Deng Yonghong, Sun Cuixiang, Hunt Diana K, Fyfe Corey, Chen Chi-Li, Grossman Trudy H, Sutcliffe Joyce A, Xiao Xiao-Yi
Discovery Chemistry, ‡Microbiology, Tetraphase Pharmaceuticals , 480 Arsenal Way, Watertown, Massachusetts 02472, United States.
J Med Chem. 2017 Mar 23;60(6):2498-2512. doi: 10.1021/acs.jmedchem.6b01903. Epub 2017 Mar 15.
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.
