WO2007070986A1 - Flavones - Google Patents

Abstract

The present invention relates to flavone compounds and their use in methods of treating or preventing parasitic infections, fungal infections and cell proliferative disorders. The present invention also relates to the use of flavone compounds in methods of controlling pests.

Description

FLAVONES

FIELD OF THE INVENTION

This invention relates to bioactive molecules. More particularly, this invention relates to flavones of potential therapeutic benefit and/or of use as a pharmaceutical or an agrochemical.

BACKGROUND OF THE INVENTION

Bio-discovery is a growing field, which investigates and screens for bioactive natural products from natural environments, including plants, microorganisms, coral and other marine life. In the search for bioactive natural products, natural material is screened for molecules having properties that may be of therapeutic benefit for potential use in a range of treatments, for example treatments for cancer, antifungal treatments, antibiotic treatments, antiparasitic treatments and anti-inflammatory treatments.

Flavones are molecules that may be naturally-occurring or synthesised. For example, reference is made to Datta, S. C. et. al (Indian Journal of Chemistry, 7, Aug,

1969 p 746-750) andNatarjan et. al (Indian Journal of Chemistry 9, August, 1971, pp

813-814) which disclose the synthesis of some flavones, however, they do not propose any use for the synthesised flavones.

SUMMARY OF THE INVENTION

The present invention arises from the discovery of flavones which have potentially new therapeutic uses as cytotoxic, antiparasitic, fungicidal and insecticidal agents.

One aspect of the invention, provides for compounds of the formula (I) for use as a cytotoxic, antiparasitic, fungicidal and insecticidal agent

wherein:

X and Y are independently selected from sulfur, oxygen, NH, N(C₁-C₃ alkyl) and CR'R"; R¹ and R¹⁰ are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C_2O alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R' and R" are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-Ci₄ aryl, -C₃-Ci₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-Ci₀ haloalkyl, -C₁-Ci₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl and -CpC₁₀ haloalkoxy; each R is independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -Ci-C₁₀ dihaloalkyl, -Ci-C₁₀ trihaloalkyl and -C₁-Ci₀ haloalkoxy; and each Z is independently selected from oxygen, sulfur, -NH- and -N(C₁-C₃ alkyl)-; or where R¹ is connected to R², and/or R² is connected to R³, and/or R³ is connected to R⁴, and/or R⁵ is connected to R⁶, and/or R⁶ is connected to R⁷, and/or R⁷ is connected to R⁸, and/or R⁸ is connected to R⁹, and/or R⁹ (or R⁵) is connected to R IQ wherein the linkage comprises a -Ci-C₈ disubstituted (fused) saturated or unsaturated carbo- or heterocyclic ring further substituted with a group selected from R, -(C=Z)R and -Z(C=X)R, or a pharmaceutically, agriculturally or pesticidally acceptable salt thereof.

In the compound of formula (I)₃ where any one or more of R¹ to R¹⁰, R' and R" is C₂-C₂₀ alkenyl, one or more of R¹ to R¹⁰, R' and R" may further comprise an aryl or heteroaryl group.

In one embodiment of the compound of formula (I), where any one or more of R¹ to R¹⁰, R' and R" is C₂-C₂₀ alkenyl the alkenyl units may be singular or multiple.

In another embodiment of the compound of formula (I), where any one or more of R¹ to R¹⁰, R' and R" is C₂-C₂₀ alkynyl, one or more of R¹ to R¹⁰, R' and R" may further comprise an aryl or heteroaryl group.

In yet another embodiment of the compound of formula (I), where any one or of R¹ to R¹⁰, R' and R" is C₂-C₂₀ alkynyl the alkynyl units may be singular, multiple or allenyl.

In one embodiment, the compounds of the formula (I) for use as a cytotoxic, antiparasitic, fungicidal or insecticidal agent are compounds of formula (II):

wherein:

X and Y are oxygen; R¹ to R⁴ are each independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR₅ -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R⁵ and R⁹ are -OCH₃; and

R⁶ to R⁸ and R¹⁰ are hydrogen, and each R is -C₁-C₂₀ alkyl, -C₂-C_2O alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -C₁-C₁₀ trihaloalkyl, or a pharmaceutically, agriculturally or pesticidally acceptable salt thereof.

In one embodiment of formula II, R³ and R⁴ are hydrogen.

In yet another embodiment, the compound of formula (I) is a compound of formula (III)

(HI) wherein:

X and Y are independently selected from O and S;

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and

-COR 15.

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵; or R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; or

R³ and R⁴ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R⁶ to R⁸ are independently selected from hydrogen, -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -Ci-ioalkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C_3-8cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; R¹² is selected from hydrogen, -C_1-10alkyl, -C_2-1oalkenyl, -C_2-10alkynyl,

-C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C_1-loalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl; R¹⁴ is selected from hydrogen, -d.ioalkyl, -C_2-10alkenyl, -C_2-10alkynyl,

-Cs.gcycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R )₂;

R¹⁵ is selected from hydrogen, -C^oalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen; R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl,

-C_3-8CyClOaIlCyI, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically, agriculturally or pesticidally acceptable salts thereof.

In yet other embodiments, the compound of formula (III) is a compound of formula (Ilia)

wherein:

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-10alkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C_3-8cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_1-10alkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C^oalkyl, -C_2-1oalkenyl, -C₂.i_Oalkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -d.ioalkyl, -C_2-10alkenyl, -C₂.₁₀alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen; R¹⁷ is selected from hydrogen, -Ci-ioalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically, agriculturally or pesticidally acceptable salts thereof; or a compound of formula (HIb)

wherein:

R³ and R⁴ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵ or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; R^{1 !} is selected from -Ci.ioalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -Ci.ioalkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -Ci-ioalkyl, -C₂.₁₀alken.yl,

-C_2-ioalkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -Ci.ioalkyl, -C_2-10alkenyl, -C_2-ioalkynyl, -Cs.gcycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂; R¹⁵ is selected from hydrogen, -C_1-1OaIlCyI, -C_2-1oalkenyl, -C₂-₁₀alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically, agriculturally or pesticidally acceptable salts thereof.

In preferred embodiments, one or more of the following applies:

X is oxygen or sulfur, especially oxygen; Y is oxygen or sulfur, especially oxygen;

R¹ and R² are independently selected from -OC₁-C₆ alkyl, -OC₂-C₆ alkenyl,

-OC₃-C₈ cycloalkyl, -Ohaloalkyl, -Odihaloalkyl, -Otrihaloalkyl, -Oaryl,

-Oheterocyclyl or -Oacyl; especially -OC₁-C₃ alkyl or -OC₁-C₃ trihaloalkyl; more especially methoxy or trifluoromethoxy, particularly where both R¹ and R² are methoxy; and R³ and R⁴ are hydrogen; or

R³ and R⁴ are independently selected from -OC₁-C₆ alkyl, -OC₂-C₆ alkenyl,

-OC₃-C₈ cycloalkyl, -Ohaloalkyl, -Odihaloalkyl, -Otrihaloalkyl, -Oaryl,

-Oheterocyclyl or -Oacyl; especially -OC₁-C₃ alkyl or -OC₁-C₃ trihaloalkyl; more especially methoxy or trifluoromethoxy, particularly where both R³ and R⁴ are methoxy; and R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OC₁-C₆ alkyl, -OC₂-C₆ alkenyl,

-OC₃-C₈ cycloalkyl, -Ohaloalkyl, -Odihaloalkyl, -Otrihaloalkyl, -Oaryl,

-Oheterocyclyl or -Oacyl; especially -OC₁-C₃ alkyl or -OC₁-C₃ trihaloalkyl; more especially methoxy or trifluoromethoxy, particularly where both R⁵ and R⁹ are methoxy;

R⁶ to R⁸ are independently selected from hydrogen, -OC₁-C₆ alkyl, -OC₂-C₆ alkenyl, -OC₃-C₈ cycloalkyl, -Ohaloalkyl, -Odihaloalkyl, -Otrihaloalkyl, -Oaryl, -Oheterocyclyl or -Oacyl; especially where at least one of R⁶ to R⁸ is hydrogen; especially where all of R to R are hydrogen; R¹⁰ is hydrogen. In one embodiment, the compound is 5,6,2'6'-tettamethoxyfiavone (EBI-53), also known as zapotin:

In another embodiment, the compound is 7,8,2'6'-tetramethoxyflavone

(EBI-53-2):

In a first aspect of the invention, there is provided a method of treating or preventing a parasitic infection comprising administering to a subject, a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect of the invention, there is provided a method of treating or preventing a parasitic infection comprising administering to a subject, a compound of formula (III) or a pharmaceutically acceptable salt thereof.

In yet another aspect of the invention, there is provided a method of treating or preventing breast cancer, ovarian cancer or prostate cancer comprising administering to a subject, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, there is provided a method of treating or preventing breast cancer, ovarian cancer or prostate cancer comprising administering to a subject, a compound of formula (III) or a pharmaceutically acceptable salt thereof. In yet another aspect of the invention, there is provided a method of treating or preventing a fungal infection comprising administering to a subject or crop, a compound of formula (I) or a pharmaceutically or agriculturally acceptable salt thereof. In a further aspect of the invention, there is provided a method of treating or preventing a fungal infection comprising administering to a subject or crop, a compound of formula (III) or a pharmaceutically or agriculturally acceptable salt thereof. hi yet another aspect of the invention, there is provided a method of treating or preventing a pest infestation comprising administering to a subject, crop or environment, a compound of formula (I) or a pharmaceutically, agriculturally or pesticidally acceptable salt thereof. hi a further aspect of the invention, there is provided a method of treating or preventing a pest infestation comprising administering to a subject, crop or environment, a compound of formula (III) or a pharmaceutically, agriculturally or pesticidally acceptable salt thereof.

The compounds of the invention, particularly EBI-53 and EBI-53-2 may be present in a plant extract obtained from a plant or plant part, such as those plants described below. Preferably the compound of the compound EBI-53 is the major active constitiuent of the plant extract.

Thus the invention provides compounds of formula (I) that are useful in treatment or prophylaxis of at least one of a cell proliferative disorder such as tumours, leukaemia and related disorders, infestation of humans and/or animals by parasites, treatment or prophylaxis of fungal infections of humans, animals and/or plants or for controlling a pest as an infestation of humans and/or animals and/or in an environment such as an agricultural, household or industrial environment. The parasite may be an ectoparasite and/or an endoparasite such as a parasitic nematode with a free-living life cycle stage. Examples of suitable pests include insects, including insects that infest crops or that infest humans and/or animals, flies, fleas, ticks, lice, cockroaches and pests such as spiders.

The above compounds and uses are of great benefit to society with the potential to cure or ease the suffering of the large populations who suffer directly or indirectly from parasitic infection, cell proliferative disorders and fungal infections and where the compounds have the potential to protect crops and/or animals and/or environments from pest or insect attack.

The term "alkyl" refers to optionally substituted linear and branched hydrocarbon groups having 1 to 20 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, -C₁-C₆ alkyl which includes alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl. The alkyl group may be substituted with one or more substituent independently selected from -F, -Cl, -Br, -I, -CO₂R, -CN, -OR, -SR, -N(R)₂, -NO₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₂, -P(R)₃, -P(=O)(R)₃, -OSi(R)₃, -OB(R)₂ wherein R is as defined above.

The term "alkenyl" refers to optionally substituted unsaturated linear or branched hydrocarbon groups, having 2 to 20 carbon atoms and having at least one double bond. Where appropriate, the alkenyl group may have a specified number of carbon atoms, for example, -C₂-C₆ alkenyl which includes alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Non-limiting examples of alkenyl groups include, ethenyl, propenyl, isopropenyl, butenyl, s- and t-butenyl, pentenyl, hexenyl, hept-l,3-diene, hex-l,3-diene, non-1, 3,5-triene and the like. Suitable optional substituents are the same as those for alkyl groups.

The term "alkynyl" refers to optionally substituted unsaturated linear or branched hydrocarbons, having 2 to 20 carbon atoms, comprising at least one triple bond. Where appropriate, the alkynyl group may have a specified number of carbon atoms, for example, -C₂-C₆ alkenyl which includes alkynyl groups having 2, 3, 4, 5 or 6 carbon atoms in linear or branched arrangements. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Suitable optional substituents are the same as those for alkyl groups.

The terms "cycloalkyl" and "carbocyclic" refer to optionally substituted saturated or unsaturated mono-cyclic, bicyclic or tricyclic hydrocarbon groups. Where appropriate, the cycloalkyl group may have a specified number of carbon atoms, for example, -C₃-C₆ cycloalkyl is a carbocyclic group having 3, 4, 5 or 6 carbon atoms in the ring. Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl and the like. Suitable optional substituents are the same as those for alkyl groups.

"Aryl" means a -C₆-C₁₄ membered monocyclic, bicyclic or tricyclic ring system having up to 7 atoms in each ring wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. The aryl group may be substituted, with any mode of substitution, with one or more substituents independently selected from -F, -Cl, -Br, -I, -NO₂, -CF₃, -CN, -COR, -CO₂R, -OR, -SR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₂, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂. The aryl may comprise 1-3 benzene rings. If two or more aromatic rings are present, then the rings may be fused together, so that adjacent rings share a common bond.

"Heterocyclic" or "heterocyclyl" refers to a non-aromatic ring having 3 to 8 atoms in the ring and of those atoms 1 to 4 are heteroatoms said ring being isolated or fused to a second ring selected from 3 - to 7-membered alicyclic ring containing O to 4 heteroatoms, wherein said heteroatoms are independently selected from O, N and S. Heterocyclic groups include partially and fully saturated heteroaryl derivatives. Heterocyclic groups may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and are both saturated and unsaturated, which also includes all forms of carbohydrate moieties. Non-limiting examples of heterocyclic include pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazepinyl, oxepinyl, thiapinyl, imidazolinyl, thiomorpholinyl, and the like. Each heterocyclyl group may be optionally substituted as for alkyl groups above.

The term "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo).

The term "acyl" used herein refers to an alkanoyl or aroyl group as defined by (C=O)R' where suitable R' groups include, but are not limited to, -C₁-C₂₀alkyl, -C₂-C₂₀alkenyl, -C₂-C₂oalkynyl, -C₃-Cscycloalkyl, aryl, heterocyclyl, heteroaryl, -C₁-C₇alkylaryl, -C₁-C₇alkylcycloalkyl, -CrC₇alkylcylcoalkenyl,

-C!-C₇alkylheterocyclyl, -d-C₇alkylheteroaryl, -d-C₇alkoxyalkyl,

-d-C₇alkylthioalkyl, -d-C₇alkylthioaryl, -d-dalkoxyaryl and the like.

The term "heteroaryl" as used herein means a stable monocyclic or bicyclic ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring containing from 1-4 heteroatoms, selected from sulfur, oxygen and nitrogen. Heteroaryl includes, but is not limited to, oxazolyl, thiazolyl, thienyl, furyl, 1-isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl, indolizinyl, isoindolyl, indolyl, purinyl, phthalazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazoyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indoleninyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, pyrido[4,3-b]pyridinyl, acridinyl, carbazolyl, quinoxalinyl, pyrazolyl, benzotriazolyl, thiophenyl, isoquinolinyl, pyridinyl, tetrahydroquinolinyl, benzazepinyl, benzodioxanyl, benzoxepinyl, benzodiazepinyl, benzothiazeipinyl, benzothiepinyl and the like. Each heteroaryl group may be optionally substituted as for aryl groups above. Yet another aspect of the invention provides a pharmaceutically, agriculturally or pesticidally acceptable salt of a compound of formulae (I) to (III).

The terms "pharmaceutically acceptable salts", "agriculturally acceptable salts" or "pesticidally acceptable salts" as used herein refer to salts which are toxicologically safe for systemic or topical administration to a human or animal or those that may be safely applied to plants or the environment. Suitable pharmaceutically, agriculturally or pesticidally acceptable salts may be selected from the group including, but not limited to, alkali and alkali earth, ammonium, aluminium, iron, amine, glucosamine, chloride, sulphate, sulphonate, bisulphate, nitrate, citrate, tartrate, bitarate, phosphate, carbonate, bicarbonate, malate, maleate, napsylate, fumarate, succinate, acetate, benzoate, terephthalate, palmoate, pectinate and s-methyl methionine salts, piperazine and the like.

It will also be recognised that the compounds of the present invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisometric form. The invention thus also relates to compounds in substantially isometric form at one or more asymmetric centres, e.g. greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be obtained from natural sources, by asymmetric synthesis, for examples, using chiral intermediates, or by chiral resolution.

The compounds of the invention may be obtained by isolation from a plant or part of a plant, or by derivatisation of the isolated compound, or the compounds may be synthesised from known starting materials.

Still yet another aspect of the invention provides a method of isolating one or more compounds of formulae (I) to (III), which method includes the step of extracting said one or more compounds from a plant or plant part.

Preferably, the plant is of the family Rutaceae.

Preferably the genus is Zanthophyllum, Zanthoxylum or Casimiroa. More preferably the species is Zanthophyllum octandra, Casimiroa edulis, Zanthoxylum brachyacanthum, Zanthoxylum nitidum, Zanthoxylum ovalifolium, Zanthoxylum parviflorum, Zanthoxylum rhetsa and Zanthoxylum veneβcum.

The parts of plants may include fruit, seed, bark, leaf, flower, roots and wood. Preferably the extract is obtained from the seed.

For example, the biomass obtained from seeds, leaves and bark of the plant is subject to initial solvent extraction, for example, with a polar solvent such as methanol. The initial extraction is then concentrated and diluted with water and subject to extraction with a second solvent, for example, ethyl acetate. The solvent samples from the second extraction are pooled and subject to separation by preparative HPLC fractionation. The fractions are analysed by analytical HPLC and pooled according to the retention time of compounds found in the samples. The pooled fractions are weighed, bioassayed and analysed by analytical HPLC. Further fractionation using one or more preparative HPLC is performed to isolate specific compounds. Each compound is bioassayed and its structure identified by UV, NMR and mass spectrometric techniques.

Other compounds of the invention may be obtained by derivatising compounds isolated from plants or parts of plants, especially from the genuses

Zanthophyllum, Zanthoxylum or Casimiroa, especially from the species Zanthophyllum octandra or Casimiroa edulis, especially the seeds of ^'Zanthophyllum octandra or Casimiroa edulis.

Derivatives of compounds of the invention may be obtained by techniques known in the art. For example, alkyl ethers may be cleaved to hydroxy groups, by a number of methods such as BBr₃ in dichloromethane or AlCl₃ in ethanethiol. Free hydoxy groups may be selectively protected and deprotected to allow derivatisation at one or a selection of hydroxy groups present. Suitable methods of protection and deprotection can be found in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons Inc., 3^rd Edition, 1999.

Hydroxy groups may also be derivatised by etherification or acylation. For example, ethers may be prepared by formation of an alkoxide ion in the presence of base and reacting the alkoxide with an appropriate alkylhalide, alkenylhalide, alkynylhalide, or arylhalide. Similarly acylation may be achieved by formation of an alkoxide ion and reaction with an appropriate carboxylic acid or activated carboxylic acid (such as an anhydride). Acyl groups may be hydrolysed to provide alcohols by acid or base hydrolysis as known in the art.

Silyl groups may be introduced onto hydroxy groups to provide silyl ethers using mild base and a silyl chloride reagent, for example Me₃SiCl and triethylamine in THF or agents such as MeSiNHCO₂SiMe₃ in THF. Sulfonates may be readily introduced onto hydroxy groups by reaction with a suitable sulfonate group. For example, methanesulfonates may be introduced by treatment of a hydroxy group with MsCl and triethylamine in dichloromethane. Tosylate groups may be introduced by reacting a hydroxy group with TsCl and pyridine. Allylsulfonates may be introduced by reacting a hydroxy group with allylsulfonyl chloride and pyridine in dichloromethane.

1,2-diols may form heterocyclic ketals, for example, by reacting a 1,2-diol with (MeO)₂CH₂, 2,6-lutidine and TMSOTf or acetone in TsOH.

Ketones may be reduced to secondary alcohols by reducing agents such as lithium aluminium hydride and other metal hydrides without reducing double bonds, including α-unsaturated ketones.

Non-aromatic double bonds and triple bonds may be reduced to single bonds using catalytic reduction, for example, H₂/Pd. Double bonds may also be oxidised to epoxides using oxidising agents such as per acids, for example, mCPBA or dioxiranes, such as DMDO and TFDO. Double bonds may also be subject to addition reactions to introduce substituents such as halo groups, hydroxy or alkoxy groups and amines.

A person skilled in the art would be able to determine suitable conditions for obtaining derivatives of isolated compounds, for example, by reference to texts relating to synthetic methodology, examples of which are Smith M.B. and March J., March's Advanced Organic Chemistry, Fifth Edition, John Wiley & Sons Inc., 2001 and Larock R.C., Comprehensive Organic Transformations, VCH Publishers Ltd., 1989. Furthermore, selective manipulations of functional groups may require protection of other functional groups. Suitable protecting groups to prevent unwanted side reactions are provided in Green and Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons Inc., 3^rd Edition, 1999.

The compounds of the invention may also be synthesised by methods known in the art. For example, EBI-53 may be prepared by a known synthetic route, {Indian J. Chem., 1969, 7, 746-750; Tetrahedron, 1967, 23, 4607-4612) as shown in Scheme 1.

Similarly compounds such as EBI-53-2 may be synthesised by a similar method as shown in Scheme 2.

It is clear that different functionality may be introduced into the flavone by using starting materials with varying substituents and substitution patterns, such as varying the substituents on the α-hydroxyacetophenone or the aldehyde used in the synthesis.

While in some cases, the compounds of the invention may be administered alone, it is more convenient to administer them as a pharmaceutical, agricultural or pesticidal composition.

A further aspect of the invention provides a pharmaceutical composition for treatment or prophylaxis of a cell proliferative disorder, comprising an effective amount of one or more compounds of formulae (I) to (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically, agriculturally or pesticidally acceptable carrier, diluent and/or excipient.

An additional aspect of the invention provides a pharmaceutical composition for treatment or prophylaxis of a parasitic infestation of a human or an animal comprising an effective amount of one or more compounds of formulae (I) to (IH), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

Dosage form and rates for pharmaceutical use and compositions are readily determinable by a person of skill in the art. Dosage forms include tablets, dispersions, suspensions, injections, solutions, syrups, troches, capsules, suppositories, aerosols, transdermal patches and the like.

These dosage forms may also include injecting or implanting devices designed specifically for, or modified to, controlled release of the pharmaceutical composition.

Controlled release of the therapeutic agent may be effected by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids and certain cellulose derivates such as hydroxypropylmethyl cellulose. In addition, the controlled release may be affected by using other polymer matrices, liposomes and/or microspheres.

Pharmaceutically acceptable carriers for systemic administration may also be incorporated into the compositions of this invention.

Suitably, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. By "pharmaceutically acceptable excipient" is meant a solid or liquid filler, diluent or encapsulating substance that may be safely used in systemic administration. Depending upon the particular route of administration, a variety of carriers, well known in the art may be used. These carriers or excipients may be selected from a group including sugars, starches, cellulose and its derivates, malt, gelatine, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water.

Any suitable route of administration may be employed for providing a patient with the pharmaceutical composition of the invention. For example, oral, rectal, parenteral, sublingual, buccal, intravenous, intraarticular, intra-muscular, intra-dermal, subcutaneous, inhalational, intraocular, intraperitoneal, intracerebroventricular, transdermal and the like may be employed.

Pharmaceutical compositions of the present invention suitable for administration may be presented in discrete units such as vials, capsules, sachets or tablets each containing a predetermined amount of one or more pharmaceutically active compounds of the invention, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion. Such compositions may be prepared by any of the method of pharmacy but all methods include the step of bringing into association one or more pharmaceutically active compounds of the invention with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the agents of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product in to the desired presentation.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. hi tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration. For preparing suppositories, a low melting wax, such as admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions . For example, parenteral inj ection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with their agents expected to enhance delivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 1 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.

The active compounds of formulae (I) to (III) and of the pharmaceutical composition of this invention are present in an amount sufficient to prevent, inhibit or ameliorate cell proliferative disorders, in particular, breast cancer, ovarian cancer and prostate cancer. Alternatively the active compound of formulae (I) to (III) is present in an amount sufficient to prevent, inhibit or ameliorate infestation of humans and/or animals by a parasitic infection.

A parasitic infestation includes, but is not limited to, an endoparasite and/or an ectoparasite infestation, such as a parasitic nematode with a free-living life cycle stage.

In another embodiment, the active compound of formulae (I) to (HI) is present in an amount to prevent, inhibit or ameliorate a fungal infection in humans and/or animals.

A suitable dosage of the compounds of formulae (I) to (III) and the pharmaceutical compositions containing such may be readily determined by those skilled in the art.

In a still further aspect of the invention, there is provided a method of treatment or prophylaxis of a cell proliferative disorder selected from breast cancer, ovarian cancer and prostate cancer comprising administering to a subject, an effective amount of one or more compounds according to formula (I) or a pharmaceutically acceptable salt thereof.

The cell proliferative disorder may include any disease or condition resulting from or characterized by aberrant or deregulated cell proliferation. Non-limiting examples include malignancies such as tumours, leukaemia and related disorders, but particularly breast tumours, ovarian tumours and prostate tumours.

In yet another aspect of the invention provides method of treating or prophylaxis of a parasitic infestation of a human or animal comprising administering to a subject, an effective amount of one or more compounds of formulae (I) to (III), or a pharmaceutically acceptable salt thereof. The parasitic infestation may include an infestation of a human and/or another animal by an endoparasites and/or ectoparasites, such as a parasitic nematode with a free-living life cycle stage.

In a preferred embodiment of this aspect, the parasite is a helminth (worm), especially nematodes, trematodes and cestodes, such as Haemonchus contortus, Trichinella spiralis, H. placei, Bursaphelenchus xylophilus, Ostertagia circumcincta,

O. ostertagi, Mecistocirrus digitatus, Trychostrongylus axei, Trichuris trichiura,

T. vulpis, T. campanula, T. suis, T. ovis, Bunostomum trigonocephalum,

B. phleboyomum, Oesophagostomum columbianum, O. radiatum, Cooperia curticei,

C. punctata, C. oncophora, C. pectinata, Strongyloides papillosus, Chabertia ovina, Ancylostoma duodenale, A. braziliense. A. tubaeforme, A. caninum, Ascaris lumbricoides, Enterobius vermicularis, E. gregorii, Ascaris lumbricoides, Paragonimus Westermani, Clonorchis sinensis, Fasciola hepatica, Taenia solium, T. saginata, Capillaria aerophila, Necator americanus, species of the genus Trichuris, Baylisascaris, Aphelenchoides, Meliodogyne, Heterodera, Globodera, Nacobbus, Pratylenchus, Ditylenchus, Xiphinema, Longidorus, Trichodorus, Nematodirus.

In yet another aspect of the invention, there is provided a method of treating or prophylaxis of a fungal infection in a human or animal comprising administering to a subject, an effective amount of one or more compounds of formulae (I) to (III), or a pharmaceutically acceptable salt thereof. In a preferred embodiment of this aspect, the fungal infection is caused by Absidia corymbifera, Acremonium sp., Agaricus bisporus, Agaricus campestris, Alternaria alternate, Aphanoascusflavescens, Apophysomyces elegans, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aureobasidium pullulans, Basidiobolus ranarum, Beauveria bassiana, Bipolaris (Drechslera) australiensis, Candida albicans, Candida sp., Chaetomium globosum, Cryptococcus neoformans, Chrysosporium sp., Cladophialophora bantiana, Cladophialophora carrionii, Cladosporium cladosporioides, Coccidioides immitis, Conidiobolus coronatus, Cunninghamella bertholletiae, Curvularia lunata, Epicoccum nigrum, Epidermophyton floccosum, Exophiala jeanselmei, Exophiala spinifera, Exophiala werneckii, Exserohilum sp., Fonsecaea pedrosoi, Fusarium solani, Gelasinospora sp., Geotrichum candidum, Gliocladiumsp., Gymnoascus sp., Hendersonula toruloidea, Histoplasma capsulatum, Lasiodiplodia theobromae, Leptosphaerulina sp., Madurella mycetomatis, Malassezia furfur, Microsporum audouinii, Microsporum canis, Microsporum ferrugineum, Microsporum gypseum, Microsporum nanum, Mortierella wolfii, Mucor sp., Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium sp., Penicillium marneffei, Phialophora sp., Phialophora verrucosa, Pithomyces chartarum, Pseudallescheria boydii, Pseudoarachniotus sp., Rhizomucor pusillus, Rhizopus sp., Rhizopus homothallicus, Rhizopus oryzae, Rhizopus sexualis, Rhizopus stolonifer, Saksenaea vasiformis, Scedosporium apiospermum, Scedosporiumprolificans, Scopulariopsis brevicaulis, Scytalidium sp., Sepedonium sp., Sordaria fimicola, Sporothrix schenckii, Stemphylium sp., Syncephalastrum sp., Trichoderma harzianum, Trichophyton concentricum, Trichophyton equinum, Trichophyton mentagrophytes var. inter digitale, Trichophyton mentagrophytes var. mentagrophytes, Trichophyton mentagrophytes var. quinckeanum, Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton soudanense, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton roseum, Ulocladium sp., Veronaea botryose, Verticillium sp., Wangiella dermatitidis. In yet another aspect of the invention, there is provided the use of one or more of the compounds according to formulae (I) to (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of a cell proliferative disorder selected from breast cancer, ovarian cancer and prostate cancer.

In still another aspect of the invention, there is provided the use of one or more of the compounds according to formulae (I) to (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of infestation of humans and/or animals by a parasite. The parasite infestation may be infestation by an ectoparasite and/or an endoparasite, such as a parasitic nematode with a free-living life cycle stage.

In still another aspect of the invention, there is provided the use of one or more of the compounds according to formulae (I) to (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of a fungal infection in humans and/or animals.

The term "subject" as used herein includes humans, primates, livestock animals (eg. sheep, pigs, cattle, horses, donkeys), laboratory test animals (eg. mice, rabbits, rats, guinea pigs), companion animals (eg. dogs, cats) birds (eg. chickens, ducks, geese, parrots, cockatoos, pigeons, finches, raptors, ratites, quail, canaries), captive wild animals (eg. foxes, kangaroos, deer) and reptiles (eg. lizards and snakes). Preferably, the subject is human, a livestock animal, a companion animal or a laboratory test animal. Even more preferably, the subject is a human, a companion animal or livestock animal.

An "effective amount" means an amount necessary at least partly to attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular condition or infestation being treated. The amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the degree of protection desired, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. An effective amount in relation to a human patient, for example, may lie in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage is preferably in the range of lμg to 1 g per kg of body weight per dosage, such as is in the range of lmg to 1 g per kg of body weight per dosage, hi one embodiment, the dosage is in the range of 1 mg to 500mg per kg of body weight per dosage. In another embodiment, the dosage is in the range of 1 mg to 250 mg per kg of body weight per dosage, hi yet another embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 μg to 1 mg per kg of body weight per dosage. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals, or the dose may be proportionally reduced as indicated by the exigencies of the situation. Reference herein to "treatment" and "prophylaxis" is to be considered in its broadest context. The term "treatment" does not necessarily imply that a subject is treated until total recovery. Similarly, "prophylaxis" does not necessarily mean that the subject will not eventually contract a disease condition. Accordingly, treatment and prophylaxis include amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition. The term "prophylaxis" may be considered as reducing the severity or onset of a particular condition. "Treatment" may also reduce the severity of an existing condition.

In another aspect of the invention, the compounds of the invention are suitable for use as a pesticide. The invention therefore further provides a pesticidal composition comprising a compound of formula (I) or an agriculturally or pesticidally acceptable salt thereof and an agriculturally or pesticidally acceptable carrier.

The pesticidal composition if for use in controlling fungicidal infections of plants or infestations of plants or environments with unwanted pests and may be in the form of an emulsifiable concentrate, a flowable, a wettable powder, a soluble powder, a solution, an aerosol, a dust, a granule or a bait. A person skilled in the formulation of pesticidal compositions would be able to prepare such formulations.

Suitable carriers for pesticidal and agricultural compositions include, but are not limited to, oils, especially petroleum oils, emulsifϊers, solvents such as water or hydrocarbons, aerosol spray components such as CFCs, talc or clay. hi yet another aspect of the invention, there is provided a method of controlling pests comprising applying a pesticidally effective amount of at least one compound of formulae (I) to (III) to a subject infested with a pest or an environment infested with a pest or a plant infested with a pest. In some embodiments, the pest is an insect, especially flies, beetles, grasshoppers, locusts, butterflies and moths and their larvae or nymphs, especially the flies (Diptera) such as true flies, lice, ticks, fleas, mosquitoes, gnats and midges.

In some embodiments, the pest infests plants. Examples of such pests include, but are not limited to, Acyrthosiphon kondoi (blue-green aphid), Acyrthosiphon pisum (pea aphid), Agrotis spp. (cutworm), Agrypnus variabilis (sugarcane wireworm), Anoplognathus spp. (christmas beetles), Aphodius tørøαrøαe(blackheaded pasture cockchafer), Austroasca alfalfae (lucerne leaf hopper), Bathytricha truncate (sugarcane and maize stemborer), Bemisia tabaci (whitefly), Brachycaudus helichrysi (7eaf curl plum aphid), Brevicoryne brassicae (cabbage aphid), Bruchophagus roddi (lucerne seed wasp), Bruchus pisorum (pea weevil), Bryobia spp. (bryobia mite), Ciampa arietaria (brown pasture looper), Chortoicetes terminifera (Australian plague locust), Chrysodeitis angentifena (tobacco looper), Chrysodeitis eriosoma (green looper), Contarinia sorghicola (sorghum midge), Deroceras spp. (slugs), Diachrysia oricalcea ("soybean looper), Etiella behrii (lucerne seed-web moth), Franklinielϊa schultzei (tomato thrips), Graphognathus leucoloma (white fringed weevil), Halotydeus destructor (redlegged earth mite), Hednota pedionoma (pasture webworm), Helicoverpa armigera (corn earworm), Helicoverpa punctigera (native budworm), Helix spp. (snails), Heteronychus arator (African black beetle), Leucania convecta (common armyworm), Lipaphis erysimi (turnip aphid), Listroderes difficilis (vegetable weevil), Melanacanthus scutellaris (brown bean bug), Merophyas divulscma (lucerne leaf roller), Myzus persicae (green peach aphid), NaIa lividipes (black field earwig), Mythimna convector (common armyworm), Nezara viridula (green vegetable bug), Nysius vinitor (rutherglen bug), Nysius clevelandensis (grey cluster bug), Oncopera rufobrunnea (underground grass grub), Orondina spp. (false wireworm), Othnonius batesi (black soil scarabs), Penthaleus major (blue oat mite), Persectania ewingii (southern armyworm), Petrobia lateens f brown wheat mite), Pieris rapae (cabbage white butterfly), Piezodorus hybneri (redbanded shield bug), Plutella xylostella (cabbage moth/diamondback moth), Rhopalosiphum maidis (corn aphid), Sericesthis spp. (small brownish cockchafers), Sitona discoideus fsitona weevil), Sminthurus viridis (lucerne flea), Spodoptera exigua (lesser armyworm), Spodoptera letura (cluster caterpillar Spodoptera mauritia (lawn armyworm), Stomopteryx simplexella (soybean moth), Tetranychus ludeni (bean spider mite), Tetranychus urticae (two spotted mite), Therioaphis trifoliif. maculata (spotted alfalfa aphid), Thrips tabaci (onion thrips), Thrips imaginis (plague thrips), Zizina labradus (grass blue butterfly), Zygrita diva (lucerne crown borer).

In other embodiments, the pests infest subjects and environments other than plants. Examples of such pests include, but are not limited to, lice, ants including Camponotus spp., Lasius alienus, Acanthomyops interjectus, Monomoήum pharaonis, Solenopsis molesta, Tetramorium caepitum, Monomorium minimum, Prenolepis impairs, Formica exsectoides, Iridomyrmex pruinosus, Cremastogaster lineolata, Tapinoma sessile, Paratrechinalongicornis, cockroaches, mosquitos, bed bugs including Leptoglassus occidentalis, Acrosternum Mare, Chlorochroa sayi, Podius maculiventris, Murgantia histrionica, Oncopeltusfasciatus, Nabis alternatus, Leptopterna dolabrata, Lygus lineolaris, Adelpocoris rapidus, Poecilocapsus lineatus, Onus insidiosus, Corythucha ciliata, bees, wasps, black widow spider, booklice, boxelderbug, brown recluse spider, clothes moths including Tineolaspp., Tinea spp., Trichophaga spp., carpet beetles, centipedes, clover mites, cluster and face flies, cigarette and drugstore beetles, crickets including Acheta spp., Gryllus spp., Gryllus spp., Nemobius spp., Oecanthus spp., Ceuthophilus spp., Neocurtilla spp., daddy-long-legs, domestic flies, drain flies, earwigs, European hornet, fleas including Ctenocephalides felis, Ctenocephalides canis, Ctenocephalides spp.,

Nosopsyllus fasciatus, Nosopsyllus spp., Xenopsylla cheopis, Xenopsylla spp.,

Cediopsylla simplex, Cediopsylla spp. , fungus gnats, ground beetles, hide and larder beetles, horse/cattle/deer/pig flies, house dust mites including Dermatophagoides farinae, Dermatophagoides pteronyssinus, Dermatophagoides spp., mites including

Ornithonyssus sylviarum, Dermanyssus gallinae, Orniihonyssus bacoti,

Liponyssoides sanuineus, Demodex folliculorum, Sarcoptes scabiei hominis,

Pyemotes tritici, Acarus siro, Tyrophagus putrescentiae, Dermatophagoides sp., human lice, humbacked flies, Indian meal moth, millipedes, mud daubers, multicolored asian lady beetle, house borer, midges and crane flies, periodical and "dog-day" cicadas, powderpost beetles, roundheaded and flatheaded borers, pseudoscorpions, psyllids or jumping plant lice, spider beetles, sac spiders, sap beetles, termites, silverfish and firebrats, sowbugs and pillbugs, springtails, stinging hair caterpillars, tarantulas, vinegar flies, wasps and hornets, wharf borer, woods cockroach, yellowjacket wasps, fungus beetles, seed weevils, sawtoothed and merchant grain beetles, confused and red flour beetles, granery and rice weevils, indian meal moth, mealworms, drain flies, ticks including Dermacentar spp., Ixodes spp., Rhipicenphalus spp., carpenter bees, assassin bugs, human lice, chiggers, mystery bugs, stinging hair caterpillars, black-legged tick, mayflies, black flies, horsehair worms, crickets, gypsy moths, grasshoppers, gnats, midges, locusts and mosquitoes including Aedes albopictus, Aedes Canadensis Aedes triseriatus, Aedes tivittatus, Aedes vexans, Aedes spp., Anopheles quadrimaculatus, Anopheles spp., Coquillettidia perturb ans, Coquillettidia spp., Culex pipiens, Culex spp. In yet another aspect of the invention, there is provided a method of treating or preventing a fungal infection in a plant comprising applying an agriculturally effective amount of at least one compound of formulae (I) to (III) to a plant or agricultural environment infected with a fungus. An agriculturally or pesticidally effective amount may be determined by those skilled in the art using known methods and would typically range from 5 g to 500 g per hectare.

In some embodiments the fungal infection is caused by a fungus that infects plants, such as Armillaria mellea, Armillaria spp., Ashbya gossypii, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus spp., Blumeria graminis, Blumeria spp., Botryosphaeria dothidea, Botrytis cinerea, Botrytis spp., Candida albicans, Candida tropicalis, Candida spp., Candida dubliniensis, Cercospora kikuchii, Cercospora spp., Cladosporium fulvum, Cladosporium spp., Claviceps purpurea, Coccidioides immitis, Cochliobolus carbonum, Cochliobolus heterostrophus, Cochliobolus victoriae, Colletotrichum gloeosporioides, Colletotrichum lagenarium, Colletotrichum lindemuthianum, Colletotrichum trifolii, Colletotrichum musae, Colletotrichum spp., Coprinus cinereus, Cryphonectria parasitica, Cryptococcus neoformans, Diaporthe perjuncta, Eutypa spp., Diplodia spp., Diaporthe spp., Dothiorella dominicana, Dothiorella mangiferae, , Dothiorella spp., Fomes spp., Fusarium graminearum, Fusarium oxysporumfsp lycopersici, Fusarium oxysporum, Fusarium solani, Fusarium spp., Geotrichum candidum, Geotrichum spp., Gibberella pulicaris, Leptosphaeria maculans, Magnaporthe grisea, Melampsoralini, Moniliniaspp., Mycosphaerella graminicola, Mycosphaerella spp., Nectria haematococca, Neurospora crassa, Neurospora spp., Penicillium chrysogenum, Penicillium spp., Pestal spp. Phanerochaete chrysosporium, Phoma spp., Phomopsis spp., Phylosticta spp., Phycomyces blakesleeanus, Phytophthora infestans, Phytophthora ramorum, Phytophthora sojae, Phytophthora spp., Plasmopara viticola, Phomopsis viticola, Phomopsis spp., Pneumocystis carinii, Puccinia graninis, Puccinia spp., Pyrenophora teres, Pythiumspp., Rhizopus oryzae, Rhizopus stolonifer, Rhizopus spp., Rhizoctonia solani, Rhizoctonia spp., Saccharomyces spp., Saccharomyces cerevisiae, Schizosaccharomyces pombe, Sclerotia sp., Sclerotinia sclerotiorum, Sclerotinia spp., Trichoderma harizanum, spp., Ustilago maydis. As used herein, the term "environment infested with a pest" may be any environment but includes an "agricultural environment", a "household environment" and an"industrial environment". An "agricultural environment" refers to an environment in which agriculture is carried out, for example, the growing of crops, trees and other plants of commercial importance. The agricultural environment includes not only the plant itself, but also the soil and area around the plants as they grow and also areas where parts of plants, for example, seeds, grains, leaves or fruit may be stored.

A "household environment" includes environments that are inhabited by humans or animals and may include indoor environments such as carpets, curtains, cupboards, bedding and the air inside a house. An "industrial environment" includes environments which are used for industrial purposes such as manufacture, storage or vending of products. Industrial environments include warehouses, manufacturing plants, shops, storage facilities and the like. hi this aspect, a preferred compound of formulae (I) to (III) is EBI-53

(5 ,6,2 ' 6 ' -tetramethoxyflavone) .

The invention further provides use of a compound of formula (I) as an agrochemical.

Accordingly, the compound of formulae (I) or (III) may be formulated in an appropriate manner for delivery to crops, pastures, forests and other agricultural environments, preferably for the alleviation and/or eradication of one or more insect pests or fungal infections. hi this specification, the terms "comprises", "comprising" or similar terms are intended to mean a non-exclusive inclusion, such that a method, system or apparatus that comprises a list of elements does not include those elements solely, but may well include other elements not listed.

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 : Flowchart for initial solvent extraction of compounds of formula (I); FIG. 2A: Flowchart showing the solvent partition for the aqueous concentrate obtained from the extraction shown in Fig 1;

FIG. 2B: Flowchart showing the solvent partition for the ethyl acetate residue obtained from the extraction shown Fig 1 ; FIG. 3: Flowchart showing the steps in preparative HPLC chromatography;

FIG. 4: Graphically represents selective inhibition of tumour cell growth in culture by EBI-53;

FIG. 5: Graphically represents selective inhibition of tumour cell growth in

B 16 melanoma in C57BL/6 mice treated daily with intraperitoneal injection of EBI-53, at doses of 40 μg/mouse/day on days 2-7, 80 μg/mouse/day on days 8-11 and

160 μg/mouse/day on days 12-13.

FIG. 6: Graphically represents selective inhibition of tumour cell growth in

B16 melanoma in C57BL/6 mice treated daily with intraperitoneal injection of

EBI-53, at doses of 32 μg/mouse/day on day 2 then 160 μg/mouse/day.

DETAILED DESCRIPTION

ACTIVITY SCREENING

A solvent extraction sample from Zanthophyllum octandra containing compounds of formulae (I) to (III) were tested to determine therapeutic activity by screening (A) in a range of Microbial Screening Technologies bioassays, notably NemaTOX, ProTOX, MycoTOX, CyTOX and DipteraTOX, and (B) a range of anticancer assays. For ease of description these bioassays will be described briefly prior to the extraction and chemical structure elucidation methodologies. Bioassays included: NemaTOX (alternatively referred to herein as Ne) is an anthelmintic bioassay, applicable to all parasitic nematodes with free-living life cycle stages, and can be used as a screen to detect activity and define the species spectrum of compounds against parasitic nematodes and examine the impact of pre-existing resistance to other anthelmintic classes on potency. Haemonchus contortus was utilised for this assay. The effect on larval development was determined in this assay by the method described by Gill et al. (1995) Int. J. Parasitol. 25: 463-470. Briefly, in this assay nematode eggs were applied to the surface of an agar matrix containing the test sample and allowed to develop through to the L3, infective stage (6 days). At this time the stage of larval development reached and any unusual features (deformity, paralysis, toxicity) were noted by microscopic examination.

ProTOX, (alternatively referred to herein as Bs) is an antibacterial bioassay, broadly applicable to most aerobic and anaerobic bacteria. The bioassay features a solid phase agar base into which the test compound has been incorporated together with a chromogen. As the bacteria multiply in the well, the chromogen is metabolised from blue in a two-step process to a colourless compound. Compounds with potent bactericidal activity inhibit bacterial metabolism of the chromogen while bacteriostatic compounds induce limited metabolism as indicated by an intermediate pink colour. ProTOX is broadly applicable to a range of gram-positive and gram-negative bacteria under aerobic and microaerophilic conditions. ProTOX assays were carried out using Bacillus subtilis.

Briefly, in ProTOX, the bacteria (24 hours broth) were applied to the surface of an agar matrix containing the test sample and allowed to grow for 48 hours. The assay was monitored at 24 and 48 hours and the active wells noted. Known antibiotics yield consistent colour transitions which were concentration and time dependent. These patterns provided an important guide to the early recognition of interesting characteristics. Bactericidal actives were assessed as having no colour change at both 24 and 48 hours while bacteriostatic actives were assessed as active at 24 hours but less potent or inactive at 48 hours. MycoTOX (alternatively referred to herein as Tr) is a non-chromogenic bioassay used to detect activity against filamentous fungal pathogens of plants and animals. The bioassay features a solid phase agar base into which the test compound has been incorporated. As the growth patterns of filamentous fungi are readily apparent on the agar surface the extent of mycelial growth, sporulation (if relevant to the species under investigation) and colour changes with maturation are measured. Compounds with potent antifungal activity inhibit germination of fungal spores and provide a stark contrast to wells containing inactive compounds with the excessive fungal growth. Lower concentrations of such compounds, or compounds exhibiting a more fungistatic mode of action, show reductions in mycelial growth, extent of sporulation or reductions in other characteristic patterns of colony maturation.

MycoTOX, involved a fungus (spore suspension or mycelial fragments) being applied to the surface of an agar matrix containing the test chemical and allowed to grow for a period of up to a week (depending on species). The assay was monitored at two discrete times to identify key development phases in the life cycle (for example mycelial growth and extent of sporulation) and the active wells noted. The monitoring times were dependent on the fungal species under investigation.

The MycoTOX assays were carried out using Trichophyton rubrum. In the below examples the alternative reference to the MycoTOX test as Tr to indicates the use of Trichophyton rubrum. CyTOX (alternatively referred to herein as Cy) is a microtitre plate bioassay use to identify potential antitumour actives. CyTOX is a chromogenic bioassay with broad application to a wide range of tumour and non-tumour cell lines. The colour transitions in CyTOX are proportional to cell metabolism and turnover and hence offer useful recognition patterns to support the diagnostic classification of actives within a framework of known cytotoxic and antitumour actives.

CyTOX features a liquid media into which the test compound has been incorporated together with a chromogen. As the cells grow and divide the chromogen is metabolised from purple in a single step process to a colourless metabolite. CyTOX was undertaken using NSl murine myeloma cell line as a guide to mammalian cell toxicity.

Briefly, in CyTOX the cells were applied to the media containing the test chemical and allowed to grow for 72 hours. The assay was monitored at 24, 48 and 72 hours and the active wells identified. DipteraTOX,

DipteraTOX is referred to herein as DipG, DipP and DipH. DipG represents no grazing of larva. DipP represents no pupae formation and Dip H represents no hatching of flies. A value of A in DipG, Dip P or Dip H represents very active and a value of P represents active. In DipteraTox the fly eggs were applied to the surface of an agar matrix containing 250 μg per mL of the test chemical and allowed to hatch, develop and pupate for a period up of two weeks. The assay was monitored at two discrete times to determine the extent of grazing of the agar matrix at Week 1 and the presence of adult flies at Week 2. Activity was scored qualitatively as active or inactive at Days 7 and 14 to denote failure to feed and failure to development to the adult stage, respectively. Anticancer assays included: SRB assay for inhibition of growth of cells cultured as monolayers

Briefly, cells were seeded at 2-5,000 per microtitre well (96-well plate) in 10% FCS- RPMI 1640 culture medium, treated, and allowed to grow until the controls were nearly confluent (5-6 days). The wells were then washed twice with PBS, fixed with ethanol for a minimum of 5 minutes and washed with water. SRB solution (50 μL of 0.4% in 1% acetic acid) was added and left at room temperature for a minimum of 15 minutes. The plate was washed rapidly with tap water and then twice with 1 % acetic acid. After addition of 100 μL/well of 10 mM Tris base (unbuffered, pH > 9), plates were left for a minimum of 5 minutes, then the absorbance was read at 564 nm on an ELISA reader, with a 3 second prior shaking. After subtraction of a blank (wells with no cells, absorbance typically about 0.04), growth inhibition was calculated as % of the untreated control and plotted against dose.

Assay for inhibition of growth of cells cultured in suspension

Suspension cells were seeded into round-bottom microtitre plates in 10%

FCS-RPMI 1640 culture medium, treated and allowed to grow for 5-6 days. To measure cell growth, 20 μL of a combined MTS/PMS solution (Promega Cell ProliferationAssay Kit Cat#G5430) was added to each well of the 96 well assay plate. After 1 -4 hours the plates were placed in the ELISA plate reader and the absorbance read at 490 nm. After subtraction of a blank (wells with no cells, absorbance typically about 0.4), growth inhibition was calculated as % of the untreated control and plotted against dose In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples.

EXAMPLE l METHODS Extraction

Biomass samples of seeds from Zanthophyllum octandra where collected and subject to the following extraction process. These samples and their subsequent fractions are referred in the below example as EB 82. Phase 1 - Extraction The biomass is generously covered with methanol and shaken (~2 L, overnight) followed by filtration to give the first extract. This process is repeated a second time (~2 L, ~5 hours) to generate the second extract. Each extract is examined by analytical HPLC and bioassayed (FIG. 1). The sequential methanol extracts are combined and the solvent removed by rotary evaporation to afford an aqueous concentrate.

Phase 2 - Solvent Partition

The aqueous concentrate from the extraction is diluted with water to 400 mL. The diluted sample (code 'Cr') is subsampled for HPLC and bioassay, then shaken with an equal volume of ethyl acetate (EtOAc) in a separatory funnel and the individual layers, EtOAcI and H2O1, collected. Note, occasionally a precipitate would form that was insoluble in either layer. This precipitate was collected by filtration and dissolved in methanol (code 'Me'). The lower aqueous layer (H2O1) was twice more extracted with ethyl acetate to give EtO Ac2 and EtO Ac3 along with the remaining H2O3 layer. Subsamples of all layers are examined by analytical HPLC and bioassay (FIG. 2A). The sequential ethyl acetate extracts are pooled and the solvent removed by rotary evaporation to afford a residue that is weighed. On occasions, analytical HPLC indicated the EtOAc extract contained considerable amounts of extremely lipophilic (RT >9 minutes) material. To remove this material a 10:9:l-hexane:methanol:water partition was performed (FIG. 2B). Phase 3 - Preparative HPLC Fractionation

The residue from the solvent partition is investigated by analytical HPLC to find optimum chromatographic conditions for separation of the metabolites present. Using these optimum conditions the residue (~2 g) is fractionated by preparative reverse phase HPLC (C 18, single injection) into 100 fractions (FIG. 3). Subsamples of all 100 fractions are examined by analytical HPLC. After analysis of the HPLC traces, the 100 fractions are consolidated into 20 to 30 pooled fractions (pools), some of which may be >80% pure. These pooled fractions are weighed, bioassayed and examined by analytical HPLC. Solvent Partition Summary for EB82

Biomass samples of Zanthophyllum octandra under went extraction and solvent partitioning, using phase 1 and 2 described above. Table 1 summarises the amounts of extractable material obtained from Zanthophyllum octandra after solvent partitioning with ethyl acetate. TABLE 1: Weights after Ethyl Acetate Partition of Extracts

^eighfcTotal sample weight in grams of plant material supplied and used for the study. ²EtOAc: Ethyl acetate extractables. ³%Ext: Ethyl acetate extractables expressed as a percentage of the total sample weight. Preparative HPLC

The preparative HPLC was carried out on a system consisting of two Shimadzu LC-8A Preparative Liquid Chromatographs with static mixer, Shimadzu SPD-MlOAVP Diode Array Detector and Shimadzu SCL-IOAVP System Controller. The column used was 50 x 100 mm (diameter x length) packed with Cl 8 Platinum EPS (Alltech).

Approximately 2 grams of ethyl acetate extracted material was dissolved in dimethyl sulphoxide (4 mL) and subjected to preparative HPLC with typical conditions being 60 mL/minute with gradient elution of 30% to 100% acetonitrile/water over 20 minutes followed by acetonitrile for 10 minutes. One hundred fractions (20 mL) were collected, evaporated under nitrogen, and then combined on the basis of HPLC analysis. UV Analysis UV spectra were acquired during HPLC with the Shimadzu SPD-Ml OAVP

Diode Array Detector as mentioned above. NMR Analysis

All NMR spectra were acquired in d6-dimethyl sulphoxide and referenced to the residual dimethyl sulphoxide signals or deuterated chloroform (CDCl₃) and referenced to residual chloroform signals. ID NMR spectra, ¹H and ¹³C [APT], were acquired at 300 and 75 MHz respectively on a Varian Gemini 300BB (Palo Alto CA. USA) spectrometer.2D NMR spectra, HSQC, HMBC, COSY and TOCSY, and a ID NMR ¹H spectrum were acquired on a Bruker DRX600 (600 MHz) NMR spectrometer. Analysis of NMR data was performed using ACD/SpecManager and

ACD/Structure Elucidator, both version 6.0 from Advanced Chemistry Development, Inc. (Toronto, ON, Canada). Electrospray Mass Sepctrometry Analysis (ES-MS)

AU positive electrospray mass spectra were performed on a Finnigan/Mat TSQ7000 LCMS/MS (San Jose CA. USA).

EXAMPLE 2 EB82 : Extraction and Solvent Partition

Extraction and solvent partitioning of EB82 afforded 2.9 g of material. Each of the extraction and solvent partition layers were tested for bioactivity using the above bioassays. It can be seen from Table 2 that ethyl acetate layers contained high NemaTOX, MycoTOX and CyTOX activity. TABLE 2: Activity of Extracts and Solvent Partitions.

⁴LD₉₉ in μg/mL. The successive aqueous concentrated extracts were subjected to HPLC. The column used was 50 x 100 mm (diameter x length) packed with Cl 8 Platinum EPS (Alltech).

Approximately 2 grams of extracted material was dissolved in dimethyl sulphoxide (4 mL) and subjected to preparative HPLC with typical conditions being 60 mL/minute with gradient elution of 30% to 100% acetonitrile/water over 20 minutes followed by acetonitrile for 10 minutes.

For comparison purposes the first ethyl acetate partition and the third water layers were analysed by HPLC. There was little or no compounds of interest remaining in the third water layer of the third water/ethyl acetate solvent partition. First Preparative HPLC Fractionation

In a manner similar to that described in Phase 3 above the EB 82 ethyl acetate solvent partition samples where pooled and further worked up using preparative HPLC chromatograph.

The preparative HPLC was used to produce 100 fractions. These fractions were pooled depending on the relative concentration of compounds indicated in the preparative HPLC chromatograph. The bioactivity of each fraction or pooled fraction resulting from the preparative HPLC was determined using the above bioassay methods. The results are summarised below at Table 3.

⁴ LD₉₉ in μg/mL calculated as weight of chemical in last well with activity, however the real value may be lower as end point not attained. ⁵Wt is weight in mg.

EXAMPLE 3

CHEMICAL STRUCTURAL ELUCIDATION EBI-53

The pool of like material (fractions 29 to 31, 305.4 mg, from the gradient preparative HPLC run) was dissolved in methanol and subjected to preparative HPLC (10 niL/min with isocratic elution of 55% water/acetonitrile over 30 minutes, through a 5 μm Phenomenex Luna C 18(2) 20 x 100 mm column). Fractions 7 to 9 were combined, concentrated under vacuum, freeze dried and the resulting product was analysed by UV spectroscopy, HPLC analysis (Retention time: 5.45 minutes), ES-MS and NMR. From the HPLC, ES-MS and NMR analysis it was determined that EB82.LA4.76-7/9 contained the following compound:

referred to herein as EBI-53 (5,6,2'6'-tetramethoxyflavone). NMR data and assignment are shown in Table 4.

TABLE 4: NMR Data for EBI-53 in DMSO-de at 75/600 MHz.

No. δ ^I3C δ ¹H Multiplicity (J in Hz)

2 158.7

3 114.2 6.08 S

4 176.4

4a 118.4

5 146.5

6 113.8 7.34 d (9.3)

7 119.3 7.52 d (9.3)

8 149.5

8a 151.4

9 61.1 3.76 S

10 56.6 3.85 S

I¹ 110.4

2',6' 157.9

3',5' 104.3 6.78 d (8.5)

4' 132.5 7.46 t (8.5)

7',8' 56.0 3.75 S The structure shown above, EBI-53, was chosen as a result of direct comparison with literature data.

EBI-53 has a structural isomer shown below:

referred to herein as EBI-53-2 (7,8,2'6'-tetramethoxyflavone). EB82.LA4.76-7/9 may comprise EBI-53-2.

Either of both of EBI-53 and EBI-53-2 may be present in a plant extract obtained from a plant or plant part, such as those plants described herein.

Preferably the EBI-53 is the major active constitiuent.

EXAMPLE 4 Synthesis of EBI-53 {Indian J. Chem., 1969, 7, 746-750; Tetrahedron, 1967, 23, 4607-4612.)

KOH

86% MeOH (70%) RCHO

Synthesis of the key intermediate 6 was straightforward and gave good to excellent overall yields. Even though intermediate 4 is commercially available it was decided to start with the inexpensive diketone 1, which was converted into 4 following literature procedures [Tetrahedron Letters 1996, 37, 1007-1010 (step 1); Bull. Korean. Chem. Soc. 2003, 24, 1057-1058 (step 2 and 3)]. Regioselective oxidation and subsequent selective methylation of 4 lead to 6, which provided the right substitution pattern for EBI-53 (Phytochemistry 1990, 29, 633-637). Oxidation to 5 was not efficient (46%), but since no byproduct was formed (recovered starting material 42%), the reaction was acceptable. To obtain flavone 8 multiple routes are possible. Hydroxyketone 6 was transformed into chalcone 7 via Knoevenagel- Condensation with commercially available 2,6-dimethoxybenzaldehyde (RCHO). Acid catalysed ring formation (to the flavanone) and subsequent oxidation with dichlorodicyanoquinone (DDQ) when applied to chalcone 7 were unsuccessful. Finally direct conversion to flavone 8 (EBI-53; also known as Zapotin) was obtained in moderate yields using iodine in DMSO at high temperature (130°C) (Bioorg. & Med. Chem. Lett. 2004, 14, 1165-1167).

Experimental section: 3-Oxocyclohex-l-enyl acetate (2): To a solution of cyclohexan-l,3-dione (Hg, lOOmmol) in dichloromethane (150 mL) was added triethylamine (20 mL) followed by addition of acetylchloride (7.5 mL, 110 mmol) at 0°C. The reaction mixture was allowed to warm up to room temperature over 1 hour. The mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was then concentrated and subjected to column chromatography on silica using petroleum spirit / ethyl acetate 2:1 as solvent.

Yield: 11.54 g (75%) ¹H NMR (CDCl₃, 300 MHz) δ 5.75 (bt, IH), 2.41-2.39 (m, 2H), 2.27-2.24 (m, 2H), 2.10-06 (s, 3H), 1.94-1.91 (m, 2H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 199.22, 169.51, 167.06, 117.14, 36.39, 27.99, 20.92 (CH₂) , 20.92 (CH₃) ppm. Lit.: Bull. Korean. Chem. Soc. 2003, 24, 1057-1058.

2-AcetyI-3-hydroxycyclohex-2-enone (3): To a solution of 2 (11.54 g, 74 mmol) in acetonitrile (150 mL) was added triethylamine (22 mL) and potassium cyanide (200mg). The reaction mixture was stirred for 72 hours at room temperature. After evaporation of the solvent the crude product was dissolved in ethyl acetate (150 mL) and washed with HCl (IM, 300 mL) and brine (150 mL). The organic layer was reduced and the crude subjected to column chromatography on silica (petroleum spirit / ethyl acetate 4:1). Yield: 7.4 g (64%) ¹H NMR (CDCl₃, 300 MHz) δ 2.64 (t, J= 4.8 Hz₅ 2H), 2.57 (s, 3H), 2.46 (t, J= 4.8 Hz, 2H), 1.95 (p, J= 4.8 Hz, 2H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 203.14, 198.66, 195.40, 113.41, 38.60, 33.25, 28.82, 18.99 ppm. Lit: Tetrahedron Letters 1996, 37, 1007-1010.

2-Hydroxy-6-methoxy-acetophenone (4): To a solution of 3 (7 g, 43.75 mmol) in methanol (350 niL) was added iodine (22.2 g, 87.5 mmol). The reaction mixture was refluxed for 17 hours. The mixture was diluted with dichloromethane (200 mL) and washed with sodium thiosulfite (Na₂S₂O₅, IM, 250 mL, 2x) and brine (150 mL). The organic layer was concentrated and the crude mixture subjected to column chromatography (petroleum spirit / ethyl acetate 10:1). Yield: 6 g (83%) ¹H NMR (CDCl₃, 300 MHz) δ 7.31 (t, J= 5.0 Hz, IH), 6.54 (dd, J= 5.0, 0.6 Hz, IH), 6.36 (dd, J= 5.0, 0.6 Hz, IH), 3.87 (s, 3H), 2.65 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 205.11, 164.66, 161.51, 136.02, 111.33, 110.73, 101.10, 55.60, 33.60 ppm. Lit: Bull Korean. Chem. Soc. 2003, 24, 1057-1058.

2,4-Dihydroxy-6-methoxy acetophenone (5): A reddish solution of 4 ( 5.7 g, 34.3 mmol) in sodium hydroxide solution (10%, 500 mL) was added dropwise to a solution of potassium persulfate (9.37 g) in water (400 mL) at room temperature and stirred for 2 hours. The reaction mixture was then placed in a fridge over night. The pH was adjusted to -5.5 with cone. HCl (125 mL) and extracted with ethyl acetate (400 mL). The ethyl acetate layer was evaporated affording pure 4 (3 g, 52%). To the aqueous layer was added further cone. HCl (25 mL) and sodium sulfite (6.6 g) and the whole was refluxed for 2 hours. The mixture was then extracted with dichloromethane (4x 200 mL). The combined organic layers were dried and evaporated. The crude product was further purified on column chromatography on silica (petroleum spirit / ethyl acetate 3:1).

Yield: 2.5 g (40%, 85% based on recovered starting material) and a small amount of the regioisomer 2,3-dihydroxy-6-methoxy acetophenone (0.15 g, 2.4%, 5% based on recovered starting material) was obtained. ¹H NMR (CDCl₃, 300 MHz) δ 11.99 (s, IH), 7.07 (d, J= 9.0 Hz, IH), 6.62 (d, J= 9.0 Hz, IH), 3.81 (s, 3H), 2.69 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 204.39, 156.37, 147.39, 141.42, 128.93, 124.60, 114.00, 61.91, 31.35 ppm. Lit: Phytochemistry 1990, 29, 633-637; Chem. Pharm. Bull. 1984, 32, 3354-3360.

5,6-Dimethoxy-2-hydroxy acetophenone (6): To a solution of 5 (2.4 g, 13.2 mmol) in acetone (110 mL) was added potassium carbonate (11 g) and dimethylsulfate (1.7 g, 13.2 mmol). After stirring at room temperature for 2 - 3 hours another equivalent of dimethylsulfate was added and the reaction was quenched after 4 hours by adding water. The mixture was filtered and neutralized with HCl (IM) and extracted with dichloromethane (200 mL). The organic layer was washed with brine (150 mL) and the crude product was purified by column chromatography on silica (petroleum spirit / ethyl acetate 6:1).

Yield: 1.4 g (54%) ¹HNMR (CDCl₃, 400 MHz) δ 12.14 (s, IH), 7.09 (d, J= 7.3 Hz, IH), 6.65 (d, J= 7.3 Hz, IH), 3.92 (s, 3H), 3.81 (s, 3H), 2.70 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) 5205.14, 156.91, 150.96, 145.03, 122.21, 115.27, 112.56, 60.94, 57.18, 32.73 ppm. Lit.: Phytochemistry 1990, 29, 633-637; Chem. Pharm. Bull. 1984, 32, 3354-3360.

l-(6-Hydroxy-2,3-dimethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-l-one

(7): To a solution of 6 (200 mg, 1 mmol) in methanol/water (70:30, 25 mL) was added 2,6-dimethoxybenzaldehyde (166 mg, 1 mmol) and potassium hydroxide (2 g). The reaction mixture was refluxed for 17 hours and acidified with HCl (IM). The orange precipitate was collected and washed with water and dried. Yield: 250 mg (73%) ¹H NMR (CDCl₃, 400 MHz) δ 12.29 (s, IH), 8.40-8.30 (m, 2H), 7.28 (t, J= 6.3 Hz, IH), 7.09 (d, J= 6.8 Hz, IH), 6.70 (d, J= 6.8 Hz, IH) 6.56 (d, J= 6.3 Hz, IH), 3.94 (s, 6H), 3.85 (s, 3H), 3.84 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 196.04, 160.58, 157.11, 150.59, 145.29, 135.47, 131.72, 129.09, 120.89, 116.60, 113.09, 112.63, 103.70, 61.98, 57.11, 55.85 ppm. Lit: Phytochemistry 1990, 29, 633-637. Zapotin (8): To a solution of 7 (200 mg, 0.58 mmol) in dimethylsulfoxide (50 mL) was added a catalytic amount of iodine (~10 mg) and heated to 130°C for 5-10 hours. The reaction mixture was poured into ice water (100 mL) and sodium sulfite (300 mg in 20 mL water) was added. The mixture was extracted with dichloromethane (2x 50 mL). The organic layers were concentrated and the crude product purified with column chromatography on silica (petroleum spirit / ethyl acetate 1:1). Spectroscopic data of 8 is identical with provided EBI-53.

Yield: 69 mg ( 35%) ¹U NMR (CDCl₃, 400 MHz) δ 7.36 (t, J=6.3 Hz, IH), 7.25 (d, J= 6.9 Hz₅ IH), 7.17 (d, J= 6.9 Hz, IH), 6.60 (d, J= 6.3 Hz, 2H), 6.24 (s, IH), 3.96 (s, 3H)₅ 3.89 (s, 3H), 3.77 (s, 6H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 178.12, 158.80, 158.51, 152.65, 149.59, 147.90, 131.98, 119.38, 118.91, 115.22, 113.69, 111.35, 103.92, 61.83, 57.24, 55.97 ppm. Lit: Bull Chem. Soc. Jpn. 2003, 76, 835-836; Bioorg. & Med. Chem. Lett. 2004, 14, 1165-1167.

EXAMPLE 5 Synthesis of EBI-53-2

For further determination an isomer of EBI-53 was synthesised and NMRs were recorded and compared to EBI-53.

The methylation of commercial available triol 10 lead to the trimethoxy acetophenone 11. All attempts to methylate selectively at position (3 and 4) resulted in either no reaction or complete methylation. However, it was possible to deprotect regioselectively at position 2 using AlCl₃ in acetonitrile at 40°C within 1 hour. Knoevenagel condensation and ring formation/oxidation with iodine hi DMSO were successful. It should be noted that cyclisation was better (70%) in this case than for EBI-53. The sequence of deprotection and Knoevenagel condensation can be run in reverse order and provide a slightly better yield (69% instead of 63%).

Comparison between NMR spectra of EBI-53 and EB 1-53-2 provides further evidence regarding the identity of EBI-53 being 5,6,2'6'-tetramethoxyflavone.

Experimental Section:

2,3,4-Trimethoxy acetophenone (11): To a solution of 10 (1.66 g, 10 mmol) in acetone (50 mL) was added potassium carbonate (11 g) and dimethylsulfate (6 niL, 30 mmol). After stirring at 45°C for 17 hours the reaction was quentched by adding water. The mixture was filtered and neutralized with HCl (IM) and extracted with dichloromethane (200 mL). The organic layer was washed with brine (150 mL) and the crude product was purified by column chromatography on silica (petroleum spirit / ethyl acetate 5:1).

Yield: 1.85 g (88%) ¹HNMR (CDCl₃, 300 MHz) δ 7.50 (d, J= 8.8 Hz, IH), 6.68 (d, J= 8.8 Hz, IH)₅ 3.94 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 2.58 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 198.01, 157.44, 154.30, 128.99, 125.78, 125.57, 106.99, 61.30, 60.80, 56.06, 30.97 ppm. Lit.: Phytochemistry 1990, 29, 633-637; Chem. Pharm. Bull. 1984, 32, 3354-3360. 3,4-Dimethoxy-2-hydroxy acetophenone (12): To a cooled solution (0°C) of 11 (1.1 g, 5 mmol) in acetonitrile (10 mL) under argon was added a solution OfAlCl₃ in acetonitrile (1 g, 10 mL) in one portion. The mixture was stirred at 45°C for 1 hour. The reaction was quenched by adding HCl (IM, 100 mL) and refluxed for 10 minutes. The product was collected by filtration.

Yield: 820 mg (80%) ¹H NMR (CDCl₃, 300 MHz) δ 12.56 (s, IH), 7.46 (d, J= 9.0 Hz, IH), 6.46 (d, J= 9.0 Hz, IH), 3.90 (s, 3H), 3.86 (s, 3H), 2.55 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 203.21, 158.50, 157.05, 138.45, 126.98, 115.32, 102.86, 60.64, 56.10, 26.36 ppm. Lit: Bioorg. & Med. Chem. Lett. 2004, 14, 1165-1167; Phytochemistry 1995, 39, 1201-1210.

l-(2-Hydroxy-3,4-dimethoxyphenyl)-3-(2,6-dimethoxyphenyI)prop-2-en-l-one

(13): To a solution of 12 (200 mg, 1 mmol) in methanol/water (70:30, 25 mL) was added 2,6-dimethoxybenzaldehyde (166 mg, 1 mmol) and potassium hydroxide (2 g). The reaction mixture was refluxed for 17 hours and acidified with HCl (IM). The orange precipitate was collected and washed with water and dried. Yield: 240 mg (70%) ¹HNMR (CDCl₃, 400 MHz) δ 8.33 (d, J= 15.7, IH), 8.03 (d, J=15.7, IH), 7.64 (d, J= 9.1, IH), 7.27 (t, J= 8.4 Hz, IH), 6.55 (d, J= 8.4 Hz, IH), 6.49 (d, J= 9.1 Hz, IH), 3.91 (s, 3H), 3.90 (s, 6H), 3.89 (s, 3H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 194.17, 160.44, 158.19, 158.06, 136.54, 135.68, 131.87, 128.95, 126.05, 122.62, 115.98, 112.66, 103.71, 102.57, 60.58, 56.01, 55.85 ppm (OH missing). Lit.: Phytochemistry 1990, 29, 633-637.

l-(2,3,4-Trimethoxyphenyl)-3-(2,6-dimethoxyphenyl)prop-2-en-l-one (14): To a solution of 11 (210 mg, 1 mmol) in methanol/water (70:30, 25 mL) was added 2,6- dimethoxybenzaldehyde (166 mg, 1 mmol) and potassium hydroxide (2 g). The reaction mixture was refluxed for 17 hours and acidified with HCl (IM). The orange precipitate was collected and washed with water and dried. Yield: 250 mg (70%) ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (d, J= 16.2, IH), 7.83 (d, J=I 6.2, IH), 7.42 (d, J= 8.8, IH), 7.24 (t, J= 8.4 Hz, IH), 6.72 (d, J= 8.8 Hz, IH), 6.55 (d, J= 8.4 Hz, IH), 3.91 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (s, 6H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 192.95, 160.31, 156.39, 134.67, 131.20, 129.32, 129.00, 127.58, 125.64, 107.08, 103.73, 61.98, 60.98, 56.01, 55.79 ppm. Lit: Phytochemistry 1990, 29, 633-637.

l-(2-Hydroxy-3,4-dimethoxyphenyl)-3-(2,6-dimethoxyphenyI)prop-2-en-l-oiie (13): To a cooled solution (O⁰C) of 14 (237 mg, 0.66 mmol) in acetonitrile (10 niL) under argon was added a solution OfAlCl₃ in acetonitrile (1 g, 10 mL) at once. The mixture was stirred at 45°C for 1 hour. The reaction was quenched by adding HCl (IM, 100 mL) and refluxed for 1 hour. The product was collected by filtration.

Yield: 200 mg (88%) Spectral data identical to that on page 10. Lit. : Bioorg. & Med. Chem. Lett. 2004, 14, 1165-1167; Phytochemistry 1995, 39, 1201-1210.

EBI-53-2 (9): To a solution of 13 (170 mg, 0.5 mmol) in dimethylsulfoxide (25 mL) was added a catalytic amount of iodine and heated to 130°C for 5-10 hours. The reaction mixture was poured into ice water (100 mL) and sodium sulfite (300 mg in 20 mL water) was added. The mixture was extracted with dichloromethane (50 mL, 2x). The organic layers were concentrated and the crude product purified with column chromatography on silica (petroleum spirit / ethyl acetate 1:1). Yield: 120 mg (70%) ¹HNMR (CDCl₃, 400 MHz) δ 7.97 (d, J= 9.0 Hz, IH),

7.37 (t, J= 8.4 Hz, IH), 7.02 (d, J= 9.0 Hz, IH), 6.61 (d, J= 8.4 Hz, 2H), 6.41 (s, IH), 3.96 (s, 3H), 3.92 (s, 3H), 3.77 (s, 6H) ppm. ¹³C NMR (CDCl₃, 75 MHz) δ 178.20, 160.37, 158.60, 156.20, 136.83, 132.10, 120.94, 118.79, 114.33, 111.51, 109.61, 103.97, 61.54, 56.42, 55.88 ppm. Lit: Bull. Chem. Soc. Jpn. 2003, 76, 835-836; Bioorg. & Med. Chem. Lett. 2004, 14, 1165-1167.

EXAMPLE 6

The bioassay results of Table 5a and 5b clearly indicate that compound EBI-53 has efficacy as (A) a cytotoxic agent and therefore would be useful in the treatment and prophylaxis of cell proliferative diseases such as tumours, leukaemia, lymphoma and related disorders especially breast cancer, ovarian cancer and prostate cancer, (B) an antiparasitic and therefore would be useful in the treatment of infestation by a parasite such as an ectoparasite and/or an endoparasite of a human and/or an animal, and (C) an insecticide and therefore would be useful in the eradication and/or growth inhibition of a an insect including a broad range of insect species and (D) a fungicide and therefore be useful in the eradication and/or growth inhibition of fungi including a broad range of fungal species. TABLE 5a: - Bioassays of EBI-53

⁴ LD₉₉ in μg/mL calculated as weight of chemical in last well with activity, however the real value may be lower as end point not attained. ⁵Wt is weight in mg.

TABLE 5b: Bioassays of EBI-53

EXAMPLE 7 Materials and Methods

The human tumour cell lines were: MCF-7 and T47D, breast cancer; DU145 and PC3, prostate cancer; CI80-13S, ovarian cancer; MM96L, melanoma; HT29, colon cancer. Neonatal foreskin fibroblasts (NFF) were used as normal control cells.

Cells were cultured at 37°C in 5% carbon dioxide/air, in RPMI 1640 medium containing 10% fetal calf serum.

For growth inhibition assays in culture, cells (2000-5000/well) were seeded in 96-well plates in duplicate, treated with drug next day and allowed to grow for a further 5-6 days . The plates were then washed in PB S (phosphate-buffered saline, pH 7.2), fixed with ethanol and stained by addition of 50 μL 0.4% SRB (sulforhodamine) per well in 1% acetic acid. The plate was left at room temperature for a minimum of 15 minutes, then washed rapidly with tap water and then twice with 1 % acetic acid. After addition of 100 μL/well of 10 mM Tris base (unbuffered, pH > 9), plates were left for a minimum of 5 minutes, then the absorbance was read at 564 run on the ELISA reader, with a 3 second prior shaking. After subtraction of a blank (wells with no cells, typically about 0.04), growth inhibition was calculated as % of the untreated control and plotted against dose.

Animal experiments were conducted under QIMR Animal Ethics Committee approvals. The B16 mouse melanoma model was obtained by injecting 0.5 million B16 mouse melanoma cells subcutaneously into each of the 2 flanks of a male C57BL/6 mouse. EBI-53 was injected intraperitoneally in 25% propylene glycol in 0.1 M saline. The human tumour xenografts were obtained by injecting 2 million of the respective tumour cell line into each of 4 sites on the flanks of male nude mice (BALB/c background). Tumour size was measured with electronic callipers in mm and converted to volume (cubic mm) using the formula:

Tumour volume = length x breadth x breadth /2. Results

The results in Figure 4 show that all 5 human tumour cell lines were more sensitive to growth inhibition by synthetic EBI-53 than the normal cells (NFF). Four of the tumour lines exhibited IC50 values (dose required to inhibit growth by 50%) at approximately 0.2 μg/mL whereas NFF had IC50 of 3 μg/mL. Similar results were obtained from EBI-53 purified from a plant.

In contrast, a synthetic isomer of EBI-53 was less potent by a factor of 10-100.

For the mouse tumour study, preliminary dose finding experiments indicated that the maximum tolerated dose (MTD) commenced at 20-40 μg/mouse/day intraperitoneally but increased with repeated dosing to up to 200 μg/day. This was presumably due to drug-induced activation of metabolic clearance.

Subsequent experiments with the B 16 model (3 mice/group) showed a trend for efficacy (FIGS. 5 and 6). EXAMPLE 8

Effect of EBI-53 on Cell Cycle

Method:

Cells (500,000 per 30 mm well) were treated with drug for 20 hours, then harvested (trypsin), fixed in ethanol, stained with 50 μg/mL propidium iodide in PBS containing 1 mg/mL Rnase and 1% Triton XlOO, and the DNA content per cell analysed at 488 nm on a flow cytometer.

Results:

MCF7 human breast cancer cells showed loss of S -phase cells and an increase in G2/M phase cells (from 13% to 20% total) following treatment with 1 μg/mL EBI-53. The EBI-53 isomer had no effect at this concentration.

HT29 colon cancer cells exhibited a much stronger G2/M block, at a lower dose of AEBI53 (0.1 μg/mL). Again, the EBI-53 isomer had no effect. These results suggest that EBI-53 binds to a protein target which either directly or indirectly blocks cell division; tubulin is one possible target, because a number of hydrophobic molecules (eg taxol) bind to it and block cells in G2/M phase. It will be appreciated by the skilled person that the present invention is not limited to the embodiments described in detail herein, and that a variety of other embodiments may be contemplated which are nevertheless consistent with the broad spirit and scope of the invention.

All computer programs, algorithms, patent and scientific literature referred to in this specification are incorporated herein by reference in their entirety.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A method of treating or preventing a parasitic infection comprising administering to a subject, a compound of formula (I)

wherein:

X and Y are independently selected from sulfur, oxygen, NH, N(C₁-C₃ alkyl) and CR'R";

R¹ and R¹⁰ are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-Cj₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-Ci₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R' and R" are independently selected from hydrogen, -Ci-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-Ci₀ haloalkyl, -C₁-C_1O dihaloalkyl, -C₁-Ci₀ trihaloalkyl and -C₁-Ci₀ haloalkoxy; each R is independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -Ci-Ci₀ trihaloalkyl; and each Z is independently selected from oxygen, sulfur, -NH- and -N(C₁-C₃ alkyl)-; or where R¹ is connected to R², and/or R² is connected to R³, and/or R³ is connected to R⁴, and/or R⁵ is connected to R⁶, and/or R⁶ is connected to R⁷, and/or R⁷ is connected to R⁸, and/or R⁸ is connected to R⁹, and/or R⁹ (or R⁵) is connected to R¹⁰ wherein the linkage comprises a -C₁-C₈ disubstituted (fused) saturated or unsaturated carbo- or heterocyclic ring further substituted with a group selected from R, -(C=Z)R and -Z(C=X)R, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the compound is a compound of formula (II):

wherein:

X and Y are oxygen;

R¹ to R⁴ are each independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-Ci₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R⁵ and R⁹ are -OCH₃; and

R⁶ to R⁸ and R¹⁰ are hydrogen, and each R is -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-Cj₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -C₁-C₁₀ trihaloalkyl; or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein R³ and R⁴ are hydrogen.

4. The method according to claim 1, wherein the compound is a compound of formula (III):

(III) wherein: X and Y are independently selected from O and S;

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; or

R³ and R⁴ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵;

R⁶ to R⁸ are independently selected from hydrogen, -OR¹¹, -SR¹², -N(R^I3)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C].₁₀alkyl, -C_2-i₀alkenyl, -C_2-10alkynyl,

aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_1-loalkyl, -C_2-10alkenyl, -C_2-10alkynyl₅ -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C^oalkyl, -C_2-10alkenyl, -C_2-1oalkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -C^oalkyl, -C_2-1oalkenyl, -C₂.₁oalkynyl,

aryl, heterocyclyl, heteroaryl and -N(R¹³)₂; R¹⁵ is selected from hydrogen, -C_1-10alkyl, -C₂-i_Oalkenyl, -C_2-1oalkynyl,

-C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C_2-i_Oalkenyl, -C_2-10alkynyl, -Cs.gcycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically acceptable salts thereof.

5. The method according to claim 1, wherein the compound is a compound of formula (Ilia):

(Ilia) wherein:

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and

-COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴,

-CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-1OaIlCyI, -C₂.₁oalkenyl, -C^oalkynyl, -Q-scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -Cj._ϊoalkyl, -C_2-10alkenyl, -C_2-i_Oalkynyl, -C₃.₈cycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -C_1-10alkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -Cj.joalkyl, -C_2-i₀alkenyl, -C_2-1OaIk)OIyI, -Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen; R , 17 is selected from hydrogen, -C_1-loalkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically acceptable salts thereof.

6. The method according to ;laim 1, wherein the compound is a compound of formula (HIb):

(IHb) wherein: R³ and R⁴ are independently selected from -OR¹ \ -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴,

-CN, -NO₂ and -COR¹⁵ or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen; R⁵ and R⁹ are independently selected from -OR¹¹ , -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴,

-CN₅ -NO₂ and -COR¹⁵;

R¹¹ is selected from -Ci.₁₀alkyl, -C_2-10alkenyl, -C₂-ioalkynyl, -Cs.gcycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -Ci.i_Oalkyl, -C₂-i₀alkenyl, -C_2-10alkynyl, -C_3-8cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -d-iQalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -Cs-scycloalkyl, aryl, heterocyclyl and heteroaryl; R . 14 is selected from hydrogen, -Ci_₁₀alkyl, -C₂.₁₀alkenyl, -C_2-1oalkynyl, -C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C_1-1QaIlCyI, -C_2-10alkenyl, -C_2-10alkynyl,

aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -Ci.₁₀alkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically acceptable salts thereof.

7. The method according to claim 1, wherein the compound is 5,6,2'6'~tetramethoxyflavone.

8. A method of treating or preventing a fungal infection in a subject or a plant comprising administering to a subject, a compound of formula (I)

wherein:

X and Y are independently selected from sulfur, oxygen, NH, N(Cj-C₃ alkyl) and CR'R";

R¹ and R¹⁰ are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-Ci₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -Cj-C_1O dihaloalkyl, -Ci-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR₅ -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R₅ -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R' and R" are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -Ci-C₁₀ haloalkyl, -Ci-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl and -C₁-C₁₀ haloalkoxy; each R is independently selected from hydrogen, -Ci-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -Ci-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-Ci₀ haloalkyl, -C₁-Ci₀ dihaloalkyl and -Ci-Ci₀ trihaloalkyl; and each Z is independently selected from oxygen, sulfur, -NH- and -N(C₁-C₃ alkyl)-; or where R¹ is connected to R², and/or R² is connected to R³, and/or R³ is connected to R⁴, and/or R⁵ is connected to R⁶, and/or R⁶ is connected to R⁷, and/or R⁷ is connected to R⁸, and/or R⁸ is connected to R⁹, and/or R⁹ (or R⁵) is connected to R¹⁰ wherein the linkage comprises a -C₁-Cg disubstituted (fused) saturated or unsaturated carbo- or heterocyclic ring further substituted with a group selected from R, -(C=Z)R and -Z(C=X)R, or a pharmaceutically or agriculturally acceptable salt thereof.

9. The method according to claim 8, wherein the compound is a compound of formula (II):

wherein:

X and Y are oxygen;

R¹ to R⁴ are each independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -Ci-C₁₀ haloalkyl, -Ci-C₁₀ dihaloalkyl, -C₁-Ci₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R⁵ and R⁹ are -OCH₃; and

R⁶ to R⁸ and R¹⁰ are hydrogen, and each R is -C₁-C₂₀ alkyl, -C₂-C_2O alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-Ci₄ aryl, -C₃-Ci₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -Ci-Cio alkoxy, -Ci-Ci₀ alkyl, -Ci-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -C₁-C₁₀ trihaloalkyl; or a pharmaceutically or agriculturally acceptable salt thereof.

10. The method according to claim 9, wherein R³ and R⁴ are hydrogen.

11. The method according to claim 8, wherein the compound is a compound of formula (III):

(Ill) wherein: X and Y are independently selected from O and S; R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; or

R³ and R⁴ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; R⁶ to R⁸ are independently selected from hydrogen, -OR¹¹, -SR¹², -N(R¹³)₂,

-S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-loalkyl, -C_2-1oalkenyl, -C₂-₁₀alkynyl, -Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_Moalkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -d-njalkyl, -C_2-i₀alkenyl, -C₂.₁₀alkynyl, -C^scycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -C_1-10alkyl, -Ci-_ϊoalkenyl, -C_2-1oalkynyl, -C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C_Moalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -Cs.scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C_2-1oalkenyl, -C₂-i_Oalkynyl, -Cs.scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically or agriculturally acceptable salts thereof.

12. The method according to claim 8, wherein the compound is a compound of formula (Ilia):

(Ilia) wherein:

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-loalkyl, -C_2-i₀alkenyl, -C_2-ioalkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_1-10alkyl, -Ca-_ϊoalkenyl, -C₂.i_Oalkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C_Moalkyl, -C_2-10alkenyl, -C₂-₁oalkynyl, -Cs-scycloalkyl, aryl, heterocyclyl and heteroaryl; R is selected from hydrogen, -Ci_i_Oalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -Ci.ioalkyl, -C₂.₁₀alkenyl, -C₂.₁₀alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -Ci.i_Oalkyl,

-C_2-ioalkynyl, -Cs-scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically or agriculturally acceptable salts thereof.

13. The method according tθ ( ;laim 8, wherein the compound is a compound of formula (HIb):

("Ib) wherein:

R³ and R⁴ are independently selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵ or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -Ci_-10alkyl, -C_2-10alkenyl, -C_2-1oalkynyl,

aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; R¹² is selected from hydrogen, -C_1-10alkyl, -C_2-1oalkenyl, -C₂.₁₀alkynyl, -C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -Cs.gcycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-1oalkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C^oalkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C₂.₁₀alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically or agriculturally acceptable salts thereof.

14. The method according to claim 8, wherein the compound is 5,6,2'6'- tetramethoxyflavone .

15. A method of controlling pests comprising applying a pesticidally effective amount of a compound of formula (I) to a subj ect or an environment infested with a pest:

wherein: X and Y are independently selected from sulfur, oxygen, NH, N(C₁-C₃ alkyl) and CR'R";

R¹ and R¹⁰ are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, 5 -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -Ci-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R₅ -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R' and R" are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ 0 alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C_J-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -Ci-Ci₀ haloalkyl, -Ci-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl and -C₁-Ci₀ haloalkoxy; each R is independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, 5 -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -C₁-C₁₀ trihaloalkyl; and each Z is independently selected from oxygen, sulfur, -NH- and -N(C₁-C₃ alkyl)-; or where R¹ is connected to R², and/or R² is connected to R³, and/or R³ is O connected to R⁴, and/or R⁵ is connected to R⁶, and/or R⁶ is connected to R⁷, and/or R⁷ is connected to R⁸, and/or R⁸ is connected to R⁹, and/or R⁹ (or R⁵) is connected to R¹⁰ wherein the linkage comprises a -Ci-C₈ disubstituted (fused) saturated or unsaturated carbo- or heterocyclic ring further substituted with a group selected from R, -(C=Z)R and -Z(C=X)R, 5 or a pharmaceutically or pesticidally acceptable salt thereof.

16. The method according to claim 15, wherein the compound is a compound of formula (II):

wherein:

X and Y are oxygen;

R¹ to R⁴ are each independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R⁵ and R⁹ are -OCH₃; and

R⁶ to R⁸ and R¹⁰ are hydrogen, and each R is -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-Ci₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-Ci₀ dihaloalkyl and -C₁-Ci₀ trihaloalkyl; or a pesticidally acceptable salt thereof.

17. The method according to claim 16, wherein R³ and R⁴ are hydrogen.

18. The method according to claim 15, wherein the compound is a compound of formula (III):

(III) wherein: X and Y are independently selected from O and S;

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; or

R³ and R⁴ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵;

R⁶ to R⁸ are independently selected from hydrogen, -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-10alkyl, -C_2-10alkenyl, -C₂.₁₀alkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_1-10alkyl, -C₂.₁₀alkenyl, -C_2-1oalkynyl, -Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -Ci.ioalkyl, -C₂-₁₀alkenyl, -C₂.₁oalkynyl,

aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -Ci-ioalkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -Ci-ioalkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pesticidally acceptable salts thereof.

19. The method according to claim 15, wherein the compound is a compound of formula (Ilia):

Ia) wherein:

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-10alkyl, -C^oalkenyl, -C_2-10alkynyl, -C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -d._Kjalkyl, -C_2-10alkenyl, -C_2-1oalkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C^oalkynyl, -Cs.scycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -Cnoalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -Cs.scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C^oalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C_1-10alkyl, -C_2-1oalkenyl, -C₂.₁₀alkynyl, -C^scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pesticidally acceptable salts thereof.

20. The method according to claim 15, wherein the compound is a compound of formula (HIb):

ClIIb) wherein: R³ and R⁴ are independently selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵ or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹ \ -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-10alkyl, -C_2-loalkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; R¹² is selected from hydrogen, -C_1-10alkyl, -C₂-₁₀alkenyl,

-C_3-8CyClOaIlCyI, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl; R¹⁴ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl,

-Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C^oalkyl, -C_2-10alkenyl, -C_2-i_Oalkynyl,

aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen; R¹⁷ is selected from hydrogen, -Ci.₁₀alkyl, -C₂-ioalkenyl, -C_2-10alkynyl,

-C^scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pesticidally acceptable salts thereof.

21. The method according to claim 15, wherein the compound is 5,6,2'β'- tetramethoxyflavone .

22. A method of treating or preventing breast cancer, ovarian cancer or prostate cancer comprising administering to a subject, a compound of formula (I)

wherein:

X and Y are independently selected from sulfur, oxygen, NH, N(C₁-C₃ alkyl) and CR'R"; R¹ and R¹⁰ are independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C_2O alkenyl, -C₂-C_2O alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C_1O haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-C₁₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R, -SO₃R, -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R;

R' and R" are independently selected from hydrogen, -C₁-C_2O alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -Ci-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-C_1O trihaloalkyl and -C₁-C₁₀ haloalkoxy; each R is independently selected from hydrogen, -C₁-C₂₀ alkyl, -C₂-C_2O alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-Ci₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -C₁-C₁₀ trihaloalkyl; and each Z is independently selected from oxygen, sulfur, -NH- and -N(Ci-C₃ alkyl)-; or where R¹ is connected to R², and/or R² is connected to R³, and/or R³ is connected to R⁴, and/or R⁵ is connected to R⁶, and/or R⁶ is connected to R⁷, and/or R⁷ is connected to R⁸, and/or R⁸ is connected to R⁹, and/or R⁹ (or R⁵) is connected to R¹⁰ wherein the linkage comprises a -C₁-C₈ disubstituted (fused) saturated or unsaturated carbo- or heterocyclic ring further substituted with a group selected from R₅ -(C=Z)R and -Z(C=X)R₅ or a pharmaceutically acceptable salt thereof.

23. The method according to claim 22, wherein the compound is a compound of formula (II):

wherein: X and Y are oxygen;

R¹ to R⁴ are each independently selected from hydrogen, -C₁-C₂O alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-C₁₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl, -C₁-Ci₀ trihaloalkyl, halo, -CN, -NO₂, -COR, -CO₂R, -OR, -N(R)₂, -NROR, -ON(R)₂, -SOR, -SO₂R₅ -SO₃R₅ -SON(R)₂, -SO₂N(R)₂, -SO₃N(R)₃, -P(R)₃, -P(O)(R)₃, -OSi(R)₃, -OB(R)₂, -C(Z)R and -ZC(Z)R; R⁵ and R⁹ are -OCH₃; and R⁶ to R⁸ and R¹⁰ are hydrogen, and each R is -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₃-C₈ cycloalkyl, -C₆-C₁₄ aryl, -C₃-Ci₄ heterocyclyl, -C₅-C₁₄ heteroaryl, arylalkyl, heteroarylalkyl, -C₁-Ci₀ alkoxy, -C₁-C₁₀ alkyl, -C₁-C₁₀ haloalkyl, -C₁-C₁₀ dihaloalkyl and -C₁-C₁₀ trihaloalkyl; or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein R³ and R⁴ are hydrogen.

25. The method according to claim 22, wherein the compound is a compound of formula (III):

(III) wherein: X and Y are independently selected from O and S;

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R³ and R⁴ are hydrogen; or

R³ and R⁴ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵;

R⁶ to R⁸ are independently selected from hydrogen, -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; R » 11 is selected from -C_1-loalkyl, -C_2-10alkenyl, -C_2-10alkynyl, -Cs.scycloalkyl, aiyl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -Ci-ioalkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -Cs-gcycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; . each R¹³ is independently selected from hydrogen, -Ci-ioalkyl, -C₂.₁₀alkenyl, -C₂.₁₀alkynyl, -Ca-scycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C^oalkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C_1-10alkyl, -C_2-1oalkenyl, -C_2-10alkynyl, -Cs.gcycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -Ci-ioalkyl, -C_2-10alkenyl, -C₂.₁₀alkynyl, -C^scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically acceptable salts thereof.

26. The method according to claim 22, wherein the compound is a compound of formula (Ilia):

wherein:

R¹ is selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and

-COR¹⁵; R² is selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN₅ -NO₂ and -COR¹⁵; or

R¹ and R² taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and R³ and R⁴ are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹², -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵;

R¹¹ is selected from -C_1-10alkyl, -C₂-₁oalkenyl, -C₂.₁₀alkynyl, -C₃.₈cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; R¹² is selected from hydrogen, -C_1-10alkyl, -C₂-₁₀alkenyl, -C_2-10alkynyl,

-C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -C_1-10alkyl, -C₂.₁₀alkenyl, -C₂.₁₀alkynyl, -Cs.gcycloalkyl, aryl, heterocyclyl and heteroaryl; R¹⁴ is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl,

-C₃.₈cycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C_1-10alkyl, -C₂-₁₀alkenyl, -C_2-10alkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen; R¹⁷ is selected from hydrogen, -Cμioalkyl, -C_2-ioalkenyl, -C_2-10alkynyl,

-C₃.scycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically acceptable salts thereof.

27. The method according to claim 22, wherein the compound is a compound of formula (HIb):

(1Mb) wherein:

R³ and R⁴ are independently selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵ or R³ and R⁴ taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic, aryl, heterocyclic or heteroaromatic ring; and

R¹ and R² are hydrogen;

R⁵ and R⁹ are independently selected from -OR¹¹, -SR¹², -N(R¹³)₂, -S(O)_nR¹⁴, -CN, -NO₂ and -COR¹⁵; R¹¹ is selected from -Ci-ioalkyl, -C_2-10alkenyl, -C₂-ioalkynyl, -C^scycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴;

R¹² is selected from hydrogen, -C_1-10alkyl, -C_2-10alkenyl, -C_2-10alkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl, -Si(R¹⁷)₃, -B(R¹⁷)₂, acyl, -C(R¹⁶)₃ and -S(O)_nR¹⁴; each R¹³ is independently selected from hydrogen, -Cnoalkyl, -C_2-1oalkenyl,

-C_2-loalkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl;

R¹⁴ is selected from hydrogen, -d-^alkyl, -C_2-i₀alkenyl, -C_2-10alkynyl, -Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl and -N(R¹³)₂;

R¹⁵ is selected from hydrogen, -C_Moalkyl, -C_2-i₀alkenyl, -C_2-1oalkynyl, -C^cycloalkyl, aryl, heterocyclyl, heteroaryl and -OR¹⁷; each R¹⁶ is independently selected from hydrogen and halogen;

R¹⁷ is selected from hydrogen, -C^oalkyl, -d-ioalkenyl, -C₂-i₀alkynyl, -C^cycloalkyl, aryl, heterocyclyl and heteroaryl; and n is an integer from 1-3; and pharmaceutically acceptable salts thereof.

28. The method according to claim 22, wherein the compound is 5,6,2' 6'- tetramethoxyflavone .