Modulation of bacterial quorum sensing with synthetic ligands

Patent metadata

Field	Value
Publication number	US-9796694-B2
Application number	US-201414328515-A
Country	US
Kind code	B2
Filing date	Jul 10, 2014
Priority date	Mar 19, 2007
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

The present invention provides compounds and methods for modulation of the quorum sensing of bacteria. In an embodiment, the compounds of the present invention are able to act as replacements for naturally occurring bacterial quorum sensing ligands in a ligand-protein binding system; that is, they imitate the effect of natural ligands and produce an agonistic effect. In another embodiment, the compounds of the present invention are able to act in a manner which disturbs or inhibits the naturally occurring ligand-protein binding system in quorum sensing bacteria; that is, they produce an antagonistic effect. The compounds of the present invention comprise N-acylated-homoserine lactones (AHLs) comprised of a wide range of acyl groups.

First claim

We claim:

1. A compound of formula FX1:

or a pharmaceutically acceptable salt thereof,
wherein m is 1;
each R 1 , R 2 , and R 3 is hydrogen;
X is —O—;
Y is —CO—;
L is —(CH 2 ) p —, wherein p is 1 or 2;
Z is —O—;
n is 1; and
A is selected from the group consisting of an aryl group, a C 5 -C 8 cycloalkyl group, a C5-C8 cycloalkenyl group, each of which is optionally substituted with one or more substituents selected from the group consisting of a halogen, a C1-C3 alky group, a C1-C3 fluorinated alkyl group, a C1-C3 fluorinated alkoxy group, a nitrile, and a —SR group, where R is a C1-C3 alkyl group.

2. The compound of claim 1 , wherein A is a substituted aryl group.

3. The compound of claim 2 , wherein the substituted aryl group is a halogenated aryl group.

4. The compound of claim 2 , wherein the substituted aryl group is a halogenated phenyl group.

5. The compound of claim 1 , wherein A is selected from the group consisting of:

6. The compound of claim 5 , wherein p is 1.

7. The compound of claim 1 , wherein A is selected from the group consisting of:

8. The compound of claim 7 , wherein p is 1.

9. The compound of claim 7 , wherein A is selected from the group consisting of:

10. The compound of claim 9 , wherein p is 1.

11. The compound of claim 1 which is:

12. The compound of claim 1 which is:

13. A method for treating an infection of a quorum sensing bacterium comprising the step of administering an effective amount of a compound of claim 1 to a patient in need of such treatment.

14. The method of claim 13 , wherein said treatment comprises disrupting or inhibiting biofilm formation.

15. The compound of claim 1 , wherein p is 1 and A is selected from:

16. The method of claim 13 , wherein the quorum sensing bacterium is a bacterium of the genus Pseudomonas.

17. The method of claim 13 , wherein the quorum sensing bacterium is a bacterium of the species Pseudomonas aeruginosa.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Blackwell Helen E
• Geske Grant D
• Campbell Butler Jennifer C

Classifications

• C07D309/30

  Oxygen atoms, e.g. delta-lactones · CPC title

• C07D307/33 Primary

  in position 2, the oxygen atom being in its keto or unsubstituted enol form · CPC title

• A61K31/365

  Lactones · CPC title

• C07D333/32

  Oxygen atoms · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title