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.