Compositions and methods comprising a biocidal polyamine
Compounds, compositions, and methods comprising a polyamine compound are described, which may be used to kill, disperse, treat, or reduce biofilms, or to inhibit or substantially prevent biofilm formation. In certain aspects, the present invention relates to compounds, compositions, and methods comprising polyamine compounds that have antimicrobial or dispersing activity against a variety of bacterial strains capable of forming biofilms.
1. A method for dispersing or killing a biofilm, the method comprising a step of contacting the biofilm with an anti-biofilm composition, thereby dispersing or killing the biofilm;
wherein the anti-biofilm composition comprises a polyamine compound selected from the group consisting of
and a salt thereof;
wherein:
each R a is a member independently selected from the group consisting of
A 1 , A 2 , A 3 , A 4 and A 5 are each an A n member independently selected from the group consisting of N, CR a , and CR 5 ; or, alternatively, a pair of adjacent A n members join to form an additional, independently selected aryl, cycloalkyl, heterocyclyl, or heterocycloaryl ring; wherein at least one A n member and at most three A n members are each an independently selected CR a ;
each R 1a , R 1b , R 1c , and R 1d is a member independently selected from the group consisting of hydrogen, fluoro, alkyl, and fluoroalkyl;
each R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; alternatively, a pair of R 2 members from the same R a group independently selected from the group R 2a and R 2b , R 2c and R 2d , and R 2e and R 2f join to form a member independently selected from the group consisting of spirocycloalkyl, spiroheterocycyl, and oxo; or, alternatively, an R 2a and an R 2c from the same R a group join to form a ring that is independently selected from the group consisting of cycloalkyl and heterocycyl;
each R m is a member independently selected from the group consisting of —CR 2a R 2b —, —C(R 2a )═(R 2b )—, —CC—, and —C(R 2a )(R 2b )-L-C(R 2c )(R 2d )—;
each m is an integer independently selected from 1 to 16;
each L is a member independently selected from the group consisting of a bond, —O—, —C(O)O—, —NR 4 —, —NR 4 C(O)—, and —C(O)NR 4 —;
each R 3 is a member independently selected from the group consisting of —Z 1 —R 4 , —Z 1 —Y 1 —R 4 , —Z 1 —Y 1 —Y 2 —R 4 , and —Z 1 —Y 1 —Y 2 —Y 3 —R 4 ;
each R 4 is a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, arylalkyl, cycloalkylalkyl, and heteroarylalkyl; or, alternatively, for an —N(R 4 ) 2 group, one of the two R 4 in the group is a member selected from the group consisting of —(CO)OR 6a —, —(CO)N(R 6a )(R 6b ), and —C(NR 6a )N(R 6b )(R 6c ); or, alternatively, for an —N(R 4 ) 2 group, the two R 4 groups join to form a heterocyclic ring;
each R 5 is a member independently selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, aminoalkoxy, alkylamino, alkylaminoalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocycyloxy, heterocycylamino, halo, haloalkyl, fluoroalkyloxy, arylalkyl, arylalkyloxy, arylalkylamino, n6m-heteroaryl, n6m-heteroaryloxy, heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylamino, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl; wherein at least one R 5 is not hydrogen;
each Y 1 , Y 2 , and Y 3 is an independently selected group of Formula IA:
each Z 1 and Z 2 is a member independently selected from the group consisting of —N(R 4 )— and —O—; and
each R 6a , R 6b , and R 6c is a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl; or, alternatively, two R 6n members R 6a and R 6b or R 6a and R 6c join to form a heterocycyl ring;
wherein the polyamine compound comprises at least two primary or secondary amino groups; and
with the proviso that —Z 1 —R 4 and —Z 2 —R 4 are not —NH 2 .
2. The method of claim 1 , wherein the biofilm comprises an antibiotic-resistant bacterial species.
3. The method of claim 1 , wherein the polyamine compound comprises at least four primary or secondary amino groups.
4. The method of claim 1 , wherein the polyamine compound comprises at least six primary or secondary amino groups.
5. The method of claim 1 , wherein the polyamine compound is a hydrochloride salt of
6. The method of claim 3 , wherein the polyamine compound is selected from the group consisting of
and a salt thereof;
wherein each A n member is an independently selected CR 5 .
7. The method of claim 6 , wherein:
each R a is independently a group of Formula II:
each of the A n members is independently selected from the group consisting of CR a and CR 5 ; or, alternatively, a pair of adjacent A n members join to form an additional, independently selected cycloalkyl, aryl, heterocyclyl, or heterocycloaryl ring;
each R 1a , R 1b , R 1c , and R 1d is a member independently selected from the group consisting of hydrogen, fluoro, alkyl, and fluoroalkyl; and
for each R a member, at most two R m of the R a member are selected from the group consisting of —C(R 2a )═(R 2b )—, —CC—, and —C(R 2a )(R 2b )-L-C(R 2c )(R 2d ).
8. The method of claim 7 , wherein:
each R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; alternatively, a pair of R 2n members from the R a group independently selected from the group R 2a and R 2b , R 2c and R 2d , and R 2e and R 2f join to form a ring independently selected from the group consisting of spirocycloalkyl and spiroheterocycyl; or, alternatively, the R 2a and the R 2c from the R a group join to form a ring independently selected from the group consisting of cycloalkyl and heterocycyl;
each m is an integer independently selected from 1 to 12;
each R 3 is a member independently selected from the group consisting of —Z 1 —Y 1 —R 4 and —Z 1 —Y 1 —Y 2 —R 4 ; and
each Z 1 and Z 2 is an independently selected NR 4 .
9. The method of claim 6 , wherein:
A 1 , A 2 , A 3 , A 4 , and A 5 are each an A n member independently selected from the group consisting of CR a , and CR 5 ; or, alternatively, a pair of adjacent A n members join to form an additional cycloalkyl, aryl, heterocyclyl, or heterocycloaryl ring;
each R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
each m is an integer independently selected from 1 to 10;
each L is a member independently selected from the group consisting of a bond, —O—, and —NR 4 —;
each R 3 is a member independently selected from the group consisting of —Z 1 —R 4 , —Z 1 —Y 1 —R 4 , and —Z 1 —Y 1 —Y 2 —R 4 ; and
each Z 1 and Z 2 is an independently selected NR 4 .
10. The method of claim 9 , wherein:
each R a is independently a group of Formula V:
each R 1a , R 1b , R 1c , and R 1d is a member independently selected from the group consisting of hydrogen, fluoro, alkyl, and fluoroalkyl;
for each R a member, at most two R m of the R a member are selected from the group consisting of —C(R 2a )═(R 2b )—CC—, and —C(R 2a )(R 2b )-L-C(R 2c )(R 2d )—; and
each R 3 is a member independently selected from the group consisting of —Z 1 —Y 1 —R 4 and —Z 1 —Y 1 —Y 2 —R 4 .
11. The method of claim 6 , wherein at least one R 5 is a member independently selected from the group consisting of alkyl, hydroxyl, alkoxy, aminoalkoxy, alkylamino, alkylaminoalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, halo, fluoroalkyl, fluoroalkyloxy, arylalkyl, arylalkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyloxy, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl.
12. The method of claim 11 , wherein at least one R 5 is a member independently selected from the group consisting of hydroxyl, alkoxy, aminoalkoxy, alkylaminoalkoxy, cycloalkoxy, cycloalkylalkoxy, fluoroalkyloxy, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl.
13. The method of claim 6 , wherein each Z 1 and Z 2 is an independently selected —N(R 4 )—; and
wherein each R 6a , R 6b , and R 6c is a member independently selected from the group consisting of hydrogen and alkyl.
14. The method of claim 3 , wherein each R 1a , R 1b , R 1c , and R 1d is hydrogen;
wherein each R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f is hydrogen;
wherein each R 3 is an independently selected —Z 1 —Y 1 —R 4 ; and
wherein each L is a member independently selected from the group consisting of a bond and —O—.
15. The method of claim 14 , wherein at least one R 4 is a member independently selected from the group consisting of alkyl, arylalkyl, and cycloalkylalkyl.
16. The method of claim 3 , wherein at least one R 5 is a member independently selected from the group consisting of alkyl, hydroxyl, alkoxy, halo, fluoroalkyl, and fluoroalkyloxy.
17. The method of claim 3 , wherein R a is an independently selected group of Formula VII:
18. The method of claim 17 , wherein R a is —CH 2 [NH(CH 2 ) n ] p NHR 4 ;
wherein each n is an integer independently selected from 3 to 12; and
wherein each p is an integer independently selected from 1 to 3.
19. The method of claim 18 , wherein n is 3 or 4, and wherein R 4 is alkyl.
20. An anti-biofilm composition, the composition comprising the polyamine compound used in claim 1 .
21. The composition of claim 20 , wherein each R 1a and R 1b is a member independently selected from the group consisting of hydrogen and alkyl;
wherein each R 2a , R 2b , R 2c , and R 2d is a member independently selected from the group consisting of hydrogen, alkyl, and fluoroalkyl; and
and wherein the polyamine compound comprises at least four primary or secondary amino groups.
22. The composition of claim 20 , wherein m is 1 or 2; and
wherein L is a bond.
23. The composition of claim 20 , wherein R a is an independently selected group of Formula VII:
24. The composition of claim 23 , wherein R a is —CH 2 [NH(CH 2 ) 3 ] 2 NH(R 4 ).
25. A method for inhibiting formation of a biofilm, the method comprising a step of treating planktonic bacteria with the anti-biofilm composition used in the method of claim 20 , thereby inhibiting incorporation of the planktonic bacteria into the biofilm.