Structure Property Relationships of Carboxylic Acid Isosteres

Abstract

The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The dataset generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.

Room temperature decarboxylative cyanation of carboxylic acids using photoredox catalysis and cyanobenziodoxolones: a divergent mechanism compared to alkynylation

“…2 a Furthermore, the corresponding tetrazoles obtained after [3 + 2] cycloaddition with azides 4 are also considered as bio-isosteres of the carboxylic acid group. 5 …”

LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates

“…Though numerous carboxylic acid bioisosteres have been described, 34, 35, 42, 43 we choose to prioritize the acylsulfonamide, tetrazole, and hydroxamic acid functionalities (Table 1). These groups were selected due to their comparable pK a and/or structural similarity to the carboxylic acid functional group, 34 and they have previously demonstrated biological activity in other series.…”

Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase

“…[63] This is mainly due to the fact that pKa of the acidic proton of acyl sulfonamide (4.94) and the carboxylic acid (4.64) are very close. [64] This acidic proton appears to be the key for the activity of EET in a vasodilation assay [63] and herein we tested its importance on how EETs bind to sEH active site. In addition, the acyl sulfonamide provides a handle for us to attach a photoaffinity label in the mimic; thus, making it relatively easy to incorporate the trifluoromethyldiazirine into the EET mimics while maintaining the epoxide and the skipped polyene structure of the EETs.…”