RESUMO
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.
Assuntos
Difosfonatos/química , Difosfonatos/farmacologia , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Osteomielite/prevenção & controle , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Aminas/química , Animais , Linhagem Celular , Feminino , Fluoroquinolonas/química , Estrutura Molecular , Pró-Fármacos/química , Ratos , Relação Estrutura-AtividadeRESUMO
Osteomyelitis is a difficult to treat bacterial infection of the bone. Delivering antibacterial agents to the bone may overcome the difficulties in treating this illness by effectively concentrating the antibiotic at the site of infection and by limiting the toxicity that may result from systemic exposure to the large doses conventionally used. Using bisphosphonates as osteophilic functional groups, different forms of fluoroquinolone esters were synthesized and evaluated for their ability to bind bone and to release the parent antibacterial agent. Bisphosphonated glycolamide fluoroquinolone esters were found to present a profile consistent with effective and rapid bone binding and efficient release of the active drug moiety. They were assessed for their ability to prevent bone infection in vivo and were found to be effective when the free fluoroquinolones were not.
