3-Arylpiperidines as potentiators of existing antibacterial agents.
Important resistance patterns in Gram-negative pathogens include active efflux of antibiotics out of the cell via a cellular pump and decreased membrane permeability. A 3-arylpiperidine derivative (1) has been identified by high-throughput assay as a potentiator with an IC(50) approximately 90 microM. This report details the evaluation of the tether length, aryl substitution and the importance of the fluorine on antibiotic accumulation. Evaluation of various tether lengths demonstrated that the two-carbon tethered analogues are optimal. Removal of the fluorine has a modest effect on antibiotic accumulation and the defluorinated analogue 17 is equally potent to the original lead 1.
Thorarensen
A
A
Medicinal Chemistry, Pharmacia, 49007-4940, Kalamazoo, MI, USA. atli.thorarensen@pharmacia.com
Presley-Bodnar
A L
AL
Marotti
K R
KR
Boyle
T P
TP
Heckaman
C L
CL
Bohanon
M J
MJ
Tomich
P K
PK
Zurenko
G E
GE
Sweeney
M T
MT
Yagi
B H
BH
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000502:physiology; D004351:Drug Resistance; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects*; D005461:Fluorine / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests / Q000592:standards; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D010880:Piperidines; D005461:Fluorine