Synthetic ligands that modulate the activity of the RhlR quorum sensing receptor

Patent metadata

Field	Value
Publication number	US-11247976-B2
Application number	US-201716097541-A
Country	US
Kind code	B2
Filing date	Apr 30, 2017
Priority date	Apr 29, 2016
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

Abstract

RhlR modulators including agonist and antagonists which are useful for modulating QS phenotypes in Gram-negative bacteria. Certain compounds of general formula A-W-HG having various carbocyclic ad heterocyclic head groups (HG) and various tail groups (A), where —W— is —CO—NH—, —SO2—NH—, —CO—NH—CH2—, or —SO2—NH—CH2— are RhlR agonists or antagonists. The compounds are useful in methods of modulating quorum sensing in Gram-negative bacteria, particularly in Pseudomonas. Compositions including certain RhlR modulators are useful for decreasing the virulence of Gram-negative bacteria. Pharmaceutical compositions comprising certain RhlR modulators are useful for treatment of infections of Gram-negative bacteria.

First claim

The invention claimed is:

1. A compound of formula:
A-W-HG
where:
—W— is —CO—NH—, —SO 2 —NH—, —CO—NH—CH 2 —, or —SO 2 —NH—CH 2 —;
A is selected from cyclobutyl, and —CH 2 —cyclopropyll and
HG is selected from the group of moieties of formula:

where:
X is CH 2
Y is O or S and
Z is C=O or CH(OH).

2. The compound of claim 1 , wherein X=CH 2 , Y=O and Z=CO or CH(OH).

3. The compound of claim 1 which is:

4. The compound of claim 1 which is:

5. The compound of claim 2 , wherein W is —CO—NH—.

6. The compound of claim 1 , wherein W is —CO—NH—.

7. The compound of claim 1 , wherein HG is:

8. The compound of claim 7 , wherein A is cyclopropyl, cyclobutyl, or CH 2 cyclopropy.

9. The compound of claim 8 , wherein W is —CO—NH—.

10. A compound of formula:
A-W-HG
where:
—W— is —CO—NH—, —SO 2 —NH—, —CO—NH—CH 2 —, or —SO 2 —NH—CH 2 —;
A is selected from cyclopropyl, cyclobutyl, and —CH 2 —cyclopropyl; and
HG is selected from the group of moieties of formula:

where:
X is CH 2
Y is S; and
Z is C=O or CH(OH).

11. The compound of claim 10 , wherein X=CH 2 ; Y=S;
and Z=CO.

12. The compound of claim 10 , wherein A is cyclobutyl or —CH 2 —cyclopropyl.

13. The compound of claim 11 , wherein W is —CO—NH—.

14. The compound of claim 10 , wherein W is —CO—NH—.

15. A method for modulating RhIR of a Gram-negative bacterium which comprises contacting the bacterium with one or more compounds of claim 1 .

16. A method of treating an infection of a Gram-negative bacterium by administering to an individual in need of treatment a therapeutically effective amount of a compound of claim 1 .

17. A method of treating an infection of a Gram-negative bacterium by administering to an individual in need of treatment a therapeutically effective amount of a compound of claim 10 .

18. A method for modulating RhIR of a Gram-negative bacterium which comprises contacting the bacterium with one or more compounds of claim 10 .

Assignees

• Wisconsin Alumni Res Found

Inventors

• Blackwell Helen
• Boursier Michelle E
• Moore Joseph D

Classifications

• C07C233/06

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07D207/09

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D307/14

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07C233/60

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• C07C2601/08

  the ring being saturated · CPC title