carboxylic acids were developed including three regioisomeric thiophene classes (II–IV), as well as three isosteric furan (V, VI) and thiazole (VII) classes. Biological evaluation using a RNAP transcription inhibition assay revealed that class II compounds possess the same activity as the parent class I, whereas classes III, V–VII were active, however with lower potency. Structure–activity relationship (SAR) studies, supported by molecular modeling, elucidated the structural requirements necessary for interaction with the binding site. Beside the RNAP inhibitory effects, the new compounds displayed good antibacterial activities against Gram positive bacteria and the Gram negative E. coli TolC strain. Moreover, they showed no cross resistance with the clinically used RNAP inhibitor rifampicin (Rif) and a lower rate of resistance compared to Rif.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids

et al. 2014

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“…The esters (II) were then hydrolysed under basic conditions to afford the thiophene anthranilic acids (III) which were converted into the thiaisatoic anhydrides (IV) [32,33]. The anhydrides (IV) were reacted with various amines giving rise to the 5-aryl-3-ureidothiophene-2-carboxylic acids (V) [34].…”

Section: Synthesis and Spectroscopic Detailsmentioning

confidence: 99%

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

Sahner

Empting

Kamal

et al. 2015

European Journal of Medicinal Chemistry

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Pseudomonas infections. The present work deals with the structure-activity exploration of ureidothiophene-2-carboxylic acids as inhibitors of PqsD, a key enzyme in the biosynthetic pathway of signal molecules in the Pseudomonas QS system. We describe an improvement of the inhibitory activity by successfully combining features from two different PqsD inhibitor classes. Furthermore the functional groups, which are responsible for the inhibitory potency, were identified. Moreover, the inability of the new inhibitors, to prevent signal molecule formation in whole cell assays, is discussed.2

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“…From a short list of about 30 candidates, 18 were available from a library of chemical entities of the French CNRS (Chimiothèque Nationale). The identified inhibitors were issued from the chemical library of the CERMN (Centre d’Etudes et de Recherche sur le Médicament de Normandie), developed using a program of parallel synthesis [70,71] to produce a library of 1140 thiophen derivatives with potential pharmacological properties. Their inhibitory activity was characterized experimentally with an in vitro enzymatic assay based on the detection of inorganic pyrophosphate released upon ATP conversion into cAMP [37].…”

Section: Conformational Transition and Inhibitors Discoverymentioning

confidence: 99%

Molecular Motions as a Drug Target: Mechanistic Simulations of Anthrax Toxin Edema Factor Function Led to the Discovery of Novel Allosteric Inhibitors

Laine¹,

Martı́nez

Ladant

et al. 2012

Toxins

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Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data allowed molecular simulations analysis of various aspects of EF action mechanism, including the delineation of EF and CaM domains through their association energetics, the impact of calcium binding on CaM, and the role of catalytic site ions. Furthermore, a transition path connecting the free inactive form to the CaM-complexed active form of EF was built to model the activation mechanism in an attempt to define an inhibition strategy. The cavities at the surface of EF were determined for each path intermediate to identify potential sites where the binding of a ligand could block activation. A non-catalytic cavity (allosteric) was found to shrink rapidly at early stages of the path and was chosen to perform virtual screening. Amongst 18 compounds selected in silico and tested in an enzymatic assay, 6 thiophen ureidoacid derivatives formed a new family of EF allosteric inhibitors with IC50 as low as 2 micromolars.

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Synthesis and combinatorial approach of the reactivity of 6- and 7-arylthieno[3,2-d][1,3]oxazine-2,4-diones

Cited by 20 publications

References 14 publications

Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids

Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

Molecular Motions as a Drug Target: Mechanistic Simulations of Anthrax Toxin Edema Factor Function Led to the Discovery of Novel Allosteric Inhibitors

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