Expanding the Role of Boron in New Drug Chemotypes: Properties, Chemistry, Pharmaceutical Potential of Hemiboronic Naphthoids.

New chemotypes and bioisosteres can open a new chemical space in drug discovery and help meet an urgent demand for novel agents to fight infections and other diseases. With the aim of identifying new boron-containing drug chemotypes, this article details a comprehensive evaluation of the pseudoaromatic hemiboronic naphthoids, benzoxaza- and benzodiazaborines. Relevant physical properties in aqueous media (acidity, solubility, log P , and stability) of prototypic members of four subclasses were determined. Both scaffolds are amenable to common reactions used in drug discovery, such as chemoselective Suzuki-Miyaura, Chan-Lam, and amidation reactions. Small model libraries were prepared to assess the scope of these transformations, and the entire collection was screened for antifungal ( Candida albicans ) and antibacterial activity (MRSA, Escherichia coli ), unveiling promising benzoxazaborines with low micromolar minimum inhibitory concentration values. Select DMPK assays of representative compounds suggest promising drug-like behavior for all four subclasses. Moreover, several drug isosteres were evaluated for anti-inflammatory and anticancer activity as appropriate.