Author/Authors :
C. B. Raju ، نويسنده , , Kathleen Mortell، نويسنده , , Sampathkumar Anandan، نويسنده , , Hardwin OʹDowd، نويسنده , , Hongwu Gao، نويسنده , , Marcela Gomez، نويسنده , , Corinne Hackbarth، نويسنده , , Charlotte Wu، نويسنده , , Wen Wang، نويسنده , , Zhengyu Yuan، نويسنده , , Richard White، نويسنده , , Joaquim Trias، نويسنده , , Dinesh V. Patel، نويسنده ,
Abstract :
Negamycin 1 is a bactericidal antibiotic with activity against Gram-negative bacteria, and served as a template in an antibiotic discovery program. An orthogonally protected β-amino acid derivative 3a was synthesized and used in parallel synthesis of negamycin derivatives on solid support. This advanced intermediate was also used for N- and C-terminal modifications using solution-phase methodologies. The N-terminal modifications have resulted in the identification of active analogues, whereas the C-terminal modifications resulted in complete loss of antibacterial activity. The N-methyl negamycin analogue, 19a, inhibits protein synthesis (IC50=2.3 μM), has antibacterial activity (Escherichia coli, MIC=16 μg/mL), and is efficacious in an E. coli murine septicemia model (ED50=16.3 mg/kg).
