RETRACTED: Application of Carboxylic Acid Bioisosteres in Drug Structure Optimization

Carboxylic acids represent one of the most prevalent functional groups in pharmaceutical chemistry, yet their inherent limitations including poor membrane permeability, metabolic instability, and limited blood-brain barrier penetration necessitate innovative structural modifications. This comprehensive review examines the application of carboxylic acid bioisosteres as a fundamental strategy in drug structure optimization, analyzing their structure-property relationships, synthetic accessibility, and therapeutic applications. Various bioisosteric replacements including hydroxamic acids, sulfonic acids, squaric acid derivatives, heterocyclic systems, phosphorus-containing groups, and boronic acids are systematically evaluated through experimental data and computational modeling. The analysis reveals that successful bioisosteric replacement requires careful balance between maintaining critical pharmacophoric interactions and optimizing physicochemical properties. Hydroxamic acids demonstrate exceptional utility in metalloenzyme inhibition, while tetrazoles and oxadiazolones offer improved metabolic stability with comparable binding affinity. Novel scaffolds such as cyclic sulfonimidamides and squaramides provide enhanced membrane permeability and blood-brain barrier penetration. Quantitative approaches including average electron density calculations and molecular dynamics simulations provide mechanistic insights into bioisosteric relationships. The successful clinical translation of multiple bioisostere-containing drugs across diverse therapeutic areas validates this approach. This review establishes a practical framework for rational selection and application of carboxylic acid bioisosteres, offering valuable guidance for medicinal chemists in lead optimization and drug development programs.