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

• DOI: 10.26434/chemrxiv-2021-18gpl-v2
• Publication Date: 2022-02-01T13:10:39Z
• Authors: Luis Martínez-Crespo; Lau Halgreen; Márcio Soares; Igor Marques; Vítor Félix; Hennie Valkenier
• Keywords: Functional group

Synthetic anion transporters can be developed using receptors that are able to bind the and stabilize it in lipophilic interior of a bilayer membrane, they usually contain functional groups with acidic NHs, such as ureas, thioureas squaramides. To assess suitability acylhydrazones new group for preparation transporters, we have studied family functionalized these related groups. 1H NMR titrations DFT calculations indicate bearing acylhydrazone behave chloride two separate binding sites, which binds weaker than thiourea. Chloride transport studies show additional site has detrimental effect on thiourea-based this phenomenon is also observed bis(thio)ureas sites. We propose presence second unit hinders activity thiourea due interactions phospholipids membrane. In agreement hypothesis, extensive molecular dynamics simulations suggest molecules will tend positioned water/lipid interface, driven by interaction NHs POPC polar head water molecules. Moreover, energies poorest indeed strongest membrane phospholipids, inhibiting transport. This should considered when designing ion unless cooperatively promote recognition transmembrane