Solubility-Driven
Optimization of (Pyridin-3-yl) Benzoxazinyl-oxazolidinones Leading
to a Promising Antibacterial Agent
- Publication date
- Publisher
Abstract
The
solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones
is described, which resulted in the development of a new series of
benzoxazinyl-oxazolidinone analogues with high antibacterial activity
against Gram-positive pathogens, including that against linezolid-resistant
strains and low hERG inhibition. With regard to structure–activity
relationship (SAR) trends among the various substituents on the pyridyl
ring, relatively small and nonbasic substituents were preferable to
sterically demanding or basic substituents. Oxazolidinone ring substitution
on the pyridyl ring generated analogues with antibacterial activity
superior to imidazolidinone ring. Solubility was enhanced by the incorporation
of polar groups, especially when compounds were converted to their
prodrugs. Among the prodrugs, compound <b>85</b> exhibited excellent
solubility and a good pharmacokinetic profile. In a MRSA systemic
infection model, compound <b>85</b> displayed an ED<sub>50</sub> = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid