Binding and transport properties of a benzo[b]thiophene-based mono-(thio)urea library
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Open Access
Type
ArticleAuthor/s
Moiteiro, CristinaMarques, Igor
Ryder, William G.
Cachatra, Vasco
Carvalho, Sílvia
Chen, Li-Jun
Goodfellow, Brian J.
Gale, Philip A.
Félix, Vítor
Abstract
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 ...
See moreUsing 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. 1 H NMR titrations, X-ray crystallography studies, and DFT calculations showed that the receptors with higher chloride binding affinities were the β,β- and γ,γ-bis-benzo[ b ]thiophene and fluorinated aryl β- or γ-benzo[ b ]thiophene derivatives that synergistically bind chloride with the urea and one or two C β/γ -H ancillary binding groups. Experimental efflux studies showed that, among these small drug-like molecules, only the highly fluorinated analogues displayed anion transmembrane transport activity, suggesting that this property is dependent on the receptors' lipophilicity and hydrogen bonding ability. Moreover, LUV based assays, undertaken under electroneutral and electrogenic conditions, together with NMDG-Cl 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.
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See moreUsing 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. 1 H NMR titrations, X-ray crystallography studies, and DFT calculations showed that the receptors with higher chloride binding affinities were the β,β- and γ,γ-bis-benzo[ b ]thiophene and fluorinated aryl β- or γ-benzo[ b ]thiophene derivatives that synergistically bind chloride with the urea and one or two C β/γ -H ancillary binding groups. Experimental efflux studies showed that, among these small drug-like molecules, only the highly fluorinated analogues displayed anion transmembrane transport activity, suggesting that this property is dependent on the receptors' lipophilicity and hydrogen bonding ability. Moreover, LUV based assays, undertaken under electroneutral and electrogenic conditions, together with NMDG-Cl 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.
See less
Date
2021Source title
European Journal of Organic ChemistryPublisher
Wiley-VCHFunding information
ARC DP200100453Licence
Creative Commons Attribution 4.0Faculty/School
Faculty of Science, School of ChemistryDepartment, Discipline or Centre
SydneyNanoShare