Broad spectrum antivirulence, anti-persistence compounds
The present application provides malonamide compounds, and derivatives thereof (e.g., N-aryl malonamides (NAM), acetamides, oxalamides, and the like), that are useful, for example, for the treatment of acute, chronic/persistent, and/or relapsing infections. Pharmaceutical compositions, methods of treating diseases (e.g., bacterial infections), and methods of reducing bacterial virulence are also provided.
1. A compound selected from any one of the following compounds:
or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is selected from the group consisting of O and S;
L 1 is selected from the group consisting of methylene, methylmethylene, fluoromethylmethylene, fluoromethylene, difluoromethylene, and aminomethylene;
L 2 is selected from the group consisting of NR N1 C(O) and NR N1 C(S);
R N1 and R N2 are each independently selected from the group consisting of H and C 1-4 alkyl;
each R 1 is independently selected from the group consisting of C 1-4 haloalkyl, halo, CN, NO 2 , NH 2 , —COOH, —CONH 2 , and OH; and
each R 2 is independently selected from the group consisting of halo, CN, NH 2 , —COOH, —CONH 2 , —C(O)C 1-4 haloalkyl, —NHC(O)C 1-4 haloalkyl, —NHSO 2 -C 1-4 alkyl, and phenoxy;
wherein either R 1 is CN or R 2 is CN or phenoxy; and
wherein the compound of Formula I is not:
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 is O.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 is S.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is methylene.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is NR N1 C(O).
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from the group consisting of trifluoromethyl, halo, CN, NO 2 , NH 2 , and OH.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from the group consisting of fluoro, iodo, CN, NH 2 , —C(O)CF 3 , —NHC(O)CF 3 , —NHSO 2 CH 2 CH 3 , and phenoxy.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is selected from the group consisting of O and S;
L 1 is selected from the group consisting of methylene, methylmethylene, fluoromethylmethylene, and fluoromethylene;
L 2 is selected from the group consisting of NR N1 C(O) and NR N1 C(S);
R N1 is selected from the group consisting of H and methyl;
R N2 is selected from the group consisting of H and methyl;
each R 1 is independently selected from the group consisting of trifluoromethyl, halo, CN, NO 2 , NH 2 , and OH; and
each R 2 is independently selected from the group consisting of fluoro, iodo, CN, NH 2 , —C(O)CF 3 , —NHC(O)CF 3 , —NHSO 2 CH 2 CH 3 , and phenoxy.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is O;
L 1 is selected from the group consisting of methylene, methylmethylene, fluoromethylmethylene, and fluoromethylene;
L 2 is NR N1 C(O);
R N1 is selected from the group consisting of H and methyl;
R N2 is selected from the group consisting of H and methyl;
each R 1 is independently selected from the group consisting of trifluoromethyl, halo, CN, NO 2 , NH 2 , and OH; and
each R 2 is independently selected from the group consisting of fluoro, iodo, CN, NH 2 , —C(O)CF 3 , —NHC(O)CF 3 , —NHSO 2 CH 2 CH 3 , and phenoxy.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A compound of formula:
or a pharmaceutically acceptable salt thereof.
13. A compound selected from:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition, comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.