Bioorganic & medicinal chemistry letters · 2004
Conformationally restricted analogs of deoxynegamycin.
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Raju B, Anandan Sampathkumar, Gu Shihai, Herradura Prudencio, O'Dowd Hardwin, Kim Bum, Gomez Marcela, Hackbarth Corinne, Wu Charlotte, Wang Wen, Yuan Zhengyu, White Richard, Trias Joaquim, Patel Dinesh V
Аннотация
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.