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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-10, Vol.56 (20), p.8112-8138
Main Authors: Clark, Roger B, He, Minsheng, Deng, Yonghong, Sun, Cuixiang, Chen, Chi-Li, Hunt, Diana K, O’Brien, William J, Fyfe, Corey, Grossman, Trudy H, Sutcliffe, Joyce A, Achorn, Catherine, Hogan, Philip C, Katz, Christopher E, Niu, John, Zhang, Wu-Yan, Zhu, Zhijian, Ronn, Magnus, Xiao, Xiao-Yi
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Bacterial Infections - complications
Female
Gram-Negative Bacteria - drug effects
Gram-Negative Bacteria - growth & development
Gram-Positive Bacteria - drug effects
Gram-Positive Bacteria - growth & development
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Models, Chemical
Molecular Structure
Pneumonia - etiology
Pneumonia - prevention & control
Pyelonephritis - etiology
Pyelonephritis - prevention & control
Structure-Activity Relationship
Tetracycline Resistance - drug effects
Tetracyclines - chemical synthesis
Tetracyclines - chemistry
Tetracyclines - pharmacology
Treatment Outcome
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401211t