Simplified structural mimetics of AIPS as quorum sensing inhibitors

Patent metadata

Field	Value
Publication number	US-10597372-B2
Application number	US-201715850300-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Dec 21, 2016
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

Abstract

Compounds that regulate quorum sensing in Staphylococcal bacteria and in particular in Staphylococcus aureus are provided. Compounds are described in formulas I, II, III, IV, V and VI herein. One or more compounds herein can be employed to inhibit QS and to thus inhibit virulence in Staphylococcus bacteria and in particular in Staphylococcus aureus. Compounds herein and pharmaceutical compositions containing one or more of these compounds are useful, for example, in treating infections of Staphylococcus bacteria and in particular of Staphylococcus aureus. Methods for treating such bacterial infections are provided.

First claim

We claim:

1. A compound of formula:

or salts or solvates thereof,
where:
carbons indicated by * are independently in the L- or R-stereochemical form and the compound can be racemic, non-racemic or substantially enantiomerically pure;
W is NH or NCH 3 ;
Z is NR 3 CO—R 2 , where R 3 is hydrogen or a C1-C3 alkyl, and R 2 is hydrogen, an optionally-substituted alkyl group having 1-12 carbon atoms, an optionally-substituted cycloalkyl group having 3-12 carbon atoms, an optionally-substituted arylalkyl group, an optionally-substituted heteroarylalkyl group, an optionally-substituted heterocyclylalkyl group, an optionally-substituted cycloalkylalkyl group, an optionally-substituted aryl group, an optionally-substituted heteroaryl group, an optionally-substituted heterocyclyl group or an alkoxyalkyl group having 1-12 carbon atoms and 1-4 oxygen atoms;
L 1 is —(CH 2 )n-, where n is 2-12, or an alkoxyalkylene having 2-12 carbons and 1-4 oxygens;
each R, independently, is hydrogen or a straight-chain or branched alkyl group having 1-3 carbon atoms; and
X 1 and X 2 are independently selected from the group consisting of optionally-substituted straight-chain or branched alkyl groups having 3-8 carbon atoms, optionally-substituted cycloalkyl groups having 3-12 carbon atoms, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted heterocyclyl, optionally-substituted cycloalkylalkyl, optionally-substituted arylalkyl, optionally-substituted heteroarylalkyl and optionally-substituted heterocyclylalkyl groups;
wherein optional substitution is substitution with one or more groups selected from the group consisting of halogen, hydroxyl, nitro, cyano, isocyano, oxo, thioxo, azide, cyanate, isocyanate, acyl, haloakyl, alkyl, alkenyl, alkynyl, phenyl, halo-substituted phenyl, alkyl-substituted phenyl, benzyl, halo-substituted benzyl, alkyl-substituted benzyl, alkoxy, alkylthio, and mercapto.

2. The compound of claim 1 of formula:

or salts or solvates thereof.

3. The compound of claim 2 , wherein:
L 1 is —(CH 2 ) n —, where n is 2-9; or
L 1 is an alkoxyalkylene having 2-8 carbons and 1-3 oxygens.

4. The compound of claim 1 , wherein X 1 and X 2 are selected from sec-butyl, isobutyl, benzyl, p-OH-benzyl, p-F-benzyl, p-Cl-benzyl, m-F-benzyl, m-Cl-benzyl, cyclohexyl, cyclopentyl, or 3-indolylmethyl.

5. The compound of claim 1 , wherein X 1 and X 2 are optionally-substituted benzyl groups, where optional substitution is substitution with one or more halogen, hydroxyl, alkyl or alkoxy.

6. The compound of claim 1 of formula:

or salts or solvates thereof,
wherein n is 7 or 8.

7. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

8. A method for regulating virulence in Staphylococcus that comprises the step of contacting the bacterium with one or more compounds selected from the compounds of claim 1 .

9. The method of claim 8 for attenuating virulence in a strain of Staphylococcus.

10. A method of treating staphylococcal infection which comprises administering to an individual in need of treatment a therapeutically effective amount of one or more compounds of claim 1 .

11. The method of claim 10 , wherein the staphylococcal infection is caused by a strain of S. aureus, S. epidermidis or both.

12. A compound of formula:

or salts or solvates thereof,
where:
W is S or NR 1 , where R 1 is hydrogen or an alkyl group having 1 to 3 carbon atoms;
each R is hydrogen or methyl;
Z is —NR 3 CO—R 2 , where R 3 is hydrogen or a C1-C3 alkyl, and R 2 is hydrogen, an optionally-substituted alkyl group having 1-12 carbon atoms, an optionally-substituted cycloalkyl group having 3-12 carbon atoms, an optionally-substituted arylalkyl group, an optionally-substituted heteroarylalkyl group, an optionally-substituted heterocyclylalkyl group, an optionally-substituted cycloalkylalkyl group, an optionally-substituted aryl, an optionally-substituted heteroaryl group, an optionally-substituted heterocyclyl group or an alkoxyalkyl group having 1-12 carbon atoms and 1-4 oxygen atoms; wherein optional substitution of R 2 is substitution with one or more groups selected from the group consisting of halogen, hydroxyl, nitro, cyano, isocyano, oxo, thioxo, azide, cyanate, isocyanate, acyl, haloakyl, alkyl, alkenyl, alkynyl, phenyl, halo-substituted phenyl, alkyl-substituted phenyl, benzyl, halo-substituted benzyl, alkyl-substituted benzyl, alkoxy, alkylthio, and mercapto;
X 1 and X 2 are optionally substituted benzyl, cyclohexyl, cyclopentyl, or 3-indolylmethyl, where optional substitution is substitution with one or more halogen, hydroxyl, alkyl or alkoxy; and
L 1 is an alkoxyalkylene having 2-8 carbons and 1-3 oxygens.

13. The compound of claim 12 , where L 1 is —CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —.

14. The compound of claim 12 , where X 1 and X 2 are optionally substituted benzyl.

15. The compound of claim 12 , where W is S.

16. The compound of claim 15 , where L 1 is —CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —.

17. The compound of claim 16 , where X 1 and X 2 are both optionally substituted benzyl.

18. The compound of claim 16 , where X 1 and X 2 are benzyl, p-OH-benzyl, p-F-benzyl, p-Cl-benzyl, m-F-benzyl, or m-Cl-benzyl.

19. The compound of claim 12 which is n7OFF:

20. The compound of claim 12 , wherein optional substitution of R 2 is substitution with one or more halogen, hydroxyl, alkyl or alkoxy.

21. The compound of claim 12 , wherein R 3 is hydrogen or a methyl group and R 2 is hydrogen or an optionally-substituted alkyl group having 1-12 carbon atoms.

22. A compound, wherein R 3 is hydrogen or a methyl group and R 2 is an unsubstituted alkyl group having 1-4 carbon atoms.

23. The compound of claim 12 , wherein Z is CH 3 —CO—NH—.

24. The compound of claim 12 , wherein W is NR 1 .

25. The compound of claim 1 , of formula:

26. A pharmaceutical composition comprising one or more compounds of claim 12 and a pharmaceutically acceptable carrier.

27. The compound of claim 2 , wherein:
L 1 is —(CH 2 ) n —, where n is 3-8; or
L 1 is an alkoxyalkylene having 3 or 4 carbons and 1 oxygen, or having 4, 5 or 6 carbons and 2 oxygens.

28. The compound of claim 1 , wherein:
R 3 is hydrogen or a methyl group and
R 2 is an unsubstituted alkyl group having 1-4 carbon atoms.

29. The compound of claim 1 , wherein Z is CH 3 —CO—NH—.

30. A method for regulating virulence in Staphylococcu

Assignees

• Wisconsin Alumni Res Found

Inventors

• Blackwell Helen
• Vasquez Joseph
• Tal Gan Yiftah

Classifications

• C07D419/12

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

• C07D291/02 Primary

  not condensed with other rings · CPC title

• C07D417/12

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

• C07D285/00

  Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title