Enopeptins, uses thereof, and methods of synthesis thereto
Provided herein are inventive enopeptin compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Further provided are methods of preparation, use, and treatment.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is hydrogen or —CH 3 ;
R 2 is hydrogen, and R 3 and R 4 are joined to form an optionally substituted 6-membered heterocyclyl; or
R 2 and R 3 are joined to form a spiro-fused optionally substituted carbocyclyl or spiro-fused optionally substituted heterocyclyl, and R 4 is optionally substituted alkyl or an amino protecting group; or
R 2 and R 3 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided that R 2 and R 3 are not both hydrogen; and R 4 is optionally substituted alkyl or an amino protecting group;
R 5 is a group of formula:
wherein:
x is an integer between 1 and 10, inclusive;
R 10a and R 10b are independently hydrogen or optionally substituted alkyl; and
R 9 is hydrogen, halogen, —CN, —NO 2 ,—N 3 , substituted hydroxyl, substituted thiol, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each instance of R 6 is independently halogen, —OH, —SH, —NH 2 , —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
m is 0 or an integer of between 1 and 5, inclusive; and
R 11 is —OH, —SH, —NH 2 , substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 12 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl.
2. A compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof;
wherein:
each instance of R 7 is independently halogen, —OH, —SH, —NH 2 , —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
n is 0 or an integer of between 1 and 8, inclusive.
3. A compound of claim 1 , wherein the compound is of Formula (V):
or a pharmaceutically acceptable salt thereof,
wherein:
each instance of R 8 is independently halogen, —OH, —SH, —NH 2 , —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
q is 0 or an integer of between 1 and 4, inclusive; and
t is 0 or an integer of between 1 and 4, inclusive.
4. A compound of claim 1 , wherein the compound is of Formula (VI):
or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 , wherein the compound is of Formula (VII):
or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 , wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 , wherein the compound is of Formula (I-c):
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
9. A method of preparing a compound of Formula (I), the method comprising providing a compound of Formula (G):
or salt thereof; and coupling the compound of Formula (G), or salt thereof, with a compound of Formula (H):
or salt thereof; to provide a compound of Formula (I):
or salt thereof;
wherein:
R 1 is hydrogen or —CH 3 ;
R 2 is hydrogen, and R 3 and R 4 are joined to form an optionally substituted 6-membered heterocyclyl; or
R 2 and R 3 are joined to form a spiro-fused optionally substituted carbocyclyl or spiro-fused optionally substituted heterocyclyl, and R 4 is optionally substituted alkyl or an amino protecting group; or
R 2 and R 3 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided that R 2 and R 3 are not both hydrogen; and R 4 is optionally substituted alkyl or an amino protecting group;
R 5 is a group of formula:
wherein:
x is an integer between 1 and 10, inclusive;
R 10a and R 10b are independently hydrogen or optionally substituted alkyl; and
R 9 is hydrogen, halogen, —CN, —NO 2 —N 3 , substituted hydroxyl, substituted thiol, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each instance of R 6 is independently halogen, —OH, —SH, —NH 2 , —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
m is 0 or an integer of between 1 and 5, inclusive; and
R 11 is —OH, —SH, —NH 2 , substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R 12 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl.
10. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof, recited in claim 1 , and, optionally, a pharmaceutically acceptable excipient.
11. A method of treating a microbial infection in a subject comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, recited in claim 1 to the subject.
12. The method of claim 11 , wherein the microbial infection is a bacterial infection.
13. The method of claim 12 , further comprising administering the compound in combination with an antibiotic.
14. The method of claim 13 , wherein the antibiotic is a ribosome-targeting antibiotic.
15. The method of claim 12 , wherein the bacterial infection is resistant to other treatments.
16. The method of claim 12 , wherein the bacterial infection is multi-drug tolerant or multi-drug resistant.
17. A method of treating microbial virulence comprising contacting an effective amount of a compound or salt thereof recited in claim 1 to a microorganism.
18. The method of claim 17 , wherein the compound blocks virulence factor production.
19. The compound of claim 1 , wherein x is 1.
20. The compound of claim 19 , wherein each of R 10a and R 10b is hydrogen; and R 9 is optionally substituted alkyl.
21. The method of claim 9 , wherein x is 1.
22. The method of claim 21 , wherein each of R 10a and R 10b is hydrogen; and R 9 is optionally substituted alkyl.
23. The compound of claim 1 , wherein R 11 is optionally substituted alkyl.
24. The compound of claim 23 , wherein R 11 is —CH 3 .
25. The method of claim 9 , wherein R 11 is optionally substituted alkyl.
26. The method of claim 25 , wherein R 11 is —CH 3 .
27. The compound of claim 1 , wherein R 12 is optionally substituted alkyl.
28. The compound of claim 27 , wherein R 12 is —CH 3 .
29. The method of claim 9 , wherein R 12 is optionally substituted alkyl.
30. The method of claim 29 , wherein R 12 is —CH 3 .