Quantum Evaluation of a Comprehensive Set of Carboxylic Acid Bioisosteres: Gas versus Solvated Phases

In drug design, bioisosterism is used to enhance the pharmacokinetic and pharmacodynamic properties of a drug molecule while maintaining its biological activity. This study investigates the use of a quantum tool, namely, the average electron density (AED) tool, in evaluating 54 experimentally tested nonclassical carboxylic acid bioisosteres. In total, 65 bioisosteres were considered, including both R and S enantiomers for 11 chiral moieties. The AED values of all bioisosteric moieties deviate by up to 32% compared to the carboxylic acid group, regardless of the medium, whether in the gas phase or implicitly solvated with water. This suggests that a 32% deviation threshold is reasonable for classifying potential carboxylic acid bioisosteres.