Towards predictable transmembrane transport: QSAR analysis of anion binding and transport

Abstract

The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using 1 H NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure-activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function.Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present.Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

“…Indeed, appending an additional thiourea moiety led to enhancement of Cl À affinities of both 13 (K 1 = 150 M À1 , K 2 = 3.4 M À1 ; Figure S16) and 14 (K 1 = 530 M À1 , K 2 = 6.2 M À1 ; Figure S18) in DMSO-d 6 /0.5% H 2 O in relation to that of 7 (K = 14 M À1 ). 49 But, improvement of selectivity (relative to 7, 1.3-fold selectivity) was only observed for 14 (7-fold selectivity), whereas 13 demonstrated no selectivity (Figure S46), underscoring the importance of anion encapsulation. This idea is also supported by the higher selectivity of 12 than that of 11, given that the bulky alkyl substituents in 12 make Cl À less solvent accessible than linear alkyl substituents in 11.…”

“…Although, in general, more acidic hydrogen-bond donors are favorable for anion binding and transport (in terms of activity), 49,51 Table 2 demonstrates that Cl À > H + / OH À selectivity is severely compromised when more acidic hydrogen-bond donors are present. For example, the selectivity sequence of 11 > 9 [ 10 illustrates this effect.…”

Anion Receptors Based on Organic Frameworks: Recent Advances

“…Gale Hansch analysis [17] on a series of simple thiourea-based anion transporters 15-36 in order to determine the molecular parameters that should be optimised to produce the most effective transmembrane transporters. In this series of compounds, it was found that transport was predominantly determined by the lipophilicity (log P) of the transporter but that the Hammett constant of the substituent in the para-position of the aromatic ring (which was shown to correlate with the affinity of the transporters for anions) and the size of the transporters played significant albeit lesser roles [18].…”

Anion binding and transport properties of cyclic 2,6-bis(1,2,3-triazol-1-yl)pyridines

“…22 Without conducting a much larger quantitative structure activity relationship study, which is outside the scope of the current project, it is not possible to systematically determine which molecular parameters should be optimised to maximise the rate of transport. 23 However based on previous findings 22 it is reasonable to assume that the optimum lipophilicity observed for 6b results from compounds having shorter chain lengths not being lipophilic enough to efficiently partition into the bilayer, and above this chain length the compounds become increasingly incompatible with delivery through the aqueous phase, resulting in precipitation -i.e. this is essentially a dependence on a (log P) 2 term.…”