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

• Published in: Bioorganic chemistry 2024-04, Vol.145, p.107258-107258, Article 107258
• Main Authors: Mohammed, Anber F., Othman, Shimaa A., Abou-Ghadir, Ola F., Kotb, Ahmed A., Mostafa, Yaser A., El-Mokhtar, Mohamed A., Abdu-Allah, Hajjaj H.M.
• Format: Article
• Language: English
• Subjects: Antagonist; Antiadhesion; E. coli; FimH; Oxadiazole; Thiomannoside
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107258

[Display omitted] •Thiomannosides having aryl or heteroarylthio as aglycones were designed, synthesized, characterized, and evaluated as FimH antagonists.•Potent and synthetically feasible FimH antagonists were obtained.•Structural features for improved binding affinity were explored.•Molecular docking studies disclosed important binding modes with FimH and SAR.•These antagonists could find applications for treatment of E. coli infections or development of sensors for its detection. 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.