Conformationally restricted analogs of deoxynegamycin

Methods were developed to synthesize a number of conformationally restricted β-amino acids. Incorporation of these β-amino acids into deoxynegamycin template has resulted in structurally novel and conformationally restricted analogs. These analogs were evaluated in whole cell assays and as inhibitors of cell-free protein synthesis to assess their antibacterial properties. 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 μM; 44, IC 50=6.6 μM; 35e 2 , IC 50=1 μM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity ( Escherichia coli, MIC=4–16 μg/mL; Klebsiella pneumoniae, MIC=8 μg/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.