This paper describes how the introduction of "cationic" aliphatic amino groups in the chalcone scaffold results in potent antibacterial compounds. It is shown that the most favorable position for the aliphatic amino group is the 2-position of the B-ring, in particular in combination with a lipophilic substituent in the 5-position of the B-ring. We demonstrate that the compounds act by unselective disruption of cell membranes. Introduction of an additional aliphatic amino group in the A-ring results in compounds that are selective for bacterial membranes combined with a high antibacterial activity against both Gram-positive and -negative pathogens. The most potent compound in this study (78) has an MIC value of 2 muM against methicillin resistant Staphylococus aureus.
The wasp toxin philanthotoxin-433 (PhTX-433) is a nonselective and noncompetitive antagonist
of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine
receptors. Polyamine toxins are extensively used for the characterization of subtypes of
ionotropic glutamate receptors, in particular Ca2+-permeable AMPA and kainate receptors.
We have previously shown that an analogue of PhTX-433 with one of the amino groups replaced
by a methylene group, philanthotoxin-83 (PhTX-83) is a selective and potent antagonist of
AMPA receptors. We now describe the solid-phase synthesis of analogues of PhTX-83 and the
electrophysiological characterization of these analogues on cloned AMPA and kainate receptors.
The polyamine portion of PhTX-83 was modified systematically by changing the position of
the secondary amino group along the polyamine chain. In another series of analogues, the
acyl moiety of PhTX-83 was replaced by acids of different size and lipophilicity. Using
electrophysiological techniques, PhTX-56 was shown to be a highly potent (K
i = 3.3 ± 0.78
nM) and voltage-dependent antagonist of homomeric GluR1 receptors and was more than 1000-fold less potent when tested on heteromeric GluR1+GluR2, as well as homomeric GluR5(Q)
receptors, thus being selective for Ca2+-permeable AMPA receptors. Variation of the acyl group
of PhTX-83 had only minor effect on antagonist potency at homomeric GluR1 receptors but led
to a significant decrease in the voltage-dependence. In conclusion, PhTX-56 is a novel, very
potent, and selective antagonist of Ca2+-permeable AMPA receptors and is a promising tool
for structure/function studies of the ion channel of the AMPA receptor.
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