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Fully Synthetic Tetracyclines: Increasing Chemical Diversity to Combat Multidrug-Resistant Bacterial Infections

Chapter
Part of the Topics in Medicinal Chemistry book series

Abstract

A convergent total synthesis platform has enabled diverse modifications of the tetracycline chemical space that were previously inaccessible or difficult to access by traditional semisynthesis. Using this powerful chemical synthesis technology, new tetracycline scaffolds were designed leading to the discovery of novel, fully synthetic tetracyclines with potent, broad-spectrum antibacterial activity against multidrug-resistant (MDR) Gram-positive and Gram-negative pathogens. This discovery effort produced a number of tetracycline antibiotic development candidates currently in various stages of clinical study, including eravacycline (TP-434), which has advanced into several late-stage clinical trials in patients with complicated intro-abdominal infections (cIAI) and in patients with complicated urinary tract infections (cUTI). This chapter describes the design, synthesis, and evaluation of several fully synthetic tetracycline series, including the disubstituted tetracyclines (fluorocyclines), the heterocyclines, and the polycyclines.

Keywords

Broad spectrum Eravacycline Michael–Dieckmann reaction Multidrug resistant (MDR) Structure-activity relationship, Total synthesis TP-271 

Notes

Acknowledgments

Many thanks to Sean Connell for providing Fig. 2.

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Tetraphase Pharmaceuticals, Inc.WatertownUSA

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