Simplified structural mimetics of AIPS as quorum sensing inhibitors

Patent metadata

Field	Value
Publication number	US-11560361-B2
Application number	US-202016828412-A
Country	US
Kind code	B2
Filing date	Mar 24, 2020
Priority date	Dec 21, 2016
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

Abstract

Compounds that regulate quorum sensing in Staphylococcal bacteria and in particular in Staphylococcus aureus are provided. Compounds provided are racemic, non-racemic or substantially enantiomerically pure cyclic peptides of formula I:

or salts or solvates thereof, where variables R, W, X 1 , X 2 , and Z and are as described in the specification and L 1 is a divalent linker which contains 1-12 carbon atoms, optionally 1-4 oxygen atoms, optionally one or two carbon-carbon double bonds, and hydrogen atoms to satisfy valency. Certain dimers of the cyclic peptides are also provided. One or more cylic peptides or dimers thereof herein can be employed to inhibit QS and to thus inhibit virulence in Staphylococcus bacteria. Compounds herein and pharmaceutical compositions containing one or more of these compounds are useful in treating infections of Staphylococcus bacteria. Methods for treating such bacterial infections are also 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 S or NR 1 , where R 1 is hydrogen or an alkyl group having 1 to 3 carbon atoms;
Z is —NR 3 CO—R 2 , where R 3 is hydrogen or a C1-C3 alkyl, and R 2 is an optionally-substituted arylalkyl group; an optionally-substituted heteroarylalkyl group, an optionally-substituted heterocycylalkyl group, or an optionally-substituted cycloalkylalkyl group;
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 an 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 heterocycyl, optionally-substituted cycloalkylalkyl, optionally-substituted arylalkyl, optionally-substituted heteroarylalkyl and optionally-substituted heterocycylalkyl groups.

2. The compound of claim 1 of formula:

or salts or solvates thereof.

3. The compound of claim 1 , wherein W is S or NH.

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 is selected from optionally-substituted benzyl and X 2 is selected from cyclohexylmethyl or cyclopentylmethyl.

6. The compound of claim 1 , wherein X 1 and X 2 are optionally-substituted benzyl groups.

7. A pharmaceutical composition comprising one or more compounds of claim 1 .

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. The compound of claim 1 , wherein optional substitution of straight-chain or branched alkyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocycyl groups, cycloalkylalkyl groups, arylalkyl groups, heteroarylalkyl groups, or heterocycylalkyl groups is substitution with one or more non-hydrogen groups selected an from halogen, hydroxyl, alkyl having 1-3 carbon atoms, amino-substituted alkyl having 1-4 carbon atoms, alkoxy having 1-3 carbon atoms, amino, alkylamino having 1-3 carbon atoms, dialkyl amino where the alkyl group has 1-3 carbon atoms, aryl, haloalkyl having 1-3 carbon atoms, phenyl, benzyl, phenoxy, benzyloxy, oxo (═O), sulfhydryl, alkylthio having 1-3 carbon atoms, —CO 2 R′ where R′ is hydrogen or an alkyl having 1-3 carbon atoms, —COR′, where R′ is H or an alkyl having 1-3 carbon atoms, —CO—NR′ 2 , where each R′ is independently hydrogen or alkyl having 1-3 carbon atoms, azido (N 3 —), nitro, cyano, isocyano, thiocyano, or isothiocyano.

13. The compound of claim 1 , wherein R 2 is an optionally-substituted arylalkyl group.

14. The compound of claim 13 , wherein the arylalkyl group is optionally-substituted with a halogen.

15. The compound of claim 1 , wherein R 2 is an optionally-substituted benzyl or phenethyl group.

16. The compound of claim 15 , wherein the benzyl or phenethyl group is optionally-substituted with a halogen.

17. The compound of claim 16 , wherein X 1 and X 2 are optionally-substituted benzyl groups.

18. The compound of claim 17 , wherein the benzyl groups are optionally-substituted with a halogen.

19. The compound of claim 1 , wherein X 1 and X 2 are independently optionally-substituted benzyl groups, optionally-substituted cyclohexylmethyl groups or optionally-substituted cyclopentylmethyl groups.

20. The compound of claim 1 , wherein L 1 is —CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —.

21. The compound of claim 1 , wherein W is S.

22. The compound of claim 1 , wherein L 1 is —(CH 2 ) n —, where n is 2-9.

23. The compound of claim 1 , wherein each R is hydrogen.

24. The compound of claim 1 , wherein at least one R is CH 3 .

25. The compound of claim 2 , wherein W is S, Z is —NH—CO—R 2 , where R 2 is benzyl, each R is hydrogen, X 1 and X 2 are both benzyl groups, and L 1 is —CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 2 —.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Blackwell Helen
• Vasquez Joseph
• Tal Gan Yiftah

Classifications

• 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

• C07D291/02 Primary

  not condensed with other rings · CPC title

• C07D419/12

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