Linking bisphosphonates to the free amino groups in fluoroquinolones: preparation of osteotropic prodrugs for the prevention of osteomyelitis

J Med Chem. 2008 Nov 13;51(21):6955-69. doi: 10.1021/jm801007z. Epub 2008 Oct 4.

Abstract

Osteomyelitis is an infection located in bone and a notoriously difficult disease to manage, requiring frequent and heavy doses of systemically administered antibiotics. Targeting antibiotics to the bone after systemic administration may provide both greater efficacy of treatment and less frequent administration. By taking advantage of the affinity of the bisphosphonate group for bone mineral, we have prepared a set of 13 bisphosphonated antibacterial prodrugs based on eight different linkers tethered to the free amino functionality on fluoroquinolone antibiotics. While all but one of the prodrugs were shown in vitro to be effective and rapid bone binders (over 90% in 1 h), only eight of them demonstrated the capacity to significantly regenerate the parent drug. In a rat model of the disease, a selected group of agents demonstrated their ability to prevent osteomyelitis when used in circumstances under which the parent drug had already been cleared and is thus inactive.

MeSH terms

  • Amines / chemistry
  • Animals
  • Cell Line
  • Diphosphonates / chemistry*
  • Diphosphonates / pharmacology*
  • Female
  • Fluoroquinolones / chemical synthesis*
  • Fluoroquinolones / chemistry
  • Fluoroquinolones / pharmacology*
  • Molecular Structure
  • Osteomyelitis / prevention & control*
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Amines
  • Diphosphonates
  • Fluoroquinolones
  • Prodrugs