Chemical probes to identify anti-mycobacterial MmpL3 inhibitors
The present application provides detectable compounds useful for identifying compounds that bind (e.g., inhibit) MmpL3. Methods of identifying compounds that bind and/or inhibit MmpL3 are also provided.
1. A compound of Formula I:
A-B-C
or a salt thereof, wherein:
A is a fluorescent detectable moiety selected from the group consisting of:
B is a linking group selected from the group consisting of:
—C(O)NH—(C 1-10 alkylene)-(5-6 membered heteroaryl)-(C 1-10 alkylene)-; and
—(C 1-10 alkylene)-C(O)NH—(C 1-10 alkylene)-(5-6 membered heteroaryl)-(C 1-10 alkylene)-; and
C is an MmpL3 inhibitor moiety selected from the group consisting of:
wherein:
X 1 is selected from the group consisting of C(O)NH and NHC(O)NH;
R 1 is C 5-10 cycloalkyl, which is optionally substituted by 1, 2, 3, or 4 independently selected C 1-4 alkyl groups; and
R 2 is C(O)C 1-4 alkoxy.
2. The compound of claim 1 , or a salt thereof, wherein B is —C(O)NH—(C 1-10 alkylene)-(5-6 membered heteroaryl)-(C 1-10 alkylene)-.
3. The compound of claim 1 , or a salt thereof, wherein the fluorescent detectable moiety is:
wherein refers to the bond between A and B.
4. The compound of claim 1 , or a salt thereof, wherein the fluorescent detectable moiety is:
wherein refers to the bond between A and B.
5. The compound of claim 1 , or a salt thereof, wherein B is
—(C 1-10 alkylene)-C(O)NH—(C 1-10 alkylene)-(5-6 membered heteroaryl)-(C 1-10 alkylene)-.
6. The compound of claim 1 , or a salt thereof, wherein B is a linking group selected from the group consisting of:
—C(O)NH—(C 1-6 alkylene)-(5-6 membered heteroaryl)-(C 1-3 alkylene)-; and
—(C 1-3 alkylene)-C(O)NH—(C 1-3 alkylene)-(5-6 membered heteroaryl)-(C 1-3 alkylene)-.
7. The compound of claim 1 , or a salt thereof, wherein B is a linking group selected from the group consisting of:
—C(O)NHCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -triazolyl-CH 2 —; and
—CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 -triazolyl-CH 2 —.
8. The compound of claim 1 , or a salt thereof, wherein
X 1 is C(O)NH.
9. The compound of claim 1 , or a salt thereof, wherein X 1 is NHC(O)NH.
10. The compound of claim 1 , or a salt thereof, wherein R 1 is C 5-10 cycloalkyl, which is optionally substituted by 1, 2, or 3 independently selected C 1-4 alkyl groups.
11. The compound of claim 1 , or a salt thereof, wherein R 1 is selected from the group consisting of cyclooctyl, bicyclo[3.1.1]heptyl, and adamantyl, each of which is optionally substituted by 1, 2, or 3 methyl groups.
12. The compound of claim 1 , or a salt thereof, wherein R 2 is C(O)OCH 3 .
13. The compound of claim 1 , or a salt thereof, wherein:
A is a fluorescent detectable moiety selected from the group consisting of:
wherein refers to the bond between A and B;
B is a linking group selected from the group consisting of —C(O)NH—(C 1-6 alkylene)-(triazolyl)-(C 1-3 alkylene)- and —(C 1-3 alkylene)-C(O)NH—(C 1-3 alkylene)-(triazolyl)-(C 1-3 alkylene)-; and
C is an MmpL3 inhibitor moiety selected from the group consisting of:
wherein:
refers to the bond between B and C;
X 1 is selected from the group consisting of C(O)NH and NHC(O)NH;
R 1 is selected from the group consisting of cyclooctyl, bicyclo[3.1.1]heptyl, and adamantyl, each of which is optionally substituted by 1, 2, or 3 methyl groups; and
R 2 is C(O)OCH 3 .
14. The compound of claim 1 , or a salt thereof, wherein the compound of Formula I is a compound of Formula II, a compound of Formula III, or a compound of Formula IV:
or a salt thereof.
15. The compound of claim 1 , which is selected from the group consisting of:
or a salt thereof.
16. A composition, comprising a compound of claim 1 , or a salt thereof, and a carrier.
17. A method of identifying an inhibitor of MmpL3, comprising:
i) contacting a cell with a compound of claim 1 , or a salt thereof, to form a compound-MmpL3 complex in the cell;
ii) contacting the cell with a test compound; and
iii) measuring displacement of the compound from the compound-MmpL3 complex and formation of a test compound-MmpL3 complex in the cell.