Advances in the development of N-acylbenzo[d][1,2,3]diazaborinin-1(2H)-ols as antibacterial agents by synthesis, characterization, and antimicrobial assay

Abstract

The ability of bacteria to quickly adapt to environmental stresses, such as exposure to antimicrobial drugs, has necessitated a continued search for novel antibacterial agents with new mechanisms of attack, forever in competition with the rate of adaptation of these pathogens. Antibiotic resistant strains of a multitude of infectious diseases have appeared, imposing a huge burden from diseases once believed to have been reduced to minor health issues. Building on prior work, twenty-one new N-acyl-1-hydroxy-2,3,1-benzodiazaborinines were synthesized and characterized by high-field NMR, FTIR, ESI-MS, and other methods including X-ray crystallography for one unexpected structure. The syntheses by direct condensation using acylhydrazides gave products found to exist in one of three structural forms connected by (de/re)hydration reactions: open hydrazone (a), boron heterocycle (b), and anhydro dimer (c). Multisolvent ¹H and ¹³C NMR analyses showed that in solution these forms can readily interconvert in a solvent-dependent manner. The unanticipated structure of one target was established to be a rare ammonium borate salt arising from an extremely facile intramolecularly boron-catalyzed primary amide group hydrolysis. The new compounds were screened for activity against Escherichia coli in disk diffusion assays and seven of them demonstrated inhibitory activity, thus advancing the development of boron heterocycles towards the goal of producing next-generation antibacterial agents to combat persistently evolving resistant strains.

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