Hydrazones in anion transporters: The detrimental effect of a second binding site

19 August 2021, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

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. 1H 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.

Keywords

Anion Transport
Molecular Dynamics
Anion binding
DFT
Hydrazones
Thioureas
Artificial Transmembrane Transporters

Supplementary materials

Title
Description
Actions
Title
Electronic Supplementary Information - Experimental studies
Description
Supplementary Information for the experimental studies.
Actions
Title
Electronic Supplementary Information - Computational studies
Description
Supplementary Information for the experimental studies.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.