Synthesis and Biological Evaluation of 8-Aminomethyltetracycline Derivatives as Novel Antibacterial Agents
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- 作者：Roger B. Clark ; Minsheng He ; Yonghong Deng ; Cuixiang Sun ; Chi-Li Chen ; Diana K. Hunt ; William J. O鈥橞rien ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：October 24, 2013
- 年：2013
- 卷：56
- 期：20
- 页码：8112-8138
- 全文大小：856K
- 年卷期：v.56,no.20(October 24, 2013)
- ISSN：1520-4804
文摘
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鈥揳ctivity 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.