Recognition Properties of Carboxylic Acid Bioisosteres: Anion Binding by Tetrazoles, Aryl Sulfonamides, and Acyl Sulfonamides on a Calix[4]arene Scaffold

Abstract

Tetrazoles and acyl sulfonamides are functional groups that are common in medicinal chemistry but virtually unexplored as recognition elements in supramolecular chemistry. We report here on the anion binding properties of these highly acidic N-H functional groups. We have prepared two new calixarene-based tetrazole-containing hosts, as well as new acetyl sulfonamide and benzoyl sulfonamide hosts. We also report on analogous hosts bearing the better-known aryl sulfonamide functional group as a point of comparison. We find that these hosts are competent anion binders and that the recognition of anions by these groups is highly dependent on their conformational preferences. We also report in detail on the preferred molecular shape of each acid bioisostere as determined by calculations and structural database surveys, and discuss how these shapes impact binding in the context of the reported hosts.

Versatility of Terpyridine‐Functionalised Aryl Tetrazoles: Photophysical Properties, Ratiometric Sensing of Zinc Cations and Sensitisation of Lanthanide Luminescence

“…In terms of acidity, tetrazoles have p K a values similar to carboxylic acids, so negatively charged tetrazolates are easily accessible through deprotonation reactions , . For this reason, tetrazoles are considered to be more metabolically stable bioisosteres of carboxylic acids . The presence of four sp 2 ‐hybridised lone pairs on the nitrogen atoms allows the construction of complex molecular architectures by bridging multiple metal ions, and many of these examples have been reported for species containing both transition metals and lanthanide elements …”

Microwave-Assisted Synthesis of Bidentate Chiral Unsymmetrical Urea Derivatives of P-tert-butylcalix[4]Arene and their Anion Recognition Properties

“…3). We studied the association constants of receptors 6a-d to recognise anions CH 3 Table 2. Clearly, these receptors have some recognition ability for all anions, but have the highest selectivity and affinity for AcO − .…”

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

“…Consequently, modifications of this sort may change the overall molecular shape and result in other biological activity [47]. Carboxylic acid moieties are essential for biological activity; in particular for the substitution of the group with phosphonate, phosphonic and phosphinic acids, sulphonamides and tetrazoles ( Figure 3) [48]. These subtle changes can have a major effect on the efficacy of the drug substrate [49].…”