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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
[Synthesis and antibacterial activity of 3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives]
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. chenshengxi@sina.com
Aim:
To study the antibacterial activity against erythromycin-resistant organisms of 3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives, a new route of synthesis with 6 steps was designed.
Methods:
The starting material, erythromycin A (1), was reacted with NH2OH.HCI to give 2, which reacted with BzBr to give 3. Selective methylation of C-6 hydroxy group using iodomethane afforded 4, which was hydrolyzed with loss of the 3-cladinosyl to give 5. Compound 5 was reduced by H2 to provide 6, which was treated with substituted benzyl chlorides to provide 7 and 8.
Results:
Four unreported compounds (5-8) were synthesized. The antibacterial activity of the new compounds were tested in vitro against both erythromycin-susceptible and erythromycin-resistant organisms. The compounds 5 (MIC = 1 microgram.mL-1) and 6 (MIC = 1 microgram.mL-1) showed significant activity against Staphylococcus epidermidis 26,069 compared with erythromycin (MIC = 4 micrograms.mL-1). Compounds 5 (MIC = 16, 4 micrograms.mL-1), 7 (MIC = 32, 64 micrograms.mL-1) and 8 (MIC = 64, 32 micrograms.mL-1) showed better activity against Streptococcus pneumoniae 64 and Staphylococcus aureus 9525 than erythromycin (MIC > 128, 128 micrograms.mL-1).
Conclusion:
3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives have stronger antibacterial activity against some erythromycin-resistant organisms than erythromycin A.
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