Synthesis and Biological Evaluation of 8-Aminomethyltetracycline Derivatives as Novel Antibacterial Agents
| Autor: | Trudy H. Grossman, Minsheng He, Chi-Li Chen, Joyce A. Sutcliffe, Corey Fyfe, Wu-Yan Zhang, Zhijian Zhu, Magnus Ronn, Diana K. Hunt, Yonghong Deng, Xiao-Yi Xiao, John Niu, Christopher E. Katz, Cuixiang Sun, Catherine Achorn, William J. O’Brien, Philip C. Hogan, Roger B. Clark |
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| Rok vydání: | 2013 |
| Předmět: |
Tetracycline
Microbial Sensitivity Tests Pharmacology Gram-Positive Bacteria Mice Structure-Activity Relationship Gram-Negative Bacteria Drug Discovery medicine Animals Biological evaluation Mice Inbred BALB C Molecular Structure Pyelonephritis biology Chemistry Tetracycline Resistance Bacterial Infections Pneumonia Ribosomal RNA biology.organism_classification Anti-Bacterial Agents Bioavailability Treatment Outcome Models Chemical Tetracyclines Molecular Medicine Female Efflux Bacteria medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 56:8112-8138 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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