Benzoxaborole-Inspired pKa-Guided Search for a Borine Alternative Uncovers a Borylurea Scaffold with Unique Properties and Reactivity.

The advent of benzoxaborole drugs brought attention to hemiboronic heterocycles as an attractive chemotype, where they can be implicated in a number of biological contexts. However, the success of benzoxaboroles, a neutral-pKa scaffold, has yet to be replicated with other classes of boranol (B-OH)-containing heterocycles. Although six-membered borine homologs may exist with various permutations of endocyclic heteroatoms and functional groups, little is known about structure-property relationships. Here, a systematic study of more than 15 non-aromatic and pseudo-aromatic hemiboronic benzoborines derived from ortho-substituted arylboronic acids was achieved, using pKa as a guiding principle, to identify scaffolds that emulate benzoxaboroles. A wide range of pKa's were observed across all scaffolds, with one neutral-pKa scaffold, borylurea, found to possess stability, lipophilicity, and other attributes similarly favorable to those of benzoxaborole. The borylurea scaffold embeds more heteroatoms to engage in molecular interactions with target proteins, it presents promising DMPK characteristics, and it is readily amenable to chemical diversification. NMR studies confirmed that it reacts to form complexes with small biomolecules like monosaccharides and ribonucleosides with an efficiency superior to that of benzoxaborole in organic medium, and comparable in aqueous conditions. Altogether, this study underscores the considerable advantage of properties, reactivity, and convenience offered by neutral-pKa boroheterocycles.