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

• Published in: Journal of medicinal chemistry Vol. 51; no. 21; pp. 6955 - 6969
• Main Authors: Houghton, Tom J, Tanaka, Kelly S. E, Kang, Ting, Dietrich, Evelyne, Lafontaine, Yanick, Delorme, Daniel, Ferreira, Sandra S, Viens, Frederic, Arhin, Francis F, Sarmiento, Ingrid, Lehoux, Dario, Fadhil, Ibtihal, Laquerre, Karine, Liu, Jing, Ostiguy, Valérie, Poirier, Hugo, Moeck, Gregory, Parr, Thomas R, Far, Adel Rafai
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.11.2008; Amer Chemical Soc
• Subjects: Amines - chemistry; Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Line; Chemistry, Medicinal; Diphosphonates - chemistry; Diphosphonates - pharmacology; Female; Fluoroquinolones - chemical synthesis; Fluoroquinolones - chemistry; Fluoroquinolones - pharmacology; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Osteomyelitis - prevention & control; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; PHARMACOKINETICS; DRUG-DELIVERY; CARBOXYFLUORESCEIN; INFECTION; AGENTS; LACTONIZATION; BONE; DELIVERY SYSTEM ODDS; CIPROFLOXACIN; IN-VIVO CHARACTERIZATION; Rat; Diseases of the osteoarticular system; Diphosphonic acid derivatives; Molecular interaction; Bisphosphonates; Phosphorus Organic compounds; Prevention; Fluoroquinolone derivatives; Osteitis; Bacteria; Micrococcales; Micrococcaceae; Chemical synthesis; Staphylococcus aureus; Rodentia; Quinoline derivatives; Prodrug; In vitro; Biological activity; In vivo; Vertebrata; Biological fixation; Mammalia; Animal; Piperazine derivatives; Antibacterial agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801007z

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.