Hybrid compounds of curcumin and melatonin as neuroprotectants for neurodegenerative disorders
Hybrid compounds of curcumin and melatonin as neuroprotectants are provided. The hybrid compounds are useful for the treatment and/or prevention of Alzheimer's disease (AD), as well as other neurodegenerative diseases. The hybrid compounds exhibited superior and potent neuroprotection in an AD model.
1. A compound having the general formula:
wherein
R is a substituted aromatic group, or an unsubstituted aromatic group, or a substituted heteroaromatic group or an unsubstituted heteroaromatic group;
R2 is selected from the group consisting of H, OH, NH 2 , NO 2 and C 1 -C 8 alkoxyl;
R3 is selected from the group consisting of H and C 1 -C 4 alkyl;
X is S or O or NH or substituted-N, wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, isopropyl, tert-butyl, and an saturated or unsaturated monocyclic ring with ring size ranging from 3-7 which is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano; and
Y is selected from the group consisting of C 1 -C 4 alkyl with the proviso that if there is a double bond adjacent to the R group, then R is not a phenyl ring substituted by OCH3.
2. The compound of claim 1 , wherein said aromatic or heteroaromatic group is substituted with a hydroxyl or a substituted or unsubstituted amino group.
3. The compound of claim 1 , wherein said substituted or unsubstituted aromatic or heteroaromatic group is a substituted or unsubstituted heteroaromatic group which includes an oxygen or a nitrogen as the heteroatom.
4. The compound of claim 2 , wherein the aromatic or heteroaromatic group is further substituted with a substituent selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
5. The compound of claim 3 , wherein the aromatic or heteroaromatic group is further substituted with a substituent selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
6. The compound of claim 1 , having the general formula of formula I:
wherein R1 is selected from the group consisting of: H, OH and NH 2 and substituted-N wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
7. The compound of claim 1 , having the general formula of formula II:
wherein R1 is selected from the group consisting of: H, OH and NH 2 and substituted-N wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
8. The compound of claim 1 , wherein said compound is 5-(4-Hydroxy-3-methoxy-phenyl)-3-oxo-pent-4-enoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide.
9. The compound of claim 1 , wherein said compound is 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-5-methoxy-1H-indole-3-yl)-ethyl]-amide.
10. The compound of claim 1 , wherein said compound is 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-5-methoxy-1H-indole-3-yl)-ethyl]-amide.
11. A composition, comprising:
a compound having the general formula:
wherein
R is a substituted or unsubstituted aromatic or heteroaromatic group;
R2 is selected from the group consisting of H, OH, NH 2 , NO 2 and C 1 -C 8 alkoxyl;
R3 is selected from the group consisting of H and C 1 -C 4 alkyl;
X is S or O or NH or substituted-N, wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, isopropyl, tert-butyl, and a saturated or unsaturated monocyclic ring with ring size ranging from 3-7, which is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano; and
Y is selected from the group consisting of C 1 -C 4 alkyl with the proviso that if there is a double bond adjacent to the R group, then R is not a phenyl ring substituted by OCH3; and
a carrier, said compound being dissolved or distributed in said carrier.
12. The composition of claim 11 , wherein said substituted aromatic or heteroaromatic group is substituted with a hydroxyl or a substituted or unsubstituted amino group.
13. The composition of claim 11 , wherein said substituted or unsubstituted aromatic or heteroaromatic group is a substituted or unsubstituted heteroaromatic group which includes an oxygen or a nitrogen as a heteroatom.
14. The composition of claim 12 , wherein the substituted or unsubstituted aromatic or heteroaromatic group is further substituted with a substituent selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
15. The composition of claim 13 , wherein the aromatic or heteroaromatic group is further substituted with a substituent selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
16. The composition of claim 11 , having the general formula of formula I:
wherein R1 is selected from the group consisting of: H, OH and NH 2 and substituted-N wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
17. The composition of claim 11 , having the general formula of formula II:
wherein R1 is selected from the group consisting of: H, OH and NH 2 and substituted-N wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, wherein the phenyl is optionally substituted with one or more substituents at positions 2, 3, 5, and 6 selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano.
18. The composition of claim 11 , wherein said compound is 5-(4-Hydroxy-3-methoxy-phenyl)-3-oxo-pent-4-enoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide.
19. The composition of claim 11 , wherein said compound is 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-5-methoxy-1H-indole-3-yl)-ethyl]-amide.
20. The composition of claim 11 , wherein said compound is 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-5-methoxy-1H-indole-3-yl)-ethyl]-amide.
21. The composition of claim 11 , wherein said carrier is a solid.
22. The composition of claim 11 , wherein said carrier is a liquid.
23. The composition of claim 11 , wherein said carrier is an aqueous liquid.
24. A method of treating or slowing the progression of symptoms of a neurodegenerative disorder in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of at least one of a compound having the general formula:
wherein
R is an aromatic or heteroaromatic group;
R2 is selected from the group consisting of H, OH, NH 2 , NO 2 and C 1 -C 8 alkoxyl;
R3 is selected from the group consisting of H and C 1 -C 4 alkyl;
X is S or O or NH or substituted-N, wherein the substituent is selected from the group consisting of C 1 -C 8 alkyl, isopropyl, tert-butyl, and a saturated or unsaturated monocyclic ring with ring size ranging from 3-7 which is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano; and
Y is selected from the group consisting of C 1 -C 4 alkyl with the proviso that if there is a double bond adjacent to the R group, then R is not a phenyl ring substituted by OCH3.
25. The method of claim 24 , wherein said neurodegenerative disorder is Alzheimer's disease.
26. The method of claim 24 , wherein said compound is compound 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide represented by Formula (III):
27. The method of claim 24 , wherein said compound is 5-(4-hydroxy-phenyl)-3-oxo-pent-4-enoic acid [2-95-methoxy-1H-indole-3-yl)-ethyl]-amide represented by Formula (IV):
28. The compound of claim 1 , wherein the unsaturated monocyclic ring is an unsubstituted or substituted phenyl ring.
29. The composition of claim 11 , wherein the unsaturated monocyclic ring is an unsubstituted or substituted phenyl ring.
30. The method of claim 24 , wherein the unsaturated monocyclic ring is an unsubstituted or substituted phenyl ring.