Quinone reductase 2 inhibitor compounds and uses thereof
Provided herein according to some embodiments is a compound of Formula (I): [Formula], or a pharmaceutically acceptable salt or prodrug thereof. Compositions comprising the compound, and uses thereof for inhibiting the activity of quinone reductase-2, as well as in methods of treatment, are also provided.
1. A compound of Formula (I):
wherein R 1 is:
wherein D 1 , D 2 , D 3 , and D 4 are each independently selected from the group consisting of hydrogen, halo, alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amide, nitro, hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro, and haloalkyl, or
D 1 and D 2 , D 2 and D 3 , or D 3 and D 4 together form a fused ring that is optionally substituted,
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
2. The compound of claim 1 , wherein D 1 , D 2 , D 3 , and D 4 are each hydrogen.
3. The compound of claim 2 , wherein said compound is a compound of Formula (I)(a)(1) or a compound of Formula (I)(a)(2):
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
4. The compound of claim 2 , wherein said compound is a compound of Formula (I)(a)(2):
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
5. The compound of claim 2 , wherein said compound is a compound of Formula (I)(a)(2):
or a pharmaceutically acceptable salt or prodrug thereof.
6. A compound of Formula (I):
wherein R 1 is:
wherein X 1 , X 2 , and X 3 are each independently selected from the group consisting of carbon, nitrogen, and oxygen, and
when present, D 5 , D 6 , D 7 , and D 8 are each independently selected from the group consisting of hydrogen, halo, alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amide, nitro, hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro, and haloalkyl,
or two of D 5 , D 6 , D 7 , and D 8 together form a fused ring that is optionally substituted,
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
7. The compound of claim 6 , wherein said compound is a compound of Formula (I)(b)(1):
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
8. A compound of Formula (I):
wherein R 1 is:
wherein X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from the group consisting of carbon, nitrogen, and oxygen, wherein at least two or at least three of said X 4 , X 5 , X 6 , X 7 , and X 8 are carbon, and
when present, D 9 , D 10 , D 11 , D 12 , D 13 , and D 14 are each independently selected from the group consisting of hydrogen, halo, alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amide, nitro, hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro, and haloalkyl,
or two of D 9 , D 10 , D 11 , D 12 , D 13 , and D 14 together form a fused ring that is optionally substituted,
or wherein R 1 is:
or a pharmaceutically acceptable salt or prodrug thereof.
9. The compound of claim 8 , wherein R 1 is:
or a pharmaceutically acceptable salt or prodrug thereof.
10. A compound of Formula (I):
wherein R 1 is:
X 9 , X 10 , X 11 , and X 12 are each independently selected from the group consisting of carbon, nitrogen, and oxygen, wherein at least two of said X 9 , X 10 , X 11 , and X 12 are carbon, and
when present, D 15 , D 16 , D 17 , D 18 , and D 19 are each independently selected from the group consisting of hydrogen, halo, alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amide, nitro, hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro, and haloalkyl,
or two of D 15 , D 16 , D 17 , D 18 , and D 19 together form a fused ring, optionally substituted,
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
11. The compound of claim 10 , wherein R 1 is:
wherein said compound is optionally substituted one, two or three times with fluoromethyl, difluoromethyl or trifluoromethyl,
or a pharmaceutically acceptable salt or prodrug thereof.
12. The compound of claim 1 , wherein said compound has a positive log D value at approximately pH 4 to 5.
13. A composition comprising the compound of claim 1 and a carrier.
14. The composition of claim 13 , wherein said carrier is a pharmaceutically acceptable carrier.
15. A method for inhibiting the activity of quinone reductase-2 (QR2), comprising contacting QR2 with the compound of claim 2 .
16. The method of claim 15 , wherein said contacting is performed in vitro.
17. The method of claim 15 , wherein said contacting is performed in vivo.
18. A method of treatment for malaria in a subject in need thereof, comprising administering to said subject in a treatment-effective amount the compound of claim 1 .
19. A method of treatment for an immune disorder in a subject in need thereof, comprising administering to said subject in a treatment-effective amount the compound of claim 1 .
20. A method of treatment for lupus in a subject in need thereof, comprising administering to said subject in a treatment-effective amount the compound of claim 1 .
21. A method of treatment for a disorder associated with mitochondrial dysfunction in a subject in need thereof, comprising administering to said subject in a treatment-effective amount the compound of claim 1 .
22. The method of claim 15 , wherein said administering comprises chronic administration.
23. The method of claim 15 , wherein said administering is performed once daily.
24. The compound of claim 1 , wherein D 1 , D 2 , D 3 , and D 4 are each independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heteroaryl, hydroxyl, and haloalkyl.