Linking Bisphosphonates to the Free Amino Groups in Fluoroquinolones: Preparation of Osteotropic Prodrugs for the Prevention of Osteomyelitis

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.

Physiologic Activity of Bisphosphonates – Recent Advances

“…The most common treatments are antibiotics and surgery to remove portions of bone that are infected or dead. Thus, selective targeting of antibiotics to bone seems to be profitable, and some preliminary attempts to design and obtain osteotropic systems with fluoroquinones, [113,114] vancomycin [115] and rifamycin [116] as active components have been undertaken.…”

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

“…The prodrug demonstrated also no gastrointestinal damage, the side effect caused by DIC treatment. The ability to release bioactive moiety from prodrugs was shown to be important to achieve a therapeutic outcome for antibacterial agents [25]. Particularly, gatifloxacin linked to BPs via labile acyloxymethyl carbamate linkage prevented infection in a rat model in contrast to the parent drug as well as to other fluoroquinolone drugs but linked through nonreleasable linkages.…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…(EtO) 2 The reactivity of vinylidenebisphosphonates has been used for the synthesis of derivatives of various analogues of fluoroquinolone antibacterial agents [105,106], heteroaromatics with potential pharmaceutical applications [107,108], simple antiplasmodial agents [103,104], HIV reverse transcriptase inhibitors [59,93], potential anti-osteoporotic agents [109,110], and N-alkylated antitumor pyridines [111]. Some representatives of these compounds (35)(36)(37)(38)(39) are shown in Scheme 19.…”