ロイコマイシン類を出発物質としたラクトンの化学変換と新規アザライドの創出

概要

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For the purpose of generation of a new macrolide antibiotic which is effective against constitutive erm-resistant Streptococcus pneumoniae, a variety of novel 11-azalides were designed and synthesized starting from 16-membered macrolides, leucomycins. One step macrocyclization by a linear dialdehyde and a primary amine via reductive amination firstly gave 15-membered 11-azalide, and optimized 11-N-arylalkyl-azalide was effective against inducible erm-resistant S. pneumoniae. Then, 14-membered to 16-membered 11-azalides or 11-azalactams were systematically prepared in application of a formylcarboxylic acid, and biologically evaluated. As a result, 16-membered 11-azalide was chosen as a lead compound for further medicinal chemistry. Finally 16-membered 15-β-substituted-11-azalide was generated as a clinical candidate through determination of the position of an arylalkyl group to be inserted and its stereochemistry, optimization of the arylalkyl group and the C-3 position, and exploration of a neutral sugar moiety for enhancement of stability against metabolism. This molecule exhibited strong activities against not only constitutive erm-resistant S. pneumoniae but resistant S. pneumoniae with mef gene and resistant Streptococcus pyogenes.
社団法人有機合成化学協会の論文
2011-12-01