Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design

The
F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown
to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here,
we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 by replacing the carboxylate with a sulfonamide as in 50. Other groups which can accept H-bonds were also tolerated.
We pursued further modifications to the biphenyl aglycone resulting
in significantly improved activity. Two of the most potent compounds, 86 (IC50 = 0.051 μM) and 90 (IC50 = 0.034 μM), exhibited excellent metabolic stability
in mouse plasma and liver microsomes but showed only limited oral
bioavailability (<1%) in rats. Compound 84 also showed
a good pharmacokinetic (PK) profile in mice after IP dosing with compound
exposure above the IC50 for 6 h. These new FmlH antagonists
represent new antivirulence drugs for UTIs.