Abstract
AbstractUsing 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.
Highlights
Many important physiological functions depend on the balance of solution concentrations across cell membranes, and may involve ions with biological relevance.[1]
The asymmetrical β- and γbenzo[b]thiopheneureas 1-8 were obtained using n-butyland n-hexylamines, while the corresponding aryl ureas 19 and 24 were prepared using 3,5-bis-(trifluoromethyl)amine. In contrast with these three amine reagents, which were directly used as provided by the chemical suppliers, the aryl amines functionalised with ester alkyl chains with different fluorination degrees used to prepare asymmetrical ureas 20-23 were previously obtained from 4-nitrobenzoic acid (20) and 4-nitro-2-(trifluoromethyl)benzoic acid (21-23) following the synthetic route outlined in Scheme S4
The lower chloride binding constants measured for the thiourea analogues of the symmetrical ureas, 124 M-1 (β,β, 10) and 56M-1 (γ,γ, 12), reflect the different strength of the C-H···Cl- interactions with EHB energies of -3.1 and -2.1 kcal mol-1 respectively, as the classical hydrogen bonds contribute an equal amount of EHB energy for the According to the EHB energies for the N-H···Cl- interactions, the values become slightly more negative with fluorination of the α-benzo[b]thiophene motifs (α,α-17 versus α,α18 and α,β-14 versus α,β-15) following the increasing binding stabilisation of both complexes
Summary
Many important physiological functions depend on the balance of solution concentrations across cell membranes, and may involve ions with biological relevance.[1]. The quantum descriptor VS,max only allowed us to rationalise the chloride binding affinity between non-fluorinated and fluorinated bis-benzo[b]thiophene analogues, given that, in this comprehensive library of small-molecules, this property is not solely dictated by the acidic character of the (thio)urea binding unit.
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