Elemental exchange: Bioisosteric replacement of phosphorus by boron in drug design

Continuous efforts are being directed toward the employment of boron in drug design due to its advantages and unique characteristics including a plethora of target engagement modes, lower metabolism, and synthetic accessibility, among others. Phosphates are components of multiple drug molecules as well as clinical candidates, since they play a vital role in various biochemical functions, being components of nucleotides, energy currencyATP as well as several enzyme cofactors. This review discusses the unique chemistry of boron functionalities as phosphate bioisosteres - the boron-phosphorus elemental exchange strategy as well as the superiority of boron groups over other commonly employed phosphate bioisosteres. Boron phosphate-mimetics have been utilized for the development of enzyme inhibitors as well as novel borononucleotides. Both the boron functionalities described in this review-boronic acids and benzoxaboroles-contain a boron connected to two oxygens and one carbon atom. The boron atom of these functional groups coordinates with a water molecule in the enzyme site forming a tetrahedral molecule which mimics the phosphate structure. Although boron phosphate-mimetic molecules - FDA-approved Crisaborole and phase II/III clinical candidate Acoziborole are products of the boron-phosphorus bioisosteric elemental exchange strategy, this technique is still in its infancy. The review aims to promote the use of this strategy in future medicinal chemistry projects.

Automated summary

Continuous efforts are being made to harness the advantages and unique characteristics of boron in drug design. Pharmacological studies have shown that boron demonstrates superior performance as a substitute for phosphates. Research on boron phosphates is still in its early stages, but it has the potential to play a significant role in future medicinal chemistry projects.