title: Vectorization efforts to increase Gram-negative intracellular drug concentration: a case study on HldE-K inhibitors.
abstract: 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.
authors: Medicinal Chemistry, Mutabilis, 102 Avenue Gaston Roussel, 93230 Romainville, France.
authors: Dmytro
authors: D
authors: Atamanyuk
authors: Fabien
authors: F
authors: Faivre
authors: Mayalen
authors: M
authors: Oxoby
authors: Benoit
authors: B
authors: Ledoussal
authors: Elodie
authors: E
authors: Drocourt
authors: François
authors: F
authors: Moreau
authors: Vincent
authors: V
authors: Gerusz
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000378:metabolism; D004917:Erythromycin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000187:drug effects; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011073:Polyamines / Q000494:pharmacology; D000071228:Polyelectrolytes
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004917:Erythromycin; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D009713:Nucleotidyltransferases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011073:Polyamines; D000071228:Polyelectrolytes; C445302:D,D heptose 7-phosphate kinase-D,D-heptose 1-phosphate adenylyltransferase, E coli