ABSTRACT
The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This challenge is compounded when emphasis is placed on the preparation of new chemotypes that have distinct and practical functions. To expand the structural diversity of boron-containing heterocycles, we report herein the preparation of novel monocyclic hemiboronic acids, diazaborines. These compounds have enabled the study of a pseudoaromatic boranol-containing (B-OH) ring free of influence from an appended aromatic system. Synthetic and spectroscopic studies have provided insight into the aromatic character, Lewis acidic nature, chemical reactivity, and unique ability of the exocyclic B-OH unit to participate in hydroxy exchange, suggesting their use in organocatalysis and as reversible covalent inhibitors. Moreover, density functional theory and nucleus-independent chemical shift calculations reveal that the aromatic character of the boroheterocyclic ring is increased significantly in comparison to known bicyclic benzodiazaborines (naphthoid congeners), consequently leading to attenuated Lewis acidity. Direct structural comparison to a well-established biaryl isostere, 2-phenylphenol, through X-ray crystallographic analysis reveals that N-aryl derivatives are strikingly similar in size and conformation, with attenuated logP values underscoring the value of the polar BNN unit. Their potential application as low-molecular-weight scaffolds in drug discovery is demonstrated through orthogonal diversification and preliminary antifungal evaluation (Candida albicans), which unveiled analogs with low micromolar inhibitory concentration.
ABSTRACT
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.
ABSTRACT
The presence of pharmaceuticals and personal care products (PPCPs) in water remains a concern due to their potential threat to environmental and human health. Advanced oxidation processes (AOPs) have been receiving attention in water treatment studies to remove PPCPs. However, most studies have been focused on pure water containing a limited number of substances. In this study, the photocatalytic efficiency of commercially available titanium dioxide nanoparticles (P25) and P25 modified by silver nanoparticles (Ag-P25) were compared for their ability to degrade 23 target PPCPs (2 µg L-1) in realistic water matrices containing natural organic matter (Suwanee River NOM, 6.12 mg L-1). The experiments were completed under ultraviolet-light emitting diode (UV-LED) illumination at 365 and 405 nm wavelengths, with the latter representing visible light exposure. Under 365 nm UV-LED treatment, 99% of the PPCPs were removed using both P25 and Ag-P25 photocatalysts within 180 min of the treatment duration. The number of PPCPs removed dropped to 57% and 53% for P25 and Ag-P25 respectively under the 405 nm UV-LED irradiation. Dissolved organic carbon (DOC) and UV absorbance at 254 nm (UV254) measured at the end of the experiment indicated that the aromatic fraction of NOM was preferentially removed from the water matrix. Also, Ag-P25 was more effective in DOC removal than P25. The relationships of removal rate constants with physico-chemical properties of the substances were also determined. The molecular weight and charge were strongly associated with removal, with the former and the latter being positively and negatively correlated with the rate constants. The results of this work indicate that Ag-P25 is a promising photocatalyst to degrade persistent substances such as PPCPs and NOM even if they are present in a complex water matrix. The properties of individual substances can also be employed as an indication of their removal using this technology.