Heterocyclyl Tetracyclines. 1. 7-Trifluoromethyl-8-Pyrrolidinyltetracyclines: Potent, Broad Spectrum Antibacterial Agents with Enhanced Activity against Pseudomonas aeruginosa

Abstract

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.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…In studies with patients suffering from complicated skin and skin structure infections, it was comparable to linezolid. [322,323] Compared to eravacycline,itshows improved activity against carbapenem-resistant Enterobacteriaceae, A. baumannii,and P. aeruginosa. [320] Thef irst compound from this platform, eravacycline,w as developed by Te traphase and is in phase III.…”

“…TP-6076 is in clinical phase Iw ith af ocus on Gram-negative bacteria. [322,323] Compared to eravacycline,itshows improved activity against carbapenem-resistant Enterobacteriaceae, A. baumannii,and P. aeruginosa. Notably,TP-6076 represents the most active tetracycline against Pseudomonas discovered to date.T wo additional tetracycline derivatives,KBP-7072 [324] (structure unknown) and TP-271, [325] are in phase Ia nd are directed at Gram-positive respiratory pathogens,a mong others.…”

“…Eravacycline appears to be suitable for treating complicated intraabdominal infections and complicated urinary tract infections, but more clinical efficacy and safety data are required to fully understand its potential. TP‐6076 is in clinical phase I with a focus on Gram‐negative bacteria . Compared to eravacycline, it shows improved activity against carbapenem‐resistant Enterobacteriaceae , A. baumannii , and P. aeruginosa .…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[322,323] Verglichen mit Eravacyclin zeigt es verbesserte Wirksamkeit gegenüber Carbapenem-resistenten Enterobacteriaceae, A. baumannii und P. aeruginosa. TP-6076 befindet sich derzeit in Phase Id er klinischen Entwicklung mit einem Fokus auf der Behandlung von Infektionen durch Gram-negative Erreger.…”

“…TP-6076 befindet sich derzeit in Phase Id er klinischen Entwicklung mit einem Fokus auf der Behandlung von Infektionen durch Gram-negative Erreger. [322,323] Verglichen mit Eravacyclin zeigt es verbesserte Wirksamkeit gegenüber Carbapenem-resistenten Enterobacteriaceae, A. baumannii und P. aeruginosa. TP-6076 ist das bisher beste Te tracyclin-Derivat, welches gegen P. aeruginosa aktiv ist.…”