Synthesis and evaluation of thiomannosides, potent and orally active FimH inhibitors

Bioorg Med Chem Lett. 2018 Sep 15;28(17):2993-2997. doi: 10.1016/j.bmcl.2018.06.017. Epub 2018 Jun 12.

Abstract

FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.

Keywords: FimH inhibitor; Thiomannoside; Urinary tract infection.

MeSH terms

  • Adhesins, Escherichia coli / metabolism
  • Administration, Oral
  • Animals
  • Biofilms / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fimbriae Proteins / antagonists & inhibitors*
  • Fimbriae Proteins / metabolism
  • Mannosides / administration & dosage
  • Mannosides / chemistry
  • Mannosides / pharmacology*
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship
  • Urinary Tract Infections / drug therapy*
  • Urinary Tract Infections / urine

Substances

  • Adhesins, Escherichia coli
  • Mannosides
  • fimH protein, E coli
  • Fimbriae Proteins