Abstract
The increase in the number of bacteria that are resistant to multiple antibiotics poses a serious clinical problem that threatens the health of humans worldwide. Nadifloxacin (1) is a highly potent antibacterial agent with broad-spectrum activity. However, its poor aqueous solubility has limited its use to topical applications. To increase its solubility, it was glycosylated herein to form a range of trans-linked (3a-e) and cis-linked (7a,b) glycosides, each of which was prepared and purified to afford single anomers. The seven glycoside derivatives (3a-e, 7a,b) were examined for potency against eight strains of S. aureus, four of which were methicillin-resistant. Although less potent than free nadifloxacin (1), the α-L-arabinofuransoside (3a) was effective against all strains that were tested (minimum inhibitory concentrations of 1–8 μg/mL compared to 0.1–0.25 μg/mL for nadifloxacin), demonstrating the potential of this glycoside as an antibacterial agent. Estimation of Log P as well as observations made during preparation of these compounds reveal that the solubilities of the glycosides were greatly improved compared with nadifloxacin (1), raising the prospect of its use in oral applications.
Highlights
Staphylococci are commonly found in the environment and are major colonizers of human skin [1,2]
In 1959, the β-lactamase-resistant antibiotic methicillin was introduced, but since there has been a steady increase in the prevalence of methicillin-resistant strains of bacteria, and last-resort drugs such as vancomycin are increasingly used to treat infections [5,6]
Many attempts have been made to increase the aqueous solubility of nadifloxacin and enable it to be used in oral administration, for example by forming carboxylate salts, esters and peptides and by incorporating the drug in microemulsions and dendrimers [12,13,14,15,16,17]
Summary
Staphylococci are commonly found in the environment and are major colonizers of human skin [1,2]. An alternative approach to improve the solubility of nadifloxacin is to glycosylate the free hydroxyl group on the piperidine ring (Scheme 1). An alternative approach to improve the solubility of nadifloxacin is to glycos2yolfa1te the free hydroxyl group on the piperidine ring (Scheme 1). Since this hydroxyl group is required for nadifloxacin to have antibacterial properties, masking of this position by formation of a glycoside would serve a dual purpose. 1: nadifloxacin, 3a: α-arabinoside, 3b: β-galactoside, 3c: β-glucoside, 3d: α-mannoside, 3e: β-xyloside, 7a: α-galactoside, 7b: α-glucoside
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