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Review | Regular issue | Vol 89, No. 2, 2014, pp.281-352
Published online, 28th November, 2013
DOI: 10.3987/REV-13-785
Sixteen-Membered Macrolides: Chemical Modifications and Future Applications

Keiichi Ajito,* Tomoaki Miura, Takeshi Furuuchi, and Atsushi Tamura

*Intellectual Property Department, Meiji Seika Pharma Co., Ltd., 2-4-16, Kyobashi, Chuo-ku, Tokyo 104-8002, Japan

Abstract

To produce a novel macrolide antibiotic, which is biologically stable and effective against erythromycin-resistant Streptococcus pneumoniae constitutively expressing the erm gene, we designed and synthesized a variety of novel macrolides starting from 16-membered macrolides. Initially, metabolically stable 16-membered macrolides were produced by constructing a 4-O-alkylated cladinose moiety as a stable neutral sugar. Then, an arylalkyl group was introduced to the lactone ring to improve the antibacterial activities against resistant S. pneumoniae. Although the novel analogues, which possess an arylalkyl group at the C-3 position or the western hemisphere improved antibacterial activities against inducible resistant and efflux type S. pneumoniae, they did not have sufficient activities against constitutive erm-resistant S. pneumoniae. Further, exploration of a novel macrolactone led to identification of a unique 11-azalide framework. We systematically synthesized 14- to 16-membered azalides and azalactams, and a 16-membered azalide (azalactone) was selected as a template for further medicinal chemistry. Finally, we optimized the connecting position of an arylalkyl group, structure of an arylalkyl moiety, and a neutral sugar moiety, and we synthesized a novel 15-β-substituted 16-membered 11-azalide, which was biologically stable and effective against constitutive erm-resistant S. pneumoniae.