Does size matter? – Comparing pyranoses with septanoses as ligands of the bacterial lectin FimH

The pharmacological modulation of disease-relevant carbohydrate–protein interactions represents an underexplored area of medicinal chemistry. One particular challenge in the design of glycomimetic compounds is the inherent instability of the glycosidic bond toward enzymatic cleavage. This problem has traditionally been approached by employing S-, N-, or C-glycosides with reduced susceptibility toward glycosidases. The application of ring-extended glycomimetics is an innovative approach to circumvent this issue. On the example of the bacterial adhesin FimH, it was explored how design principles from pyranose glycomimetics transfer to analogous septanose structures. A series of ring-extended FimH antagonists exhibiting the well-proven pharmacophore necessary for targeting the tyrosine-gate of FimH was synthesized. The resulting septanoses were evaluated for their affinity to the conformationally rigid isolated lectin domain of FimH (FimHLD), as well as a structurally flexible full-length FimH (FimHFL) construct. Some elements of potent mannoside-based FimH antagonists could be successfully transferred to septanose-based ligands, ultimately resulting in a 32-fold increase in binding affinity. Interestingly, the canonical ca. 100-fold loss of binding affinity between FimHLD and FimHFL is partly mitigated by the more flexible septanose antagonists, hinting at potentially differing interaction features of the flexible glycomimetics with intermediately populated states during the conformational transition of FimHFL. [Display omitted] •Septanoses are ring-expanded glycomimetics that are not susceptible to glycosidase cleavage.•SAR of pyranose glycomimetics binding to FimH cannot be easily transferred to septanoses.•Septanoses diverge from the canonical 100-fold loss in binding affinity for the more flexible FimHFL construct.