Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel.
This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.
Hlasta
D J
DJ
R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA.
Demers
J P
JP
Foleno
B D
BD
Fraga-Spano
S A
SA
Guan
J
J
Hilliard
J J
JJ
Macielag
M J
MJ
Ohemeng
K A
KA
Sheppard
C M
CM
Sui
Z
Z
Webb
G C
GC
Weidner-Wells
M A
MA
Werblood
H
H
Barrett
J F
JF
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D016984:Enterococcus faecium / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010766:Phosphorylation; D012458:Salicylanilides / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D012458:Salicylanilides; C023342:closantel