Synthesizing FimH antagonists is challenging because of their densely functionalized and stereochemically complex C-mannoside structures, resulting in low yields and lengthy processes. We present an efficient method for synthesizing C-mannoside FimH antagonists by nickel-catalyzed reductive coupling and stereocontrolled reduction, thereby significantly simplifying the process and enabling the synthesis of FimH antagonists in just four steps with an overall yield of 34-50%. This efficient synthesis holds significant potential for the rapid development of analogues targeting the treatment of urinary tract infections or Crohn's disease caused by Escherichia coli (E. coli).

2024-04-01·Bioorganic Chemistry

Design, synthesis, biological evaluation and docking study of some new aryl and heteroaryl thiomannosides as FimH antagonists

Article

作者: Abou-Ghadir, Ola F ; Mostafa, Yaser A ; El-Mokhtar, Mohamed A ; Abdu-Allah, Hajjaj H M ; Othman, Shimaa A ; Kotb, Ahmed A ; Mohammed, Anber F

FimH is a mannose-recognizing lectin that is expressed by Escherichia coli guiding its ability to adhere and infect cells. It is involved in pathogenesis of urinary tract infections and Chron's disease. Several X-ray structure-guided ligand design studies were extensively utilized in the discovery and optimization of small molecule aryl mannoside FimH antagonists. These antagonists retain key specific interactions of the mannose scaffolds with the FimH carbohydrate recognition domains. Thiomannosides are attractive and stable scaffolds, and this work reports the synthesis of some of their new aryl and heteroaryl derivatives as FimH antagonists. FimH-competitive binding assays as well as biofilm inhibition of the new compounds (24-32) were determined in comparison with the reference n-heptyl α-d-mannopyranoside (HM). The affinity among these compounds was found to be governed by the structure of the aryl and heteroarylf aglycones. Two compounds 31 and 32 revealed higher activity than HM. Molecular docking and total hydrophobic to topological polar surface area ratio calculations attributed to explain the obtained biological results. Finally, the SAR study suggested that introducing an aryl or heteroaryl aglycone of sufficient hydrophobicity and of proper orientation within the tyrosine binding site considerably enhance binding affinity. The potent and synthetically feasible FimH antagonists described herein hold potential as leads for the development of sensors for detection of E. coli and treatment of its diseases.

2024-03-01·European Journal of Medicinal Chemistry

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

Article

作者: Cramer, Jonathan ; Pero, Bryant ; Bosko, Cristin ; Wilke, Sebastian ; Nemli, Dilara D ; Silbermann, Marleen ; Rabbani, Said ; Peczuh, Mark W ; Ernst, Beat ; Jiang, Xiaohua

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 (FimH_LD), as well as a structurally flexible full-length FimH (FimH_FL) 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 FimH_LD and FimH_FL 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 FimH_FL.

100 项与 GSK-3859747A 相关的药物交易

登录后查看更多信息