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.