Synthesis and Biological Evaluation of 8-Aminomethyltetracycline Derivatives as Novel Antibacterial Agents

• DOI: 10.1021/jm401211t
• Publication Date: 2013-09-18T18:24:06Z
• Authors: Roger B. Clark; Minsheng He; Yonghong Deng; Cuixiang Sun; Chi-Li Chen; Diana K. Hunt; William J. O’Brien; Corey Fyfe; Trudy H. Grossman; Joyce A. Sutcliffe; Catherine Achorn; Philip C. Hogan; Christopher E. Katz; John Niu; Wu-Yan Zhang; Zhijian Zhu; Magnus Ronn; Xiao-Yi Xiao
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Molecular Structure; Pyelonephritis; Tetracycline Resistance; Bacterial Infections; Microbial Sensitivity Tests; Pneumonia; Gram-Positive Bacteria; Anti-Bacterial Agents; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Treatment Outcome; Models, Chemical; Tetracyclines; Gram-Negative Bacteria; Animals; Female

The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.