Synthesis and antibacterial activity of 4″ or 6″-alkanoylamino derivatives of arbekacin

• Published in: Journal of antibiotics 2015-12, Vol.68 (12), p.741-747
• Main Authors: Sasaki, Kazushige, Kobayashi, Yoshihiko, Kurihara, Takashi, Yamashita, Yohei, Takahashi, Yoshiaki, Miyake, Toshiaki, Akamatsu, Yuzuru
• Format: Article
• Language: English
• Subjects: 639/638/45/72/1199; Amination; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Dibekacin - analogs & derivatives; Dibekacin - chemical synthesis; Dibekacin - chemistry; Dibekacin - pharmacology; Drug Resistance, Bacterial; Life Sciences; Medicinal Chemistry; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbiology; Organic Chemistry; original-article; Staphylococcus aureus - drug effects; Staphylococcus infections
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/ja.2015.61

Arbekacin, an aminoglycoside antibiotic, is an important drug because it shows a potent efficacy against methicillin-resistant Staphylococcus aureus . However, resistance to arbekacin, which is caused mainly by the bifunctional aminoglycoside-modifying enzyme, has been observed, becoming a serious problem in medical practice. To create new arbekacin derivatives active against resistant bacteria, we modified the C-4″ and 6″ positions of its 3-aminosugar portion. Regioselective amination of the 6″-position gave 6″-amino-6″-deoxyarbekacin (1), and it was converted to a variety of 6″- N -alkanoyl derivatives (6a−z). Furthermore, regioselective modifications of the 4″-hydroxyl group were performed to give 4″-deoxy-4″-epiaminoarbekacin (2) and its 4″- N -alkanoyl derivatives (12 and 13). Their antibacterial activity against S. aureus , including arbekacin-resistant bacteria, was evaluated. It was observed that 6″-amino-6″- N -[( S )-4-amino-2-hydroxybutyryl]-6″-deoxyarbekacin (6o) showed excellent antibacterial activity, even better than arbekacin.