INTRODUCTION

AMP-activated protein kinase (AMPK) is an evolutionarily conserved master regulator of energy homeostasis that coordinates metabolic pathways in order to balance nutrient supply with energy demand. AMPK is considered a key drug target to combat the growing epidemic of metabolic disorders such as obesity, type 2 diabetes, cardiovascular disease.

AMPK activity is found in all tissues, including muscle, kidney, liver, lung, and brain (PMID: 10698692). In terms of structure, AMPK is a heterotrimeric complex consisting of a catalytic subunit (a) and two regulatory subunits (P and y). The AMPK complex is evolutionarily conserved and also can be found in yeast and plants. Mammalian AMPK is composed of different isoforms of subunits: al, a2, 1, P2, yl, y2, and y3 (PMID: 11746230) leading to 12 possible heterotrimeric combinations. The a2 isoform is predominately found in skeletal and cardiac muscle AMPK; both the al and a2 isoforms are found in hepatic AMPK; while for example in adipose and T cells the al isoform AMPK predominates (PMID: 16818670, PMID 15878856).

There is no direct AMPK-activating drug available to treat metabolic disorders despite intensive efforts continuously made by the pharmaceutical industry. Several synthetic AMPK activators have been identified/developed. However, they either have no/poor oral availability (PMID: 16753576, PMID: 24900234) or there are concerns about their off-target, adverse effects, since chronic and strong AMPK activation may cause increases in cardiac glycogen content and hypertrophy (PMID: 11827995).

Finding natural bioactive molecules that moderately activate AMPK especially in muscle, liver and kidney with defined mechanism of action are likely to provide exercise-mimetic effects and help maintain/improve metabolic health. There are numerous natural compounds/extracts known to bring about some metabolic health benefits that are shown to indirectly stimulate AMPK most likely through inhibition of mitochondrial respiration. However, whether those metabolic effects are mediated by AMPK is largely elusive, and moreover there are concerns regarding side/toxic effects such as cellular or mitochondrial poisoning.

There is a clear unmet need for new natural compounds which directly activate AMPK.

SUMMARY OF INVENTION

Numerous studies have demonstrated that a wide range of different natural compounds activate AMPK. However, typically, natural compounds do not activate AMPK by directly binding to the enzyme, but instead indirectly activate AMPK by causing perturbations in mitochondrial respiration. This leads to a decrease in ATP levels of the cell and activation of AMPK through AMP/ADP binding to the nucleotide-binding site of the AMPK y subunit.

In contrast, in the present invention, we have identified natural compounds that bind directly to AMPK through the allosteric drug and metabolite (ADaM) site formed at the interface between the AMPK a and AMPK p subunits. These compounds are from the class of substituted resorcyclic acids and directly activate AMPK in cells.

The invention relates to a compound having the general formula (I), In several embodiments, the invention relates to the compound of general formula (I) wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is OH; OCH3; O-glycoside; C-gly coside; acylated O-glycoside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; O-acyl; a halogen; a primary, secondary, or tertiary alcohol; a ketone; 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 Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl; an optionally substituted and/or optionally branched C2 to C20 alkynyl, or an optionally substituted and/or optionally branched C4 to C20 polyalkynyl,

R4 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; O-acyl; a halogen; a primary, secondary, or tertiary alcohol; a ketone; 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 Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl; an optionally substituted and/or optionally branched C2 to C20 alkynyl, or an optionally substituted and/or optionally branched C4 to C20 polyalkynyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O- glycoside; sulfated O-glycoside; a sulfate;

R2 is H, OH; OCH3; O-glycoside; C-gly coside; acylated O-glycoside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; O-acyl; a halogen; a primary, secondary, or tertiary alcohol; a ketone; 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 Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl; an optionally substituted and/or optionally branched C2 to C20 alkynyl, or an optionally substituted and/or optionally branched C4 to C20 polyalkynyl,

R4 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; O-acyl; a halogen; a primary, secondary, or tertiary alcohol; a ketone; 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 Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl; an optionally substituted and/or optionally branched C2 to C20 alkynyl, or an optionally substituted and/or optionally branched C4 to C20 polyalkynyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O- glycoside; sulfated O-glycoside; a sulfate;

R2 is OH; OCH3; O-glycoside; C-gly coside; acylated O-glycoside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; O-acyl; a halogen; a primary, secondary, or tertiary alcohol; a ketone; 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 Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl; an optionally substituted and/or optionally branched C2 to C20 alkynyl, or an optionally substituted and/or optionally branched C4 to C20 polyalkynyl,

R4 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; O-acyl; a halogen; a primary, secondary, or tertiary alcohol; a ketone; 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 Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl; an optionally substituted and/or optionally branched C2 to C20 alkynyl, or an optionally substituted and/or optionally branched C4 to C20 polyalkynyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-glycoside; acylated O- glycoside; sulfated O-glycoside; a sulfate;

R2 is an optionally substituted and/or optionally branched Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

R4 is H; an optionally substituted and/or optionally branched Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate; R2 is H; an optionally substituted and/or optionally branched Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

R4 is an optionally substituted and/or optionally branched Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is an optionally substituted and/or optionally branched Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof, for use in the activation of AMPK. In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

R4 is an optionally substituted and/or optionally branched Cl to C25 alkyl; an optionally substituted and/or optionally branched, C2 to C20 alkenyl; an optionally substituted and/or optionally branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiment, the invention relates to a compound having the general formula (I), wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O- glycoside; sulfated O-glycoside; a sulfate;

R2 is OH; OCH3; O-glycoside; C-gly coside; acylated O-glycoside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3- dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l- yl (Ij), 4-hydroxy-3-methyl-2-buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3- hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3- methyl-3-buten-l-yl (lo), 3-methyl-l,3-butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7- dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl- octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-5-methyl-2-(l-methylethenyl)hexyl (2f), 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 5-methyl-2-(l-methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2- en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l- yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- l-en-2-yl)cy cl opentyl (2s), 5-methyl-2-(prop-l- en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11- Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l- yl (farnesyl) (3b), 7 -hydroxy-3, 7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2- methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl- decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3- methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 - en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1, 2, 2-trimethylcy cl opentyl (5a), hydroxymethyl (6a), 2 -hydroxy ethyl (6b), 6- hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16- hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2- (acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12- hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro- 6-methyl-2H-pyran-2-yl)methyl (7a), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3-oxopentyl (8c), 2-oxopentyl (8d), 4-methyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan- 2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1-propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10- heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), 1- hydroxymethylene-2-oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8, 11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6-methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H- pyran-2-yl)methyl (14d);

R4 is H, OH; OCH3; O-gly coside; C-gly coside; acylated O-gly coside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3- dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l- yl (Ij), 4-hydroxy-3-methyl-2-buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3- hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l -en-l-yl (In), 2-hydroxy-3- methyl-3-buten-l-yl (lo), 3-methyl-l,3-butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7- dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl- octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-5-methyl-2-(l-methylethenyl)hexyl (2f), 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 5-methyl-2-(l-methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2- en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l- yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- l-en-2-yl)cy cl opentyl (2s), 5-methyl-2-(prop-l- en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11- Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l- yl (farnesyl) (3b), 7 -hydroxy-3, 7,1 l-trimethyl-2,10-dodecadi en-l-yl (3c), 3-methyl-6-[5-(2- methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl- decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3- methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 - en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2-trimethylcyclopentyl (5a), hydroxymethyl (6a), 2 -hydroxy ethyl (6b), 6- hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16- hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2- (acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12- hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro- 6-methyl-2H-pyran-2-yl)methyl (7a), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3-oxopentyl (8c), 2-oxopentyl (8d), 4-methyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan- 2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1-propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10- heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), 1- hydroxymethylene-2-oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8, 11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6-methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H- pyran-2-yl)methyl (14d); or a derivative or analogue thereof, for use in the activation of AMPK. In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the present invention relates to a compound having the general formula (I),

wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O- glycoside; sulfated O-glycoside; a sulfate;

R2 is H, OH; OCH3; O-glycoside; C-gly coside; acylated O-glycoside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3- dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l- yl (Ij), 4-hydroxy-3-methyl-2-buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3- hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3- methyl-3-buten-l-yl (lo), 3-methyl-l,3-butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7- dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl- octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-5-methyl-2-(l-methylethenyl)hexyl (2f), 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 5-methyl-2-(l-methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2- en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l- yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- l-en-2-yl)cy cl opentyl (2s), 5-methyl-2-(prop-l- en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11- Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l- yl (farnesyl) (3b), 7 -hydroxy-3, 7,1 l-trimethyl-2,10-dodecadi en-l-yl (3c), 3-methyl-6-[5-(2- methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl- decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3- methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 - en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1, 2, 2-trimethylcy cl opentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6- hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16- hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2- (acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12- hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro- 6-methyl-2H-pyran-2-yl)methyl (7a), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3-oxopentyl (8c), 2-oxopentyl (8d), 4-methyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan- 2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1-propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10- heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), 1- hydroxymethylene-2-oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8, 11 -di en-l-yl (13a), pentadeca-8,l l,14-tri en-l-yl (13b), 8, 11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadi en-l-yl (14b), 4,6-dihydroxy-6-methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H- pyran-2-yl)methyl (14d);

R4 is OH; OCH3; O-gly coside; C-gly coside; acylated O-gly coside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3- dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l- yl (Ij), 4-hydroxy-3-methyl-2-buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3- hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3- methyl-3-buten-l-yl (lo), 3-methyl-l,3-butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7- dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl- octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-5-methyl-2-(l-methylethenyl)hexyl (2f), 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 5-methyl-2-(l-methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2- en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l- yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- l-en-2-yl)cy cl opentyl (2s), 5-methyl-2-(prop-l- en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11- Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l- yl (farnesyl) (3b), 7 -hydroxy-3, 7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2- methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl- decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3- methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 - en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1, 2, 2-trimethylcy cl opentyl (5a), hydroxymethyl (6a), 2 -hydroxy ethyl (6b), 6- hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16- hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2- (acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)-12- hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro- 6-methyl-2H-pyran-2-yl)methyl (7a), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3-oxopentyl (8c), 2-oxopentyl (8d), 4-methyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan- 2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1-propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10- heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), 1- hydroxymethylene-2-oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8, 11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6-methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H- pyran-2-yl)methyl (14d); or a derivative or analogue thereof, for use in the activation of AMPK. In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the present invention relates to a compound having the general formula (I), wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O- glycoside; sulfated O-glycoside; a sulfate;

R2 is OH; OCH3; O-glycoside; C-gly coside; acylated O-glycoside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3- dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l- yl (Ij), 4-hydroxy-3-methyl-2-buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3- hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3- methyl-3-buten-l-yl (lo), 3-methyl-l,3-butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7- dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl- octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-5-methyl-2-(l-methylethenyl)hexyl (2f), 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 5-methyl-2-(l-methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2- en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l- yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- l-en-2-yl)cy cl opentyl (2s), 5-methyl-2-(prop-l- en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11- Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l- yl (farnesyl) (3b), 7 -hydroxy-3, 7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2- methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl- decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3- methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 - en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2-trimethylcyclopentyl (5a), hydroxymethyl (6a), 2 -hydroxy ethyl (6b), 6- hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16- hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2- (acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12- hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro- 6-methyl-2H-pyran-2-yl)methyl (7a), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3-oxopentyl (8c), 2-oxopentyl (8d), 4-methyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan- 2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1-propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10- heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), 1- hydroxymethylene-2-oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8, 11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6-methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H- pyran-2-yl)methyl (14d);

R4 is OH; OCH3; O-gly coside; C-gly coside; acylated O-gly coside; acylated C-gly coside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; a C5 isoprenoid chain among the following representatives: 3 -Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3- dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l- yl (Ij), 4-hydroxy-3-methyl-2-buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3- hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l -en-l-yl (In), 2-hydroxy-3- methyl-3-buten-l-yl (lo), 3-methyl-l,3-butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7- dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl- octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-5-methyl-2-(l-methylethenyl)hexyl (2f), 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 5-methyl-2-(l-methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2- en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l- yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- l-en-2-yl)cy cl opentyl (2s), 5-methyl-2-(prop-l- en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11- Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l- yl (farnesyl) (3b), 7 -hydroxy-3, 7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2- methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl- decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3- methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 - en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1, 2, 2-trimethylcy cl opentyl (5a), hydroxymethyl (6a), 2 -hydroxy ethyl (6b), 6- hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16- hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2- (acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12- hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro- 6-methyl-2H-pyran-2-yl)methyl (7a), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3-oxopentyl (8c), 2-oxopentyl (8d), 4-methyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan- 2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1-propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10- heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), 1- hydroxymethylene-2-oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8, 11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6-methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H- pyran-2-yl)methyl (14d); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen-l-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im), 4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7- Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct- 6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4- methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2- (l-methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i),

5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l- yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l- yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f),

6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohe x-2-en-l-yl (3g), 3,7,11- trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3, 7,11,15- tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2- trimethylcyclopentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6-hydroxyheptyl (6c), 8- hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10- m ethoxyundecyl (6k), 12-m ethoxytridecyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a), 1,2- di oxopropyl (8a), 1 -oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1- oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14- oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13-hydroxy-2- oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l- yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), l-hydroxymethylene-2- oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6-methyl-3- oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d);

R4 is H; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen-l-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im),

4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7- Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct- 6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4- methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2- (l-methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i),

5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l- yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l- yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f),

6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohe x-2-en-l-yl (3g), 3,7,11- trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3, 7,11,15- tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2- trimethylcyclopentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6-hydroxyheptyl (6c), 8- hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10- m ethoxyundecyl (6k), 12-m ethoxytridecyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13-hydroxytridecyl (6n), 2-(acetyloxy)-12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a), 1,2- di oxopropyl (8a), 1 -oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1- oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14- oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13-hydroxy-2- oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l- yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), l-hydroxymethylene-2- oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadi en-l-yl (14b), 4,6-dihydroxy-6-methyl-3- oxo- 1,4-cy cl ohexadi en-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is H; a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen-l-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im),

4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7- Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct- 6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4- methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2- (l-methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i),

5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l- yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l- yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f),

6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohe x-2-en-l-yl (3g), 3,7,11- trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3, 7,11,15- tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2- trimethylcyclopentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6-hydroxyheptyl (6c), 8- hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10- m ethoxyundecyl (6k), 12-methoxytridecyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)-12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a), 1,2- di oxopropyl (8a), 1 -oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1- oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14- oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13-hydroxy-2- oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l- yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), l-hydroxymethylene-2- oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadi en-l-yl (14b), 4,6-dihydroxy-6-methyl-3- oxo- 1,4-cy cl ohexadi en-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d);

R4 is a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen-l-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im),

4-hydroxy-3-methylbut-l -en-l-yl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7- Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct- 6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4- methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2- (l-methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i),

5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l- yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l- yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 -en-l-yl (3g), 3,7,11- trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3, 7,11,15- tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2- trimethylcyclopentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6-hydroxyheptyl (6c), 8- hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10- m ethoxyundecyl (6k), 12-m ethoxytridecyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a), 1,2- di oxopropyl (8a), 1 -oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1- oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14- oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13-hydroxy-2- oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l- yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), l-hydroxymethylene-2- oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadi en-l-yl (14b), 4,6-dihydroxy-6-methyl-3- oxo- 1,4-cy cl ohexadi en-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge. In several embodiments, the invention relates to a compound having the general formula (I), wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen-l-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im),

4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7- Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct- 6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4- methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2- (l-methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i),

5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l- yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l- yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2 -en-l-yl (3g), 3,7,11- trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3, 7,11,15- tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2- trimethylcyclopentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6-hydroxyheptyl (6c), 8- hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10- m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a), 1,2- di oxopropyl (8a), 1 -oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1- oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14- oxopentadecyl (8i), 2-oxotridecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2- oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l- yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), l-hydroxymethylene-2- oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadi en-l-yl (14b), 4,6-dihydroxy-6-methyl-3- oxo- 1,4-cy cl ohexadi en-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d);

R4 is a C5 isoprenoid chain among the following representatives: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im),

4-hydroxy-3-methylbut-l-en-l-yl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip); a CIO isoprenoid chain among the following representatives: 3,7- Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct- 6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4- methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2- (l-methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i),

5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o) ), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l- yl)-3-furanyl]-2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l- yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f),

6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3-methylcyclohe x-2-en-l-yl (3g), 3,7,11- trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a C20 isoprenoid chain among the following representatives: 3,7, 11, 15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3, 7,11,15- tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b); a Cl to C25 linear or branched alkyl chain; a (cyclo) alkyl chain among the following representatives: 1,2,2- trimethylcyclopentyl (5a), hydroxymethyl (6a), 2-hydroxyethyl (6b), 6-hydroxyheptyl (6c), 8- hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14-hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10- m ethoxyundecyl (6k), 12-m ethoxy tri decyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2-(acetyloxy)- 12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a), 1,2- di oxopropyl (8a), 1 -oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1- oxopentyl (8e), 2-oxoheptyl (8f), 6-methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14- oxopentadecyl (81), 2-oxotndecyl (8j), 1 -hydroxy -2-oxopropyl (9a), 13 -hydroxy -2- oxotridecyl (9b); a (substituted) alkenyl chain among the following representatives: Ethenyl (10a), 1-propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l- yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi), 10-(acetyloxy)-8-pentadecenyl (I la), l-hydroxymethylene-2- oxopropyl (12a); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadi en-l-yl (14b), 4,6-dihydroxy-6-methyl-3- oxo- 1,4-cy cl ohexadi en-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In a preferred embodiment, the substituents below are strictly restricted to known natural structures.

In several embodiments, the invention relates to a compound having the general formula (I), wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate; R2 is a C5 isoprenoid chain among the following representatives: 3 -Hydroxy-3 -methylbutyl (1c), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), 3 -methyl- 1-buten-l-yl (Ij), 2-hydroxy-3- methyl-3-buten-l-yl (lo); a CIO isoprenoid chain among the following representatives: [3- Methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy- 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2- en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- 1- en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: (2E,6E)-3,7,l l-Trimethyl-2,6,10-dodecatrien-l-yl (famesyl) (3b), 3-methyl-6-[5-(2-methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l- yl (3d) , (2- hydroxy-2, 5, 5, 8a-tetramethyl-decahydronaphthalen- 1 -yl)methyl (3 e), 5-[2,2-dimethyl-3 - (prop-l-en-2-yl)cyclobutyl]-3-methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-m ethylhepta- 1,6- dien-2-yl)-3-methylcyclohex-2-en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a Cl to Cl 1 linear or branched alkyl chain; a substituted alkyl chain among the following representatives: 2-hydroxyethyl (6b), 1-oxopentyl (8b), 4-methyl-l -oxopentyl (8e), 6-methyl-5-oxoheptan-2-yl (8g);

R4 is H; a Cl to C25 linear or branched alkyl chain; a substituted cycloalkyl chain among the following representatives: 1,2,2-trimethylcyclopentyl (5a); a (substituted) alkenyl chain among the following representatives: 1 -Methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), nonadec- 14-en-l-yl (lOi); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8, 11-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I),

wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is a H; C5 isoprenoid chain among the following representatives: 3-Hydroxy-3- methylbutyl (1c), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 - methylbutyl (If), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), 3 -methyl- 1-buten-l-yl (Ij), 2-hydroxy-3-methyl-3-buten-l-yl (lo); a CIO isoprenoid chain among the following representatives: [3-Methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3- epoxide) (2e), 5-hydroxy-3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7- dihydroxy-3,7-dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3- acetyl-2 -hydroxy-5 -(prop- 1-en -2 -yl)cy cl opentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: (2E,6E)-3,7,11-Trimethyl-

2.6.10-dodecatrien-l-yl (famesyl) (3b), 3-methyl-6-[5-(2-methyl-l-propen-l-yl)-3-furanyl]- 2-hexen-l-yl (3d) , (2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-l-yl)met hyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2-yl)cyclobutyl]-3-methylpent-2 -en-l-yl (3f), 6-(5-hydroxy-6- methylhepta-l,6-dien-2-yl)-3-methylcyclohex-2-en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-

2.6.10-trien-l-yl (3h); a Cl to Cl l linear or branched alkyl chain; a substituted alkyl chain among the following representatives: 2-hydroxyethyl (6b), 1-oxopentyl (8b), 4-methyl-l- oxopentyl (8e), 6-methyl-5-oxoheptan-2-yl (8g); R4 is a Cl to C25 linear or branched alkyl chain; a substituted cycloalkyl chain among the following representatives: 1,2,2-trimethylcyclopentyl (5a); a (substituted) alkenyl chain among the following representatives: 1 -Methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), nonadec- 14-en-l-yl (lOi); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8, 11-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In several embodiments, the invention relates to a compound having the general formula (I), wherein

R1 and R3 are each independently OH; OCH3; O-acyl, O-gly coside; acylated O-gly coside; sulfated O-glycoside; a sulfate;

R2 is a C5 isoprenoid chain among the following representatives: 3 -Hydroxy-3 -methylbutyl (1c), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), 3 -methyl- 1-buten-l-yl (Ij), 2-hydroxy-3- methyl-3-buten-l-yl (lo); a CIO isoprenoid chain among the following representatives: [3- Methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy- 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7-dimethyloct-2- en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3 -acetyl-2 -hydroxy-5 -(prop- 1- en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t); a C15 isoprenoid chain among the following representatives: (2E,6E)-3,7,1 l-Trimethyl-2,6,10-dodecatrien-l-yl (famesyl) (3b), 3-methyl-6-[5-(2-methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l- yl (3d) , (2- hydroxy-2, 5, 5, 8a-tetramethyl-decahydronaphthalen- 1 -yl)methyl (3 e), 5-[2,2-dimethyl-3 - (prop-l-en-2-yl)cyclobutyl]-3-methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-m ethylhepta- 1,6- dien-2-yl)-3-methylcyclohex-2-en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h); a Cl to Cl 1 linear or branched alkyl chain; a substituted alkyl chain among the following representatives: 2-hydroxyethyl (6b), 1-oxopentyl (8b), 4-methyl-l -oxopentyl (8e), 6-methyl-5-oxoheptan-2-yl (8g);

R4 is a Cl to C25 linear or branched alkyl chain; a substituted cycloalkyl chain among the following representatives: 1,2,2-trimethylcyclopentyl (5a); a (substituted) alkenyl chain among the following representatives: 1 -Methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8-heptadecen-l-yl (10g), nonadec- 14-en-l-yl (lOi); or a (substituted) polyalkenyl chain among the following representatives: Pentadeca-8, 11 -di en-l-yl (13a), pentadeca-8,l l,14-tri en-l-yl (13b); or a derivative or analogue thereof, for use in the activation of AMPK.

In some embodiments, a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge.

In one preferred embodiment, said compound of formula (I) is compound 1, CAS number 13956-29-1 Cannabidiol.

Other names:

• 1,3 -Benzenediol, 2-[(lR,6R)-3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5 - pentyl-

• 1,3 -Benzenediol, 2-[3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5-pentyl- , (1R- trans)-

• Resorcinol, 2-p-mentha-l,8-dien-3-yl-5-pentyl-, trans-(-)-

• 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5 -pentyl-l,3- benzenediol

• (-)-CBD

• (-)-Cannabidiol

• (-)-trans-Cannabidiol • CBD

• Epi diol ex

• Epidyolex

• Al(2)-trans-Cannabidiol

Definitions

General chemistry terminology

The descriptions of simple chains like methyl, pentyl, dodecyl and others are self- explanatory.

For the avoidance of doubt, more complex chains have been drawn and a number attributed as a quick reference.

In all structures, the dot represents the point of insertion of the chain on the aromatic ring.

For example, if in Markush structure A, R2 is 3-methyl-2-buten-l-yl (Ih), this corresponds to structure B: The term C5 isoprenoid unit refers to the following substituents: 3-Methylbutyl (la), 4- hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2 -hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3- methyl-2-oxobutyl (1g), 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2- propen-l-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 4-hydroxy-3-methyl-2- buten-l-yl (Ik), 1 -hydroxy-3 -methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im), 3 -hydroxy-3 -methyl- 1-butenyl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 3-methyl-l,3- butadienyl (Ip).

The term CIO isoprenoid unit refers to the following substituents: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-l-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3- penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(l- methylethenyl)hexyl (2f), 3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7- dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen-l-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6- octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5- octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(l- methylethyl)cyclohexyl (2o), 7-hydroxy-3,7-dimethyloct-2-en-l-yl (2p), 6,7-dihydroxy-3,7- dimethyloct-2-en-l-yl (2q), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r), 3-acetyl-2- hydroxy-5-(prop-l-en-2-yl)cyclopentyl (2s), 5-methyl-2-(prop-l-en-2-yl)cyclohexyl (2t).

The term C15 isoprenoid unit refers to the following substituents: 3,7,11 -Trimethyldodecyl (hexahydrofamesyl) (3a), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (farnesyl) (3b), 7- hydroxy-3,7,1 l-trimethyl-2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methylprop-l-en-l-yl)furan-3-yl]hex-2-en-l- yl (3d), (2 -hydroxy -2, 5, 5, 8a- tetramethyl-decahydronaphthalen-l-yl)methyl (3e), 5-[2,2-dimethyl-3-(prop-l-en-2- yl)cyclobutyl]-3-methylpent-2-en-l-yl (3f), 6-(5-hydroxy-6-methylhepta-l,6-dien-2-yl)-3- methylcyclohex-2-en-l-yl (3g), 3,7,1 l-trimethyl-9-oxododeca-2,6,10-trien-l-yl (3h). C20 isoprenoid unit refers to the following substituents: 3,7,11,15 -Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b).

The term "alkyl" refers to a branched or unbranched saturated hydrocarbon chain having from 1 to 25 carbon atoms, or from 1 to 20 carbon atoms, or from 1 to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 7 carbon atoms, or from 1 to 5 carbon atoms, or from 1 to 3 carbon atoms. The alkyl chain may be cyclic, in which case it would be known as “cycloalkyl” group.

Non-limiting examples of branched or unbranched alkyl chains include: methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, pentyl, hexyl, heptyl, iso-hexyl, nonyl, decyl, undecyl, 9-m ethyldecyl, tetradecyl, pentadecyl, heptadecyl, eicosyl.

The term "substituted alkyl" refers to:

1) an alkyl chain as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, heterocyclylthio, thiol, alkylthio, aminosulfonyl, aminocarbonylamino, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, and - S(O)2-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; One of the oxygen substituents of the alkyl chain can be joined by single bonds to two adjacent carbon atoms of the same alkyl chain, to form an epoxy group, i.e. a three-membered epoxide ring. or

2) an alkyl chain as defined above that is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR<a> , where R<a> is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

3) an alkyl chain as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above; or

4) an alkyl chain as defined above in which one or more of the methylene group is replaced by a carbonyl group to give an oxo group. or

5) an alkyl chain as defined above in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has 1, 2, 3, 4 or 5 substituents as defined above, or is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above or has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

Non-limiting examples of substituted cycloalkyl chain include: 5-methyl-2-(l- methylethyl)cyclohexyl (2o), 1,2,2-trimethylcyclopentyl (5a).

5a

Non limiting examples of alkyl chains substituted by methyl, hydroxy, alkoxy, and/or acyloxy groups, or containing an epoxy group include: 3-Methylbutyl (la), 4-hydroxy-3 -methylbutyl (lb), 3 -hydroxy-3 -methylbutyl (1c), 2-hydroxy-3 -methylbutyl (Id), (3,3-dimethyl-2- oxiranyl)methyl (epoxyprenyl) (le), 2, 3 -dihydroxy-3 -methylbutyl (If), 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7,11 -trimethyldodecyl (hexahydrofamesyl) (3a), 3,7,11,15 -tetramethylhexadecyl (phytanyl) (4a), hydroxymethyl (6a), 2 -hydroxy ethyl (6b), 6-hydroxyheptyl (6c), 8-hydroxynonyl (6d), 12-hydroxytridecyl (6e), 2-hydroxytridecyl (6f), 2,12-dihydroxytridecyl (6g), 2-hydroxypentadecyl (6h), 14- hydroxypentadecyl (6i), 16-hydroxyheptadecyl (6j), 10-m ethoxyundecyl (6k), 12- methoxytridecyl (61), 2-(acetyloxy)pentadecyl (6m), 2-(acetyloxy)- 13 -hydroxytridecyl (6n), 2- (acetyloxy)- 12-hydroxytridecyl (6o), 2,12-bis(acetyloxy)tridecyl (6p), 2-(acetyloxy)tridecyl (6q).

A non-limiting example of alkyl chain substituted by a heterocyclyl group includes: Tetrahydro-6-methyl-2H-pyran-2-yl)methyl (7a). Non limiting examples of alkyl chain in which one or more of the methylene group is replaced by a carbonyl group include: 3-methyl-2-oxobutyl (1g), 1,2-di oxopropyl (8a), 1-oxopentyl (8b), 3 -oxopentyl (8c), 2-oxopentyl (8d), 4-m ethyl- 1-oxopentyl (8e), 2-oxoheptyl (8f), 6- methyl-5-oxoheptan-2-yl (8g), 2-oxononyl (8h), 14-oxopentadecyl (8i), 2-oxotridecyl (8j). Non limiting examples of alkyl chain in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has a hydroxy substituent include: 1 -hydroxy -2- oxopropyl (9a), 13 -hydroxy -2-oxotridecyl (9b).

The term "alkenyl" refers to a type of alkyl chain as defined above, in which two atoms of the alkyl chain form a double bond that is not part of an aromatic group. That is, an alkenyl chain contains the pattern R-C(R)=C(R)-R. In one embodiment, R refers to the remaining portions of the alkenyl chain, which may be the same or different. The alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a "cycloalkenyl" group).

The term "substituted alkenyl" refers to:

1) an alkenyl chain as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, heterocyclylthio, thiol, alkylthio, aminosulfonyl, aminocarbonylamino, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, and - S(O)2-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2;

One of the oxygen substituents of the alkenyl chain can be joined by single bonds to two adjacent carbon atoms of the same alkenyl chain, to form an epoxy group, i.e. a threemembered epoxide ring. or 2) an alkenyl chain as defined above that is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR<a> , where R<a> is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

3) an alkenyl chain as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above; or

4) an alkenyl chain as defined above in which one or more of the methylene group is replaced by a carbonyl group to give an oxo group. or

5) an alkenyl chain as defined above in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has 1, 2, 3, 4 or 5 substituents as defined above, or is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above or has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

Non-limiting examples of substituted cycloalkenyl chain include: 3-methyl-6-(l- methylethenyl)-2-cyclohexen-l-yl (2g), (2,6,6-trimethylcyclohex-2-en-l-yl)methyl (2r).

Non-limiting examples of alkenyl chains include: 3-methyl-2-buten-l-yl (3,3-dimethylallyl) (Ih), l,l-dimethyl-2 -propen- 1-yl (1,1 -dimethylallyl) (li), 3 -methyl- 1-buten-l-yl (Ij), 3,7- dimethyloct-6-en-l-yl (citronellyl) (2c), ethenyl (10a), 1 -propenyl (10b), 1 -methylethenyl (10c), 1 -methyl- 1 -propen- 1-yl (lOd), tridec-8-en-l-yl (lOe), 8-pentadecen-l-yl (lOf), 8- heptadecen-l-yl (10g), 10-heptadecen-l-yl (lOh), nonadec- 14-en-l-yl (lOi).

Non limiting examples of alkenyl chains substituted by hydroxy, and/or acyloxy groups, or containing an epoxy group include: 4-hydroxy-3-methyl-2-buten-l-yl (Ik), l-hydroxy-3- methyl-2-buten-l-yl (11), 3 -hydroxy-3 -methyl- 1-butenyl (Im), 3 -hydroxy-3 -methyl -1-butenyl (In), 2-hydroxy-3-methyl-3-buten-l-yl (lo), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3- methyl-3-(4-methyl-3-penten-l-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy- 5-methyl-2-(l-methylethenyl)hexyl (2f), 10-(acetyloxy)-8-pentadecenyl (I la).

A non-limiting example of an alkenyl chain where one of the methylene is replaced by an oxo group includes: l-hydroxymethylene-2-oxopropyl (12a). The term "alkynyl" refers to a type of alkyl chain as defined above in which two atoms of the alkyl chain form a triple bond. That is, an alkynyl chain contains the pattern R-C = C-R. In one embodiment, R refers to the remaining portions of the alkynyl chain, which may be the same or different. Non-limiting examples of an alkynyl chain include -C = CH, -C = C-CH3 and -C = C-CH2-CH3. The "R" portion of the alkynyl moiety may be branched, straight chain, or cyclic. Alkynyl chains can be optionally substituted.

The term "substituted alkynyl" refers to:

1) an alkynyl chain as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, heterocyclylthio, thiol, alkylthio, aminosulfonyl, aminocarbonylamino, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, and - S(O)2-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2;

One of the oxygen substituents of the alkynyl chain can be joined by single bonds to two adjacent carbon atoms of the same alkynyl chain, to form an epoxy group, i.e. a threemembered epoxide ring. or

2) an alkynyl chain as defined above that is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR<a> , where R<a> is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or 3) an alkynyl chain as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above; or

4) an alkynyl chain as defined above in which one or more of the methylene group is replaced by a carbonyl group to give an oxo group. or

5) an alkynyl chain as defined above in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has 1, 2, 3, 4 or 5 substituents as defined above, or is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above or has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term polyalkenyl refers to a chain in which more than one pair of atoms of the alkyl chain form a double bond that is not part of an aromatic group. That is, a polyalkenyl chain contains from 2 to 8 R-C(R)=C(R)-R patterns. In one embodiment, R refers to the remaining portions of the alkenyl chain, which may be the same or different. The polyalkenyl moiety may be branched, or straight chain.

Non-limiting examples of polyalkenyl chains include: 3-methyl-l,3-butadienyl (Ip), 3-methyl- 6-(l-methylethenyl)-2-cyclohexen-l-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-l-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-l-yl (neryl) (2i), 5-methyl-2-(l-methylethenyl)-4-hexen- 1-yl (lavandulyl) (2j), (2E,6E)-3,7,1 l-trimethyl-2,6,10-dodecatrien-l-yl (famesyl) (3b), (2E,6E,10E)-3,7,l l,15-tetramethylhexadeca-2,6,10,14-tetraen-l-yl (geranylgeranyl) (4b), pentadeca-8,l l-dien-l-yl (13a), pentadeca-8,l l,14-trien-l-yl (13b), 8,11 -heptadecadi en-l-yl (13c).

The polyalkenyl moiety containing two double bonds may be cyclic (in which case, it would also be known as a "cyclodialkenyl" group). Non limiting example of cyclodialkenyl groups include cyclopentadiene and cyclohexadiene groups. Polyalkenyl chains can be optionally substituted.

The term "substituted poly alkenyl" refers to:

1) a polyalkenyl chain as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, heterocyclylthio, thiol, alkylthio, aminosulfonyl, aminocarbonylamino, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)2-alkyl, -S(O)2- cycloalkyl, and -S(O)2-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2;

One of the oxygen substituent of the polyalkenyl chain can be joined by single bonds to two adjacent carbon atoms of the same polyalkenyl chain, to form an epoxy group, i.e. a threemembered epoxide ring. One of the oxygen substituent of the polyalkenyl chain can from a five-membered aromatic ring with four carbon atoms of the same chain, resulting in. a furan ring. or

2) a polyalkenyl chain as defined above that is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR<a> , where R<a> is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

3) a polyalkenyl chain as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above; or

4) a polyalkenyl chain as defined above in which one or more of the methylene group is replaced by a carbonyl group to give an oxo group. or

5) a polyalkenyl chain as defined above in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has 1, 2, 3, 4 or 5 substituents as defined above, or is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above or has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

Non limiting examples of polyalkenyl chains substituted by a hydroxy group, or containing a furan ring include: 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7- octadien-l-yl (21), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 7-hydroxy-3,7,l 1-trimethyl- 2,10-dodecadien-l-yl (3c), 3-methyl-6-[5-(2-methyl-l-propen-l-yl)-3-furanyl]-2-hexen-l- yl (3d).

Non limiting examples of linear or cyclized polyalkenyl chains in which one of the methylene group is replaced by a carbonyl group to give an oxo group, include: 3,7-dimethyl-5-oxo-2,6- octadienyl (2n), 3 -oxohex- l-en-2-yl (14a), l-oxo-2,4-octadien-l-yl (14b), 4,6-dihydroxy-6- methyl-3-oxo-l,4-cyclohexadien-l-yl (14c), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (14d).

The term polyalkynyl refers to a chain in which more than one pair of atoms of the alkyl chain form a triple bond. That is, a polyalkynyl chain contains from 2 to 8 R-C = C-R patterns, In one embodiment, R refers to the remaining portions of the alkynyl chain, which may be the same or different. Non-limiting example of a polyalkynyl chain include -CH2-CH2-C = C-C = CH. The "R" portion of the polyalkynyl moiety may be branched, straight chain, or cyclic.

The term "substituted polyalkynyl" refers to:

1) a polyalkynyl chain as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, heterocyclylthio, thiol, alkylthio, aminosulfonyl, aminocarbonylamino, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)2-alkyl, -S(O)2- cycloalkyl, and -S(O)2-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

2) a polyalkynyl chain as defined above that is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR<a> , where R<a> is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

3) a polyalkynyl chain as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above; or

4) a polyalkynyl chain as defined above in which one or more of the methylene group is replaced by a carbonyl group to give an oxo group. or

5) a polyalkynyl chain as defined above in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has 1, 2, 3, 4 or 5 substituents as defined above, or is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above or has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term “polyunsaturated” refers to a chain in which at least one pair of atoms of the alkyl chain form a double bond and one pair of atoms of the alkyl chain form a triple bond. That is, a polyunsaturated chain contains both R-C(R)=C(R)-R and R-C = C-R patterns, In one embodiment, R refers to the remaining portions of the polyunsaturated chain, which may be the same or different and the total number of unsaturated bonds may vary from 2 to 8. Nonlimiting examples this type of polyunsaturated chain include -CH2-CH=CH-C = CH. The "R" portion of the polyunsaturated moiety may be branched, straight chain, or cyclic.

The term "substituted polyunsaturated" refers to:

1) a polyunsaturated chain as defined above, having 1, 2, 3, 4 or 5 substituents, (in some embodiments, 1, 2 or 3 substituents) selected from the group consisting of alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, heterocyclylthio, thiol, alkylthio, aminosulfonyl, aminocarbonylamino, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(0)2-alkyl, -S(O)2- cycloalkyl, and -S(O)2-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

2) a polyunsaturated chain as defined above that is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR<a> , where R<a> is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, and -S(O)n R<a> , in which R<a> is alkyl, and n is 0, 1 or 2; or

3) a polyunsaturated chain as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above; or

4) a polyunsaturated chain as defined above in which one or more of the methylene group is replaced by a carbonyl group to give an oxo group. or

5) a polyunsaturated chain as defined above in which one of the methylene group is replaced by a carbonyl group to give an oxo group, and has 1, 2, 3, 4 or 5 substituents as defined above, or is interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above or has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-5 atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and nonaromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be optionally substituted. Rings can form part of a ring system. As used herein, the term "ring system" refers to two or more rings, In one embodiment, two or more of the rings are fused. The term "fused" refers to structures in which two or more rings share one or more bonds.

The term "halogen " may refer to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term “glycoside” refers to a compound in which at least one sugar is bound to another functional group via a glycosidic bond. Typically the glycosidic chain can comprise 1 to 4 sugar units.

The term “glycosidic bond” refers to a bond formed between the hemiacetal or hemiketal group of a sugar and the chemical group of a compound. The chemical group can be -OH (O- glycoside), or -CR1R2R3 (C-glycoside).

The terms “acylated O-glycoside” and “acylated C-glycoside” refer to a compound in which at least one hydroxyl of the glycosidic chain is esterified by an organic acid. Typical examples or organic acid may comprise acetic, substituted benzoic, cinnamic (caffeic, ferulic, p-coumaric), and/or phenylpropanoic (dihydrocaffeic) acids.

The terms “sulfated O-glycoside” and “sulfated C-glycoside” refer to a compound in which at least one hydroxyl of the glycosidic chain is esterified by sulfuric acid.

The term “methylene dioxy” may refer to functional group with the structural formula R-O- CH2-O-R', connected to the rest of a molecule by two chemical bonds.

The term “analogue” as used herein is understood to refer to a compound having a structure similar to that of another one, but differing from it in respect of a certain component. A “derivative” is a compound that can be imagined to arise or is actually be synthesized from a parent compound by replacement of one or more atoms with another atom or group of atoms.

Compound or composition thereof

It is understood that according to certain embodiments, the compound of the invention or composition thereof may be a nutraceutical composition, pharmaceutical composition, functional food, functional nutrition product, medical food, medical nutrition product, or a dietary supplement.

The terms "nutraceutical" combines the words "nutrition" and "pharmaceutical". It is a food or food product that provides health and medical benefits, including the prevention and treatment of a condition, disorder, or disease. A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against a condition, disorder, or disease. Such products may range from isolated nutrients, dietary supplements and specific diets to genetically engineered foods, herbal products, and processed foods such as cereals, soups, and beverages.

The term "nutraceutical" as used herein denotes usefulness in both nutritional and pharmaceutical fields of application. Thus, novel nutraceutical compositions can be used as supplements to food and beverages and as pharmaceutical formulations for enteral or parenteral application which may be solid formulations, such as capsules or tablets, or liquid formulations, such as solutions or suspensions.

The nutraceutical compositions according to the present invention may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film-forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilising agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste-masking agents, weighting agents, jellifying agents, gelforming agents, antioxidants and antimicrobials.

Moreover, a multi-vitamin and mineral supplement may be added to nutraceutical compositions of the invention to obtain an adequate amount of an essential nutrient, which is missing in some diets. The multi-vitamin and mineral supplement may also be useful for disease prevention and protection against nutritional losses and deficiencies due to lifestyle patterns.

The nutraceutical compositions of the invention may be in any galenic form that is suitable for administering to the body, especially in any form that is conventional for oral administration, e.g. in solid forms such as food or feed, food or feed premix, fortified food or feed, tablets, pills, granules, dragees, capsules and effervescent formulations such as powders and tablets, or in liquid forms, such as solutions, emulsions or suspensions as e.g. beverages, pastes and oily suspensions. The pastes may be incorporated in hard or soft shell capsules, whereby the capsules feature e.g. a matrix of (fish, swine, poultry, cow) gelatine, plant proteins or lignin sulfonate. Examples for other application forms are those for transdermal, parenteral or injectable administration. The dietary and pharmaceutical compositions may be in the form of controlled (delayed) release formulations.

Beverages encompass non-alcoholic and alcoholic drinks as well as liquid preparations to be added to drinking water and liquid food. Non-alcoholic drinks are e.g. soft drinks, sports drinks, fruit juices, teas and milk-based drinks. Liquid foods are e.g. soups and dairy products. The nutraceutical composition comprising the compound of the invention may be added to a soft drink, an energy bar, or a candy.

If the nutraceutical composition is a pharmaceutical formulation and the composition further contains pharmaceutically acceptable excipients, diluents or adjuvants then standard techniques may be used for their formulation, as e.g. disclosed in Remington's Pharmaceutical Sciences, 20th edition Williams & Wilkins, PA, USA. For oral administration, tablets and capsules are preferably used which contain a suitable binding agent, e.g. gelatine or polyvinyl pyrrolidone, a suitable filler, e.g. lactose or starch, a suitable lubricant, e.g. magnesium stearate, and optionally further additives.

“Functional food", "functional nutrition product", "medical food" and "medical nutrition product" relate to any healthy food claimed to have a health-promoting or disease-preventing property beyond the basic function of supplying nutrients. The general category of functional foods includes processed food or foods fortified with health-promoting additives, like "vitamin- enriched" products.

The terms “food,” “food product” and “food composition” or “diet product” mean a product or composition that is intended for ingestion by an individual such as a human and provides at least one nutrient to the individual. The compositions of the present disclosure, including the many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described herein or otherwise useful in a diet. A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fibre, fatty acids, or amino acids that may be missing or may not be consumed in sufficient quantities in a person's diet. Some countries define dietary supplements as foods, while in others they are defined as drugs or natural health products. Supplements containing vitamins or dietary minerals are included as a category of food in the Codex Alimentarius, a collection of internationally recognized standards, codes of practice, guidelines and other recommendations relating to foods, food production and food safety. These texts are drawn up by the Codex Alimentarius Commission, an organization that is sponsored by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO).

Compositions intended for an animal, include food compositions to supply the necessary dietary requirements for an animal, animal treats (e.g., biscuits), and/or dietary supplements. The compositions may be a dry composition (e.g., kibble), semi-moist composition, wet composition, or any mixture thereof. In one embodiment, the composition is a dietary supplement such as a gravy, drinking water, beverage, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or any other suitable delivery form. The dietary supplement can comprise a high concentration of the UFA and NORC, and B vitamins and antioxidants. This permits the supplement to be administered to the animal in small amounts, or in the alternative, can be diluted before administration to an animal. The dietary supplement may require admixing, or can be admixed with water or other diluent prior to administration to the animal.

“Pet food” or “pet treat compositions” comprise from about 15% to about 50% crude protein. The crude protein material may comprise vegetable proteins such as soybean meal, soy protein concentrate, corn gluten meal, wheat gluten, cottonseed, and peanut meal, or animal proteins such as casein, albumin, and meat protein. Examples of meat protein useful herein include pork, lamb, equine, poultry, fish, and mixtures thereof. The compositions may further comprise from about 5% to about 40% fat. The compositions may further comprise a source of carbohydrate. The compositions may comprise from about 15% to about 60% carbohydrate. Examples of such carbohydrates include grains or cereals such as rice, corn, milo, sorghum, alfalfa, barley, soybeans, canola, oats, wheat, and mixtures thereof. The compositions may also optionally comprise other materials such as dried whey and other dairy by-products. In some embodiments, the ash content of the pet food composition ranges from less than 1% to about 15%, and in one aspect, from about 5% to about 10%.

The moisture content can vary depending on the nature of the pet food composition. In a one embodiment, the composition can be a complete and nutritionally balanced pet food. In this embodiment, the pet food may be a “wet food”, “dry food”, or food of intermediate moisture content. “Wet food” describes pet food that is typically sold in cans or foil bags, and has a moisture content typically in the range of about 70% to about 90%. “Dry food” describes pet food which is of a similar composition to wet food, but contains a limited moisture content, typically in the range of about 5% to about 15% or 20%, and therefore is presented, for example, as small biscuit-like kibbles. In one embodiment, the compositions have moisture content from about 5% to about 20%. Dry food products include a variety of foods of various moisture contents, such that they are relatively shelf-stable and resistant to microbial or fungal deterioration or contamination. Also included are dry food compositions which are extruded food products, such as pet foods, or snack foods for companion animals.

Methods of administration of compound or composition thereof

The compound of the invention or composition thereof is preferably administered by oral administration. In some embodiments, the compound of the invention or composition thereof may be administered by intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intralesional administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhaled administration, or subcutaneous administration.

The composition of the invention can have an acute effect that can be seen in less than one month. Additionally or alternatively, the composition can have a longterm effect, and thus various embodiments comprise administration of the composition to the individual (e.g., orally) for a time period of at least one month; preferably at least two months, more preferably at least three, four, five or six months; most preferably for at least one year. During the time period, the composition can be administered to the individual at least one day per week; preferably at least two days per week, more preferably at least three, four, five or six days per week; most preferably seven days per week. The composition can be administered in a single dose per day or in multiple separate doses per day. In one embodiment, a single dose is not less than about lOOmg. In one embodiment, a single dose is not more than about lOOOmg. In one embodiment, a single dose is between about lOOmg and about lOOOmg.

AMPK activation terminology

As used herein, an "AMPK activator" refers to a compound that either increases the phosphorylation of downstream substrates of (phosphorylated or not) AMPK, and/or that increases the phosphorylation of AMPK.

As used herein, a "direct AMPK activator" refers to a compound that activates AMPK via direct interaction with at least one of its subunits.

Natural compounds activate AMPK almost exclusively through their ability to interfere with ATP production of the cell, typically by inhibiting mitochondrial respiration. As a consequence, this perturbs the adenine nucleotide levels within the cell and leads to activation of AMPK through AMP and ADP binding to the AMPK y subunit. This mechanism of AMPK activation has been termed “indirect” due to the fact that natural compounds do not directly bind to AMPK to achieve activation.

In contrast, AMPK can be “directly” activated by binding of molecules to the allosteric drug and metabolite (ADaM) binding site formed at the interface between the AMPK a subunit kinase domain and the AMPK P subunit (Bultot,et al., (2016)Am J Physiol Endocrinol Metab 311(4): E706-e719; Ducommun et al., (2014)Am J Physiol Endocrinol Metab 306(6): E688- 696; Ford et al., (2015) Biochem J 468(1): 125-132; O'Brien et al. (2015)Biochem J 469(2): 177-187).

In one preferred embodiment, the direct AMPK activator activates AMPKa2piyl.As used herein, a condition, disorder, or disease “responsive to AMPK activation" refers to one in which the symptoms would be alleviated, or the course of which would be beneficially modified, through activation of AMPK, including without limitation, a metabolic disorder, diabetes, dyslipidemia, hypertension, being overweight, and obesity. For example, the metabolic disorder of diabetes is accompanied by conditions such as diabetic nephropathy or diabetic neuropathy which may be responsive to AMPK activation.

Medical terminology

As used herein, the term "diabetes" includes insulin-dependent diabetes mellitus (i.e. IDDM, also known as type 1 diabetes) non-insulin-dependent diabetes mellitus (i.e. NIDDM, also known as type 2 diabetes), and prediabetes. Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type 2 diabetes often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. This is termed “insulin resistance”. Most type 2 diabetic patients are also overweight or obese. One of the criteria for diagnosing diabetes is the fasting plasma glucose level. A diabetic subject has a fasting plasma glucose level of greater than or equal to 126 mg/dl. A prediabetic subject is someone suffering from prediabetes. A prediabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose level of greater than or equal to 100 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2-hour plasma glucose level of >140 mg/dl and <200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes. Prevention of type 2 diabetes includes treatment of prediabetes.

As used herein, the term "dyslipidemia" encompasses abnormal levels of any lipid fractions as well as specific lipoprotein abnormalities. For example, it refers to elevation of plasma cholesterol and/or elevation of triglycerides and/or elevation of free fatty acids and/or low high- density lipoprotein (HDL) level and/or high low-density lipoprotein (LDL) level and/or high very low-density lipoprotein (VLDL) level. Dyslipidemia may for example contribute to the development of atherosclerosis and ultimately symptomatic vascular disease including coronary heart disease. Dyslipidemia may or may not be associated with diabetes.

As used herein, the term "metabolic disorder" encompasses any abnormal chemical and enzymatic reactions disrupting normal metabolism due to environmental and genetic factors (environmental factors include physical activity, nutrition), leading to excessive levels or deficiency of certain substances and dysfunction of energy homeostasis. Non-limiting examples of metabolic disorders include diabetes, dyslipidemia, hypertension, being overweight, obesity, and any combination thereof. As used herein, "AMPK-related diseases" includes pathologic or pathogenomic conditions in which the activation of AMPK provides a salutary effect. Examples of such diseases or conditions include obesity, diabetes, metabolic syndrome, acute inflammatory lung injury, heart disease, reperfusion ischemia, cancer, aging, retinal degeneration, cardiac hypertrophy, non-alcoholic fatty liver disease, hypertension, albuminuria, sporadic Alzheimer's disease, muscular dystrophy, and osteoarthritis. In addition, “AMPK-related conditions” include conditions where the activation of AMPK improves the condition associated with the primary “AMPK-related disease”. For example, diabetic nephropathy (Salotto et al. (2017) J.Pharma and Expt Thera. 361 :303-311) or diabetic neuropathy are “AMPK-related conditions” which may be associated with the “AMPK-related disease” of diabetes.

“Prevention” or “preventing” includes reduction of risk and/or severity of a condition, disorder, or disease.

The terms “treatment,” “treating,”, “treat”, “attenuate” and “alleviate” include both prophylactic or preventive treatment (that prevent and/or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder, and include treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition. The term does not necessarily imply that a subject is treated until total recovery. These terms also refer to the maintenance and/or promotion of health in a subject not suffering from a disease but who may be susceptible to the development of an unhealthy condition. These terms are also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measure. The terms “treatment,” “treat,” “attenuate” and “alleviate” are further intended to include the dietary management of a disease or condition or the dietary management for prophylaxis or prevention a disease or condition. A treatment can be patient- or doctor- related.

Obesity, which is an excess of body fat relative to lean body mass, is a chronic disease that is highly prevalent in modem society. It is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia, and some cancers, (see, e.g., Nishina, et al., Metab. 43:554-558, 1994; Grundy and Barnett, Dis. Mon.

36:641-731, 1990; Rissanen, et al., British Medical Journal, 301 :835-837, 1990).

"Obesity related disorders" refers to those diseases or conditions where excessive body weight or high "body mass index (BMI)" has been implicated in the progression or suppression of the disease or condition. Representative examples of obesity related disorders include, without limitation diabetes, diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia. See, Harrison's Principles of Internal Medicine, 13th Ed., McGraw Hill Companies Inc., New York (1994). Examples, without limitation, of inflammatory conditions include diseases of the digestive organs (such as ulcerative colitis, Crohn's disease, pancreatitis, gastritis, benign tumor of the digestive organs, digestive polyps, hereditary polyposis syndrome, colon cancer, rectal cancer, stomach cancer and ulcerous diseases of the digestive organs), stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, cerebrovascular dementia, immunological diseases and cancer in general.

The term “subject” or “individual” means any animal, including a human, that could benefit from one or more of the compounds, compositions or methods disclosed herein. Generally, the subject is a human or an avian, bovine, canine, equine, feline, hircine, lupine, murine, ovine or porcine animal. A "companion animal" is any domesticated animal, and includes, without limitation, cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses, cows, goats, sheep, donkeys, pigs, and the like. Preferably, the subject is a human or a companion animal such as a dog or cat. The term “elderly” in the context of a human means an age from birth of at least 60 years, preferably above 63 years, more preferably above 65 years, and most preferably above 70 years. The term “older adult” in the context of a human means an age from birth of at least 45 years, preferably above 50 years, more preferably above 55 years, and includes elderly subjects. For other animals, an “older adult” has exceeded 50% of the average lifespan for its particular species and/or breed within a species. An animal is considered “elderly” if it has surpassed 66% of the average expected lifespan, preferably if it has surpassed the 75% of the average expected lifespan, more preferably if it has surpassed 80% of the average expected lifespan. An elderly cat or dog has an age from birth of at least about 7 years.

As used herein, an “effective amount” is an amount that prevents a deficiency, treats a disorder, condition, or disease in a subject or, more generally, reduces symptoms, manages progression of the diseases or provides a nutritional, physiological, or medical benefit to the subject. The relative terms “improved,” “increased,” “enhanced” and the like refer to the effects of the composition disclosed herein relative to a composition lacking one or more ingredients and/or having a different amount of one or more ingredients, but otherwise identical.

General terminology

As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component” or “the component” includes two or more components.

Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of recombinant DNA technology include Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, New York (1989); Kaufman et al., Eds., Handbook of Molecular and Cellular Methods in Biology in Medicine, CRC Press, Boca Raton (1995); McPherson, Ed., Directed Mutagenesis: A Practical Approach, IRL Press, Oxford (1991). Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill Companies Inc., New York (2001). Standard medical terminology used herein has the meaning defined in Stedman's Medical Dictionary, 27th Edition, with veterinary medicine insert.

All percentages expressed herein are by weight of the total weight of the composition unless expressed otherwise. As used herein, “about,” “approximately” and “substantially” are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably - 1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or compounds, but may also include additional features or compounds. The term “and/or” used in the context of “X and/or Y” should be interpreted as “X,” or “Y,” or “X and Y.” Where used herein, the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive.

Reference is made hereinafter in detail to specific embodiments of the invention. While the invention will be described in conjunction with these specific embodiments, it will be understood that it is not intended to limit the invention to such specific embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the claims. Numerous specific details are set forth in the description in order to provide a thorough understanding of the present invention. The present invention may be practiced without some or all of these specific details. In other instances, well known methods and protocols have not been described in detail, in order not to unnecessarily obscure the present invention.

Brief description of figures

Figure 1- Compound 1 increased the phosphorylation of the AMPK substrate, ACC, in a dose-dependent manner.

Compound 1 increased the phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC), in U-2 OS Flp-In T-REx mammalian cells. U-2 OS cells were treated with varying concentrations of Compound 1 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the ratio 665/620 nm (±SEM) of 3 independent experiments.

Figure 2 - Compound 1 did not activate AMPK in cells stably expressing an ADaM- binding site AMPK mutant (pi S108A).

The pi WT or pi SI 08 A mutant were stably expressed in AMPKpip2 double knockout cells and were treated with varying concentrations of Compound 1 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation (±SEM) of 3 independent experiments.

EXAMPLES

Example 1: Compound 1 increased the phosphorylation of the AMPK substrate, acetyl- CoA carboxylase (ACC), in U-2 OS Flp-In T-REx mammalian cells.

U-2 OS Flp-In T-REx cells were seeded at 50 K in a 96-well plate and left overnight at 37 C in DMEM GlutaMAX (Thermo Fisher Scientific) supplemented with 10% (vol/vol) FBS and 100 U/ml penicillin G, and 100 pg/ml streptomycin. Cells were treated for 30 mins with varying concentrations of Compound 1 in media lacking FBS and then cells were lysed in 50 pl of Cisbio lysis buffer #1 supplemented with blocking solution as per the manufacturer’s protocol (Cisbio). Cells were lysed for 30 mins at room temperature before 16 pl of lysate was incubated with 4 pl of the HTRF antibodies (1 :40 dilution of the acceptor and donor (p)ACC antibodies, as per the manufacturers protocol). Lysates were incubated overnight with the antibodies before the 665nm/620nm ratio was determined using a MolecularDevices i3 plate reader (with a HTRF cartridge add-on).

Figure 1 shows that using the pACC HTRF assay kit (Cisbio), Compound 1 increased the phosphorylation of the AMPK substrate, ACC, in a dose-dependent manner in U-2 OS Flp-In T-REx mammalian cells. Phosphorylation of ACC is extensively used as a cellular read-out of AMPK activity.

Example 2: Compound 1 did not activate AMPK in cells expressing AMPK complexes containing a mutation at the allosteric drug and metabolite (ADaM) site (S108A).

AMPKpi/p2 double knockout U-2 OS Flp-In™ T-Rex™ cell lines were generated by Horizon Discovery (Cambridge, UK). Cells were genotyped and analysed by Western blotting to confirm that there was a complete knockout of AMPKpi/p2. We took these AMPKpi/p2 double knockout cells, and re-introduced the expression of human pi wild-type (WT) or a pi Serine 108 to alanine mutation (SI 08 A). This was achieved using the Flp-In™ system (Invitrogen) present in this cell line and stable cells expressing pi WT or a pi SI 08 A mutant were generated according to the manufacturers’ protocols. Re-expression of the pi subunit was confirmed by Western blot analysis.

Cells stably expressing pi WT or a pi S108A mutant were treated with varying concentrations of Compound 1. Cells lysates were subjected to the pACC HTRF (Cisbio) assay to determine the level of phosphorylation of the AMPK substrate, ACC, in cell lysates, as in example 1. As shown in Figure 2, Compound 1 was able to dose-dependently increase pACC in cells stably expressing the pi WT subunit. In contrast, Compound 1 was not able to increase the activity of AMPK in cells expressing the pi SI 08 A mutant. This suggests that the ability of compound 1 to activate AMPK, is mediated by its ability to bind to the ADaM-site of AMPK.