2 research outputs found
Heterocyclyl Tetracyclines. 1. 7‑Trifluoromethyl-8-Pyrrolidinyltetracyclines: Potent, Broad Spectrum Antibacterial Agents with Enhanced Activity against Pseudomonas aeruginosa
Utilizing a total synthesis approach,
the first 8-heterocyclyltetracyclines
were designed, synthesized, and evaluated against panels of tetracycline-
and multidrug-resistant Gram-positive and Gram-negative pathogens.
Several compounds with balanced, highly potent in vitro activity against
a broad range of bacterial isolates were identified through structure–activity
relationships (SAR) studies. One compound demonstrated the best antibacterial
activity against Pseudomonas aeruginosa both in vitro and in vivo for tetracyclines reported to date
Fluorocyclines. 2. Optimization of the C-9 Side-Chain for Antibacterial Activity and Oral Efficacy
Utilizing a fully synthetic route to tetracycline analogues,
the C-9 side-chain of the fluorocyclines was optimized for both antibacterial
activity and oral efficacy. Compounds were identified that overcome
both efflux (<i>tet</i>(K), <i>tet</i>(A)) and
ribosomal protection (<i>tet</i>(M)) tetracycline-resistance
mechanisms and are active against Gram-positive and Gram-negative
organisms. A murine systemic infection model was used as an oral efficacy
screen to rapidly identify compounds with oral bioavailability. Two
compounds were identified that exhibit both oral bioavailability in
rat and clinically relevant bacterial susceptibility profiles against
major respiratory pathogens. One compound demonstrated oral efficacy
in rodent lung infection models that was comparable to marketed antibacterial
agents