Hydrazones in anion transporters: the detrimental effect of a second binding site
authors Martinez-Crespo, L; Halgreen, L; Soares, M; Marques, I; Felix, V; Valkenier, H
nationality International
journal ORGANIC & BIOMOLECULAR CHEMISTRY
keywords CHLORIDE TRANSPORT; MOLECULES; LIBRARIES; POWERFUL; ENERGIES; AMBER
abstract Synthetic anion transporters can be developed using anion receptors that are able to bind the anion and stabilize it in the lipophilic interior of a bilayer membrane, and they usually contain functional groups with acidic NHs, such as ureas, thioureas and squaramides. To assess the suitability of acylhydrazones as a new functional group for the preparation of anion transporters, we have studied a family of thioureas functionalized with these and related functional groups. H-1 NMR titrations and DFT calculations indicate that the thioureas bearing acylhydrazone groups behave as chloride receptors with two separate binding sites, of which the acylhydrazone binds weaker than the thiourea. Chloride transport studies show that the additional binding site has a detrimental effect on thiourea-based transporters, and this phenomenon is also observed for bis(thio)ureas with two separate binding sites. We propose that the presence of a second anion binding unit hinders the transport activity of the thiourea due to additional interactions with the phospholipids of the membrane. In agreement with this hypothesis, extensive molecular dynamics simulations suggest that the molecules will tend to be positioned in the water/lipid interface, driven by the interaction of the NHs of the thiourea and of the acylhydrazone groups with the POPC polar head groups and water molecules. Moreover, the interaction energies show that the poorest transporters have indeed the strongest interactions with the membrane phospholipids, inhibiting chloride transport. This detrimental effect of additional functional groups on transport activity should be considered when designing new ion transporters, unless these groups cooperatively promote anion recognition and transmembrane transport.
publisher ROYAL SOC CHEMISTRY
issn 1477-0520
isbn 1477-0539
year published 2021
volume 19
issue 38
beginning page 8324
ending page 8337
digital object identifier (doi) 10.1039/d1ob01279g
web of science category 14
subject category Chemistry, Organic
unique article identifier WOS:000695970800001
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journal analysis (jcr 2019):
journal impact factor 3.412
5 year journal impact factor 3.134
category normalized journal impact factor percentile 78.07
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