Vectorization Efforts To Increase Gram-Negative Intracellular Drug Concentration: A Case Study on HldE-K Inhibitors

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• 作者：Dmytro Atamanyuk ; Fabien Faivre ; Mayalen Oxoby ; Benoit Ledoussal ; Elodie Drocourt ; Fran莽ois Moreau ; Vincent Gerusz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1908-1921
• 全文大小：544K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their Gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies.