Cover Picture: Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI (ChemMedChem 4/2016)

The front cover picture shows the X-ray structure of two bacterial FimH antagonists, 4′-(α-d-mannopyranosyloxy)-N3,N5,3′-trimethyl-[1,1′-biphenyl]-3,5-dicarboxamide (7, green) and 4′-(α-d-mannopyranosyloxy)-[1,1′-biphenyl]-3-carboxylic acid methyl ester (2, yellow), bound to the lectin domain. These α-mannosides block the adhesion and invasion of UPEC to host cells in urinary tract infections (UTIs) with low nm affinities. Optimized mannoside 7 was rationally designed using the structure of 2. Capitalizing on the improved interactions of 7 with FimH, especially with Y48 and R98, 7-[4-(α-d-mannopyranosyloxy)-3-methylphenyl]-1(2H)-isoquinolinone (22), shown centered at the bottom, was rationally designed. This restricts the amide into the bound conformation. N-substituted analogs hold a 30-fold increase in potency derived from higher FimH affinity. Lead mannoside 22 displayed the best oral bioavailability, compound exposure, and efficacy when tested in a mouse model of UTI and represents a promising new antivirulence candidate drug for UTI. More information can be found in the Communication by James W. Janetka et al. on page 367 in Issue 4, 2016 (DOI: 10.1002/cmdc.201600006).