Direct AMPK activator compounds

1. A method for activation of AMPK to treat, and/or reduce a severity of non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, the method comprising administering to the subject a compound having the general formula I,

wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OMe; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; an optionally substituted and/or optionally branched C 1 to C 20 alkyl; an optionally substituted and/or optionally branched, C 2 to C 20 alkenyl; an optionally substituted and/or optionally branched, C 4 to C 20 polyalkenyl; an optionally substituted and/or optionally branched C 2 to C 20 alkynyl, or an optionally substituted and/or optionally branched C 4 to C 20 polyalkynyl, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

2. The method according to claim 1 , wherein R1, R2, R3, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OMe; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; an optionally substituted and/or optionally branched C 1 to C 20 alkyl; an optionally substituted and/or optionally branched, C 2 to C 20 alkenyl; an optionally substituted and/or optionally branched, C 4 to C 20 polyalkenyl; an optionally substituted and/or optionally branched C 2 to C 20 alkynyl, or an optionally substituted and/or optionally branched C 4 to C 20 polyalkynyl; R4 and R5 are each independently H; OH; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; an optionally substituted and/or optionally branched C 1 to C 20 alkyl; an optionally substituted and/or optionally branched, C 2 to C 20 alkenyl; an optionally substituted and/or optionally branched, C 4 to C 20 polyalkenyl; an optionally substituted and/or optionally branched C 2 to C 20 alkynyl, or an optionally substituted and/or optionally branched C 4 to C 20 polyalkynyl, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

3. The method according to claim 1 , wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OMe; O-glycoside; a halogen; an aldehyde; a carboxylic acid; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; an optionally substituted and/or optionally branched C 1 to C 20 alkyl; an optionally substituted and/or optionally branched, C 2 to C 20 alkenyl; an optionally substituted and/or optionally branched, C 4 to C 20 polyalkenyl; an optionally substituted and/or optionally branched C 2 to C 20 alkynyl, or an optionally substituted and/or optionally branched C 4 to C 2 polyalkynyl, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

4. The method according to claim 1 , wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H; Me; OH; OMe; OCH 2 CH═CH 2 ; O-glycoside; a sulfate; a halogen; CHO; CH 2 OH; COOH, CONH 2 , COCH 3 ; CH═CH 2 ; CH 2 —CH═C(CH 3 ) 2 ; CH(CH 3 ) 2 ; CH═CH—CHO; CH(CH 3 )—OH; CH(CH 3 )—OMe; CH(CH 3 )—OC 2 H 5 ; CH(CH 3 )—O—CH 2 —CH═C(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 ) 2 ; 4-hydroxybenzyl; 4-hydroxy-3-methoxybenzyl; 4-hydroxybenzoyl; 4-hydroxybenzoyl glycoside, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

5. The method having the general formula I according to claim wherein R1, R2, R3, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OMe; O-glycoside; a halogen; an aldehyde; a carboxylic acid; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; an optionally substituted and/or optionally branched C 1 to C 20 alkyl; an optionally substituted and/or optionally branched, C 2 to C 20 alkenyl; an optionally substituted and/or optionally branched, C 4 to C 20 polyalkenyl; an optionally substituted and/or optionally branched C 2 to C 2 alkynyl, or an optionally substituted and/or optionally branched C 4 to C 20 polyalkynyl; R4 and R5 are each independently H; OH; O-glycoside; a halogen; an aldehyde; a carboxylic acid; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; an optionally substituted and/or optionally branched C 1 to C 20 alkyl; an optionally substituted and/or optionally branched, C 2 to C 20 alkenyl; an optionally substituted and/or optionally branched, C 4 to C 20 polyalkenyl; an optionally substituted and/or optionally branched C 2 to C 20 alkynyl, or an optionally substituted and/or optionally branched C 4 to C 20 polyalkynyl, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

6. The method according to claim 1 , wherein R1, R2, R3, R6, R7, and R8 are each independently selected from the group consisting of H; Me; OH; OMe; OCH 2 CH═CH 2 ; O-glycoside; a sulfate; a halogen; CHO; CH 2 OH; COOH, CONH 2 , COCH 3 ; CH═CH 2 ; CH 2 —CH═C(CH 3 ) 2 ; CH(CH 3 ) 2 ; CH═CH—CHO; CH(CH 3 )—OH; CH(CH 3 )—OMe; CH(CH 3 )—OC 2 H 5 ; CH(CH 3 )—O—CH 2 —CH═C(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 ) 2 ; 4-hydroxybenzyl; 4-hydroxy-3-methoxybenzyl; 4-hydroxybenzoyl; 4-(addedhydroxybenzoyl glycoside; R4 and R5 are each independently H; Me; OH; OCH 2 CH═CH 2 ; O-glycoside; a sulfate; a halogen; CHO; CH 2 OH; COOH, CONH 2 , COCH 3 ; CH═CH 2 ; CH 2 —CH═C(CH 3 ) 2 ; CH(CH 3 ) 2 ; CH═CH—CHO; CH(CH 3 )—OH; CH(CH 3 )—OMe; CH(CH 3 )—OC 2 H 5 ; CH(CH 3 )—O—CH 2 —CH═C(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 ) 2 ; 4-hydroxybenzyl; 4-hydroxy-3-methoxybenzyl; 4-hydroxybenzoyl; 4-hydroxybenzoyl glycoside, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

7. The method according to claim 1 , wherein R1, R2, R3, R6, R7, and R8 are each independently selected from the group consisting of H; Me; OH; OMe; OCH 2 CH═CH 2 ; O-glycoside; a sulfate; Br; CHO; CH 2 OH; COOH, CONH 2 , COCH 3 ; CH═CH 2 ; CH 2 —CH═C(CH 3 ) 2 ; CH(CH 3 ) 2 ; CH═CH—CHO; CH(CH 3 )—OH; CH(CH 3 )—OCH 3 ; CH(CH 3 )—OC 2 H 5 ; CH(CH 3 )—O—CH 2 —CH═C(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 ) 2 ; 4-hydroxybenzyl; 4-hydroxy-3-methoxybenzyl; 4-hydroxybenzoyl; 4-hydroxybenzoyl glycoside; R4 and R5 are each independently H; Me; OH; OCH 2 CH═CH 2 ; O-glycoside; a sulfate; Br; CHO; CH 2 OH; COOH, CONH 2 , COCH 3 ; CH═CH 2 ; CH 2 —CH═C(CH 3 ) 2 ; CH(CH 3 ) 2 ; CH═CH—CHO; CH(CH 3 )—OH; CH(CH 3 )—OCH 3 ; CH(CH 3 )—OC 2 H 5 ; CH(CH 3 )—O—CH 2 —CH═C(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 )—(CH 2 ) 3 —CH(CH 3 ) 2 ; 4-hydroxybenzyl; 4-hydroxy-3-methoxybenzyl; 4-hydroxybenzoyl; 4-hydroxybenzoyl glycoside, and/or optionally a OCH 3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

8. The method according to claim 1 , wherein said compound is selected from the group consisting of:

(i) Lusianthridin known as 7-Methoxy-9,10-dihydrophenanthrene-2,5-diol;

(ii) 7-Methoxy-9,10-dihydrophenanthrene-2,3,5-triol;

(iii) 2,5-Phenanthrenediol, 9,10-dihydro, 9,10-Dihydrophenanthrene-2,5-diol;

(iv) 9,10-Dihydrophenanthrene-2,4,7-triol, 9,10-Dihydro-2,4,7-phenanthrenetriol, 2,4,7-Trihydroxy-9,10-dihydrophenanthrene, 2,4,7-Phenanthrenetriol, 9,10-dihydro; and

(v) Cannithrene 1, Cannabidihydrophenanthrene, 9,10-Dihydro-7-methoxy-3,5-phenanthrenediol, 3,5-Phenanthrenediol, 9,10-dihydro-7-methoxy, 7-Methoxy-9,10-dihydrophenanthrene-3,5-diol.

9. The method according to claim 1 , wherein the subject is a human or a companion animal.

10. The method according to claim 9 , wherein the subject is a human.

11. The method according to claim 9 , wherein the activation of the AMPK further improves a condition, disorder, or disease selected from the group consisting of cardiometabolic health, obesity, type 2 diabetes, cardiovascular disease, and cancer.

12. The method according to claim 1 , wherein the activation of the AMPK is a direct activation mechanism.

13. The method according to claim 1 , wherein the activation of the AMPK occurs in muscle and/or liver tissues.

14. The method according to claim 1 , wherein the AMPK comprises an α2 subunit, a β1 subunit, and a γ1 subunit.

15. The method according to claim 1 , wherein the compound is obtained from a plant or plant extract.

16. A method according to claim 1 , wherein the compound of formula I is administered as a medicament.

17. The method according to claim 1 , wherein the compound is administered in a composition selected from the group consisting of a food, a beverage, and a dietary supplement.

18. A method according to claim 16 , wherein the compound of general formula I is selected from the group consisting of:

(i) Lusianthridin known as 7-Methoxy-9, 10-dihydrophenanthrene-2,5-diol;

(ii) 7-Methoxy-9,10-dihydrophenanthrene-2,3,5-triol;

(iii) 2,5-Phenanthrenediol, 9,10-dihydro, 9,10-Dihydrophenanthrene-2,5-diol;

(iv) 9,10-Dihydrophenanthrene-2,4,7-triol, 9,10-Dihydro-2,4,7-phenanthrenetriol, 2,4,7-Trihydroxy-9,10-dihydrophenanthrene, 2,4,7-Phenanthrenetriol, 9,10-dihydro;

(v) Cannithrene 1, Cannabidihydrophenanthrene, 9,10-Dihydro-7-methoxy-3,5-phenanthrenediol, 3,5-Phenanthrenediol, 9,10-dihydro-7-methoxy, 7-Methoxy-9,10-dihydrophenanthrene-3,5-diol.