Drug
resistance in bacteria is a serious threat, and drugs with
novel modes of action are constantly needed. Fosmidomycin is a naturally
occurring antibiotic that inhibits the nonmevalonate pathway via inhibition
of the enzyme 1-deoxylulose-5-phosphate reductoisomerase (DXR). This
work is the first report in which a boronic acid is evaluated as an
isostere of the retrohydroxamate moiety of fosmidomycin. We report
the novel synthesis of a γ-borono phosphonate analog of fosmidomycin
and its corresponding prodrugs. We evaluate the inhibition of DXR
and the antimicrobial activity of γ-borono phosphonate compounds
against Escherichia coli wild type, E. coli Δglycerol-3-phosphate transporter,
and Mycobacterium smegmatis. Despite
its structural similarities, the γ-borono phosphonate compound
shows antimicrobial activity against E. coli with a mechanism of action that is different from fosmidomycin.
This was proven with an underutilized method for studying in vitro
inhibition of the MEP pathway in E. coli via isopentenyl pyrophosphate chemical rescue. These results indicate
that these compounds may serve as a promising scaffold for developing
a new class of antimicrobial agents.
The synthesis and utility of three benzoxaborole protecting groups are reported. These protecting groups improve organic solubility and allow otherwise incompatible reactions (oxidations, substitutions, and mild reductions) to be achieved in the presence of the benzoxaborole moiety. 3-( N, N-Dimethylamino)-1-propanol was determined to be useful in one-step sequences and is readily cleaved upon workup. Two other groups, N-methylsalicylidenimine and 2-[1-(methylimino)ethyl]phenol, are suitable for multistep syntheses. Deprotection with mild aqueous acid allows for chromatography-free isolation of the benzoxaborole in high yields.
Subcutaneous (SC) ketamine has been found to be effective in pain management, though reports of injection site irritation and sterile abscesses exist with currently available ketamine HCl formulations. Such adverse SC reactions are commonly associated with low pH, high osmolality and/or high injection volumes. An optimal SC formulation of ketamine would thus have a pH and osmolality close to physiological levels, without compromising on concentration and, thus, injection volume. Such a formulation should also be buffered to maintain the pH at the acceptable level for extended time periods. As many of these physicochemical properties are interrelated, achieving these aims represented a significant challenge in formulation development. We describe the development of a novel Captisol®-based formulation strategy to achieve an elevated pH, isosmotic and buffered formulation of ketamine (hence, three birds, one excipient) without compromising on concentration. This strategy has the potential to be readily adapted to other amine-based APIs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.