Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents

  • J Med Chem. 2013 Oct 24;56(20):8112-38. doi: 10.1021/jm401211t.
Roger B Clark  1 ,  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
Affiliations
  • 1. Discovery Chemistry, ‡Microbiology, and §Process Chemistry R&D, Tetraphase Pharmaceuticals, Inc. , 480 Arsenal Street, Watertown, Massachusetts 02472, United States.
PMID: 24047201 DOI: 10.1021/jm401211t
Abstract

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.

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