Enzyme inhibiting compounds and methods
The invention provides compounds, compositions, and methods for studying the Rohmer pathway and for treating bacterial infections or parasitic infections. The parasitic infection can be a protozoan infection, such as malaria. The compounds and compositions can also be used as antibiotics, for example, to kill bacteria or parasites, or to inhibit bacterial or parasite growth. The invention further provides inhibitors of isoprenoid biosynthesis enzymes, and methods of inhibiting the activity of isoprenoid biosynthesis enzymes. The compounds can be, for example, alkynes or allenes that bind to a unique Fe of an Fe4S4 cluster of an isoprenoid biosynthesis enzyme.
1. A compound of Formula III:
wherein
R 1 is H; CF 3 ; N(R x ) 2 where each R x is independently H, (C 1 -C 4 )alkyl; (C 1 -C 4 )alkanoyl; or (C 1 -C 4 )alkyl substituted by hydroxy, halo, amino, or nitro; or R 1 is absent when X is N;
X is C or N;
n is 0, 1, or 2;
L 1 is O, S, NR 2 , or C(R 3 )(R 4 );
L 2 is O, S, NR 2 , or C(R 3 )(R 4 );
each R 2 is independently H or (C 1 -C 4 )alkyl;
each R 3 is independently H, halo, or (C 1 -C 4 )alkyl; and
each R 4 is independently H, halo, or (C 1 -C 4 )alkyl;
or a salt or solvate thereof.
2. The compound of claim 1 wherein L 1 is O; and L 2 is O, CH 2 or CF 2 .
3. The compound of claim 2 wherein R 1 is H, -Me, or —CH 2 OH; and L 2 is O or CH 2 .
4. The compound of claim 3 wherein the compound is:
or a salt or solvate thereof.
5. The compound of claim 1 wherein R 1 is H, -Me, or —CH 2 OH; L 1 is O or S; and L 2 is O, CH 2 or CF 2 .
6. The compound of claim 5 wherein the compound is:
or a salt or solvate thereof.
7. A method of inhibiting the activity of an isoprenoid biosynthesis enzyme that includes an Fe 4 S 4 cluster, comprising contacting the enzyme with a compound of claim 1 , wherein the compound forms a bioorganometallic complex with an iron atom of the Fe 4 S 4 cluster of the isoprenoid biosynthesis enzyme, thereby inhibiting the activity of the enzyme.
8. A method of treating a bacterial infection or parasitic infection in a mammal, wherein the bacterial infection or parasitic infection is caused by a bacteria or parasite that has of an isoprenoid biosynthesis enzyme that includes an Fe 4 S 4 cluster, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1 , wherein the compound forms a bioorganometallic complex with an iron atom of the Fe 4 S 4 cluster of the isoprenoid biosynthesis enzyme of the bacteria or parasite, thereby inhibiting the activity of the isoprenoid biosynthesis enzyme of the bacteria or parasite and treating the bacterial infection or parasitic infection.
9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
10. The compound of claim 1 wherein L 2 is O.
11. The compound of claim 1 wherein L 2 is CH 2 .
12. The compound of claim 1 wherein L 2 is CF 2 .
13. The compound of claim 1 wherein n is 0.
14. The compound of claim 1 wherein n is 1.
15. The compound of claim 1 wherein n is 2.
16. The compound of claim 1 wherein X is C.
17. The compound of claim 1 wherein X is N.
18. The compound of claim 1 wherein R 1 is H.
19. The compound of claim 1 wherein R 1 is -Me.
20. The compound of claim 1 wherein R 1 is —CH 2 OH.
21. The compound of claim 1 wherein the compound is:
or a salt or solvate thereof.
22. The compound of claim 1 wherein the compound is:
or a salt or solvate thereof.
23. The compound of claim 1 wherein the compound is:
or a salt or solvate thereof.
24. The compound of claim 1 wherein the compound is:
or a salt or solvate thereof.
25. The compound of claim 1 wherein the compound is:
or a salt or solvate thereof.
26. A pharmaceutical composition comprising a compound of claim 25 and a pharmaceutically acceptable diluent or carrier.