WO2024038162A1 - Akhdardiol for use in preventing or treating fungal infections - Google Patents
Akhdardiol for use in preventing or treating fungal infections Download PDFInfo
- Publication number
- WO2024038162A1 WO2024038162A1 PCT/EP2023/072734 EP2023072734W WO2024038162A1 WO 2024038162 A1 WO2024038162 A1 WO 2024038162A1 EP 2023072734 W EP2023072734 W EP 2023072734W WO 2024038162 A1 WO2024038162 A1 WO 2024038162A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- use according
- infection
- candida
- fungal infection
- Prior art date
Links
- 208000031888 Mycoses Diseases 0.000 title claims abstract description 41
- 206010017533 Fungal infection Diseases 0.000 title claims abstract description 40
- RIQATFSOVFFVRX-HMGBVJPOSA-N (1s,4as,4br,7s,8ar,10ar)-7-ethenyl-1-(hydroxymethyl)-1,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol Chemical compound C([C@@]12C)CC[C@](C)(CO)[C@@H]1CC[C@]1(O)[C@@H]2CC[C@@](C=C)(C)C1 RIQATFSOVFFVRX-HMGBVJPOSA-N 0.000 title claims abstract description 29
- RIQATFSOVFFVRX-UHFFFAOYSA-N Thermarol Natural products CC12CCCC(C)(CO)C1CCC1(O)C2CCC(C=C)(C)C1 RIQATFSOVFFVRX-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 241000222122 Candida albicans Species 0.000 claims abstract description 20
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- 241000222120 Candida <Saccharomycetales> Species 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 33
- 229940095731 candida albicans Drugs 0.000 claims description 11
- 235000017060 Arachis glabrata Nutrition 0.000 claims description 9
- 244000105624 Arachis hypogaea Species 0.000 claims description 9
- 235000010777 Arachis hypogaea Nutrition 0.000 claims description 9
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- 241000222126 [Candida] glabrata Species 0.000 claims description 9
- 208000032343 candida glabrata infection Diseases 0.000 claims description 9
- 229960004884 fluconazole Drugs 0.000 claims description 9
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 235000020232 peanut Nutrition 0.000 claims description 9
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- 235000007340 Hordeum vulgare Nutrition 0.000 claims description 6
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- 241000222199 Colletotrichum Species 0.000 claims description 4
- 241000223195 Fusarium graminearum Species 0.000 claims description 4
- 241000223221 Fusarium oxysporum Species 0.000 claims description 4
- 241001330975 Magnaporthe oryzae Species 0.000 claims description 4
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- 235000015919 Ustilago maydis Nutrition 0.000 claims description 4
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 claims description 4
- 241001360088 Zymoseptoria tritici Species 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 3
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- 241001530056 Athelia rolfsii Species 0.000 claims description 3
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- 241000315044 Passalora arachidicola Species 0.000 claims description 3
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- 235000021536 Sugar beet Nutrition 0.000 claims description 3
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- 208000011323 eye infectious disease Diseases 0.000 claims description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 3
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- 229960002722 terbinafine Drugs 0.000 claims description 3
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 claims description 3
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- 208000010484 vulvovaginitis Diseases 0.000 claims description 3
- 241000221573 Melampsora Species 0.000 claims description 2
- 241000893980 Microsporum canis Species 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
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- XXDNQIGMWSPXAO-UHFFFAOYSA-N phenanthren-1-ylmethanol Chemical compound C1=CC2=CC=CC=C2C2=C1C(CO)=CC=C2 XXDNQIGMWSPXAO-UHFFFAOYSA-N 0.000 description 9
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- 239000002253 acid Substances 0.000 description 5
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- RWSPPPHWQNMROI-UHFFFAOYSA-N isoakhdartriol Natural products CC1(CCC2C(O)(CCC3C(C)(CO)C(O)CCC23C)C1)C=C RWSPPPHWQNMROI-UHFFFAOYSA-N 0.000 description 2
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- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
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- 241000144583 Candida dubliniensis Species 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
- A01N31/06—Oxygen or sulfur directly attached to a cycloaliphatic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the invention relates to diterpenoids and their use in the treatment of fungal infections.
- vaginal Candida infection is a common problem, affecting most women at times (more than 75%), but posing a larger and extremely bothersome as well as recurrent problem for a number of women (8%).
- Symptoms include itching, soreness or irritation, reddened and swollen vaginal tissues, pain with urination and intercourse, typically adhesive white and clumpy curd-like discharge (like cottage cheese) or normal to thin and watery discharge.
- Candida albicans is the most common pathogen, often present in smaller amounts normally in the vagina, mouth, digestive tract and on the skin without causing infection, but with changes in the normal flora, such as after antibiotic treatment, Candida can overgrow and infect.
- the virulence of Candida albicans is mediated by a transformation from planktonic cells into hyphae. The hyphal form, i.e.
- filamentous cells has the ability to invade tissue and induce inflammation, mediated by candidalysin, a cytotoxic peptide toxin that destroy the epithelial cells of the vagina (Moyes et al. (2016) Nature 532, 64-68).
- Candida thrives on the glycogen present in vaginal mucosa, and infection is also facilitated by the effect on the mucosa of increased estrogen levels during pregnancy, and also by the weakened immune system during gestation. Contraceptive pills can cause a similar effect, as can menstruation, as well as other stress factors. Diabetes is another common facilitator.
- ACI phenanthrenemethanol
- ZCI Pimar-15-ene-8,18-diol or Akhdardi
- the IUPAC name for akhdardiol is (lS,4aS,4bR)-7-ethenyl-l- (hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren- 8a-ol.
- Kits comprising such compositions and instructions on such methods are also contemplated herein.
- the present invention relates further to an antifungal agent against the genus Candia, particularly an antifungal agent having an effect of prophylaxis, treatment, cure, alleviation of symptoms, prevention of recurrence and the like against candidiasis caused by said pathogenic fungus, which contains (lS,4aS,4bR,7S,8aR,10aR)-7- Ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-l-phenanthrenemethanol (ACI) or a pharmaceutically acceptable salt thereof as active ingredient(s).
- ACI Ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-l-phenanthrenemethanol
- the present invention solves the problems of the related art by an antifungal agent, (lS,4aS,4bR,7S,8aR,10aR)-7-Ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl- 1-phenanthrenemethanol (ACI), also called 1-Phenanthrenemethanol, 7- ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, [lS-(lo,4ao,4bp,7P,8aa, 10aP)] - (ZCI) or Akhdardiol and with the CAS Registry Number, 41756-41-6.
- ACI phenanthrenemethanol
- ZCI Akhdardiol and with the CAS Registry Number, 41756-41-6.
- the IUPAC name for akhdardiol is (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)-l,4a,7- trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol.
- the invention is broadly drawn to an anti-fungal composition for the growth reduction of one or more target fungi whose growth is reduced by an effective amount of 1-Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI).
- ⁇ is the use of 7-ethenyltetradecahydro-8a-hydroxy- l,4a,7-trimethyl-, [lS-(lo,4ao,4bp,7P,8aa,10aP)]- (ZCI) or an anti-fungal composition comprising the compound for use to prevent or treat a candidiasis in a human or animal subject.
- the IUPAC name for akhdardiol is (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)- l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol.
- a antifungal agent comprising or consisting of 1-Phenanthrenemethanol, 7- ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI) or a pharmaceutically acceptable salt thereof, for use a prevention and/or treatment of a fungal infection in human and/or animal subject.
- pathogenic fungi selected from the group consisting of Candida albicans, Candida, dubliniensis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida parapsilosis, Malassezia spp., Aspergillus fumigatus, Aspergill
- any one of the embodiment 1 to 2 wherein the use is prevention and/or treatment of a fungal infection caused by one or more fungi selected from the group consisting of terbinafine-resistant Trichophyton rubrum, fluconazole-resistant Candida albicans, fluconazole-resistant Candida krusei and fluconazole-resistant Candida glabrata,
- An anti-fungal composition for the growth reduction of one or more target fungi whose growth is reduced by an effective amount of 1-Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI) or salts, ethers and esters; polymorphs; solvates, including hydrates; clathrates; stereoisomers; enantiomers; metabolites and pro-drugs; conjugates; pure forms; particle size; isomers and mixtures thereof or complexes thereof.
- composition according to embodiment 18 that is formulated for topical or systemic administration.
- composition according to embodiment 18, wherein diluent medium is water-based, or is a particulate solid.
- composition according to embodiment 18, wherein the formulation is a polymeric nanoformulation or a lipidic polymeric nanoformulation.
- An anti-fungal concentrate composition that upon dilution provides the antifungal composition of embodiment 18.
- a method of controlling fungal diseases in a crop that is at risk of being diseased comprising the steps of: contacting at least a portion of a plant and/or an area adjacent to a plant with a composition according to any one of the embodiments 18 to 21.
- the fungal pathogen is selected from the group consisting of the causal agents of: brown rust of corn ⁇ Puccinia polysora), grey leaf spot of corn ⁇ Cercospora zeae-maydis), rice panicle blast ⁇ Magnaporthe grisea), Cercospora leaf spot of sugar beet ⁇ Cercospora beticola), net blotch of barley ⁇ Pyrenophora teres), powdery mildew of barley ⁇ Blumeria graminis f. sp.
- the fungal pathogen is selected from the group consisting of Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora lini.
- compositions comprising (lS,4aS,4bR)-7- ethenyl-l-(hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a- decahydrophenanthren-8a-ol [Akhdardiol] or a pharmaceutically acceptable salt or ester thereof for use in the prevention and/or treatment of a fungal infection in a human and/or animal subject.
- the subject is immunocompromised, for example infected with Human Immunodeficiency Virus.
- the fungal infection is a skin infection, such as athlete's foot.
- the fungal infection is a lung infection, such as pneumonia. In embodiments thereof, the fungal infection is nail fungus infection.
- the fungal infection is an eye infection, an oral infection or an oesophageal infection.
- the fungal infection is candidaemia or is Candida sepsis.
- the fungal infection is caused by one or more selected from the group consisting of Candida albicans, Candida dubliniensis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida parapsilosis, Malassezia spp., Aspergillus fumigatus, Aspergillus niger, Penicillium sp., Cladosporium sp, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Epidermophyton spp and Microsporum canis, more particular, fungal infection is one or more selected from the group consisting of terbinafine-resistant Trichophyton rubrum, fluconazole-resistant Candida albicans, fluconazole-resistant Candida krusei and fluconazole-resistant Candida glabrata.
- compositions are for the prevention and/or treatment of a candidiasis, for example vulvovaginal candidiasis or a vulvovaginitis or vaginosis caused by one or more of Candida albicans, Candida glabrata and Gardenerella vaginalis.
- a candidiasis for example vulvovaginal candidiasis or a vulvovaginitis or vaginosis caused by one or more of Candida albicans, Candida glabrata and Gardenerella vaginalis.
- compositions are formulated for topical or systemic administration and include nanoformulations, such as polymeric nanoformulations or lipidic polymeric nanoformulations.
- Another aspect of the inventions are methods of preventing or treating a fungal infection in a crop comprising the steps of contacting at least a portion of a plant and/or an area adjacent to a plant with a composition comprising (lS,4aS,4bR)-7- ethenyl-l-(hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a- decahydrophenanthren-8a-ol [Akhdardiol].
- the fungal infection is caused by a fungus selected from the group consisting of brown rust of corn ⁇ Puccinia polysora), grey leaf spot of corn ⁇ Cercospora zeae-maydis), rice panicle blast ⁇ Magnaporthe grisea), Cercospora leaf spot of sugar beet ⁇ Cercospora beticola), net blotch of barley ⁇ Pyrenophora teres), powdery mildew of barley ⁇ Blumeria graminis f. sp. tritici), Ramularia leaf spot of barley Ramularia collo-cygni), powdery mildew of wheat ⁇ Blumeria graminis f. sp.
- fungus selected from the group consisting of Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora lini.
- Akhdardiol refers to (lS,4aS,4bR,7S,8aR,10aR)-7-Ethenyltetradecahydro-8a- hydroxy-l,4a,7-trimethyl-l-phenanthrenemethanol (ACI), and is also called 1- Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, [lS-(la,4aa,4bp,7P,8aa,10aP)]- (ZCI) or Pimar-15-ene-8,18-diol with the CAS Registry Number, 41756-41-6.
- the IUPAC name for Akhdardiol is (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)- l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol and has the below formula
- salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
- salts of amino acids such as arginate and the like
- salts of organic acids like glucuronic or galactunoric acids and the like
- isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
- tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
- Candida auris (OS299), C. albicans strains SC5314, C. glabrata ATCC 2001 and C. parapsilosis ATCC 22019, C. utilis (ATCC 9950), and Saccharomyces cerevisiae (ATCC 7754), Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora Uni are used.
- ACI 1-phenanthrenemethanol with CAS Registry Number, 41756-41-6, is available from Ambinter, (France), ASW MedChem, Inc., New Brunswick, NJ, 08901 (United States) and Aurora Fine Chemicals LLC (United States).
- Crystal Data for 2(C2oH3402), H2O (M 630.96 g/mol): orthorhombic, space group P2i2i2i (no.
- the in vitro antifungal activity was evaluated against Candida auris (OS299), C. albicans strains SC5314, C. glabrata ATCC 2001, C. parapsilosis ATCC 22019, C. utilis (ATCC 9950), and Saccharomyces cerevisiae (ATCC 7754) using a 96-well microplate broth dilution method essentially as described before (Hu et al. (2021) Front Pharmacol 12, 761751).
- the (frozen) storage, maintenance and preparation of working culture suspensions were carried out following established procedures described in a previous study (Hu et al., cited above). Miconazole (50 pg/mL) was used as positive control, while 2% DMSO served as negative (solvent) control.
- Biofilm activity was determined in duplicate after 24 h of incubation in RPMI 1640 plus MOPS medium using a resazurin reduction assay.
- the antifungal concentration that caused 50% reduction in the metabolic activity of the biofilm compared with the control (incubated in the absence of the antifungal agent) was determined, and the concentration resulting in 50% reduction in the metabolic activity was considered as the biofilm IC50 (BICso).
- biofilm IC50 concentration resulting in 50% reduction in the metabolic activity
- BICso biofilm IC50
- hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, cytotoxicity as well as overall toxicity class, and LDso values were predicted using ProTox Sahoo et al. (2021) Biomedicines 9(11), 1505)
- FIG. 1 shows (A) the asymmetric unit of akhdardiol with displacement ellipsoids drawn at the 30% probability level. Only one disordered position of the ethylene fragments is shown.
- FIG. 2 provides a structural formulation of 1-Phenanthrenemethanol, 7- ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI) or Akhdardiol.
- Table 1 Antifungal activity of akhdardiol isolated from the leaves of T. riparia
- Table 2 Hydrogen-bond geometry (A°).
- Symmetry codes (i) -1 + x, y, z; (ii) 1/2 + x, 3/2 -y, 1 - z.
Abstract
Disclosed herein is akhdardiol or a pharmaceutically acceptable salt thereof for use in a method of treating fungal infections in a patient, comprising identifying a patient in need of treatment and administering a therapeutically effective amount thereof. The present invention relates further to an antifungal agent against the genus Candida, particularly an antifungal agent having an effect of prophylaxis, treatment, cure, alleviation of symptoms, prevention of recurrence and the like against candidiasis caused by said pathogenic fungus, which contains akhdardiol.
Description
AKHDARDIOL FOR USE IN PREVENTING OR TREATING FUNGAL INFECTIONS
Field of the invention
The invention relates to diterpenoids and their use in the treatment of fungal infections.
Description of the Related Art
The incidence of fungal infections has markedly increased over the last few decades. Many of these fungi have developed resistance to front line antifungal agents such as the azoles and the polyenes, preventing adequate treatment and/or prevention of disease. The increase in fungal infections and resistance to traditional therapies is a significant public health threat worldwide. These infections are becoming more common, in part due to an increase in those susceptible to such infections. This subpopulation includes the immunocompromised: individuals undergoing chemotherapy, those receiving immunosuppressive drugs following transplantations, and those immunosuppressed due to diseases, such as AIDS or malignancies.
For instance vaginal Candida infection is a common problem, affecting most women at times (more than 75%), but posing a larger and extremely bothersome as well as recurrent problem for a number of women (8%). Symptoms include itching, soreness or irritation, reddened and swollen vaginal tissues, pain with urination and intercourse, typically adhesive white and clumpy curd-like discharge (like cottage cheese) or normal to thin and watery discharge.
Candida albicans is the most common pathogen, often present in smaller amounts normally in the vagina, mouth, digestive tract and on the skin without causing infection, but with changes in the normal flora, such as after antibiotic treatment, Candida can overgrow and infect. However, the knowledge of the occurrence of vulvovaginal infections is to a large degree incomplete due to the psychosocial stigma associated with genital infections. The virulence of Candida albicans is mediated by a transformation from planktonic cells into hyphae. The hyphal form, i.e. filamentous cells, has the ability to invade tissue and induce inflammation, mediated by candidalysin, a cytotoxic peptide toxin that destroy the epithelial cells of the vagina (Moyes et al. (2016) Nature 532, 64-68).
Candida thrives on the glycogen present in vaginal mucosa, and infection is also facilitated by the effect on the mucosa of increased estrogen levels during pregnancy,
and also by the weakened immune system during gestation. Contraceptive pills can cause a similar effect, as can menstruation, as well as other stress factors. Diabetes is another common facilitator.
Accordingly, both the limited spectrum of antifungal drugs currently in clinical use and the emergence of resistant fungi make necessary the development of new effective antifungal drugs with minimal side effects.
SUMMARY OF THE INVENTION
Disclosed herein are methods of treating fungal infections in a patient, comprising identifying a patient in need of treatment and administering a therapeutically effective amount of (lS,4aS,4bR,7S,8aR,10aR)-7-Ethenyltetradecahydro-8a- hydroxy-l,4a,7-trimethyl-l-phenanthrenemethanol (ACI), also called 1- Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, [lS-(lo,4ao,4bp,7P,8aa,10aP)]- (ZCI) or Pimar-15-ene-8,18-diol or Akhdardiol and with the CAS Registry Number, 41756-41-6, or a pharmaceutically acceptable salt thereof. The IUPAC name for akhdardiol is (lS,4aS,4bR)-7-ethenyl-l- (hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren- 8a-ol.
Kits comprising such compositions and instructions on such methods are also contemplated herein.
The present invention relates further to an antifungal agent against the genus Candia, particularly an antifungal agent having an effect of prophylaxis, treatment, cure, alleviation of symptoms, prevention of recurrence and the like against candidiasis caused by said pathogenic fungus, which contains (lS,4aS,4bR,7S,8aR,10aR)-7- Ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-l-phenanthrenemethanol (ACI) or a pharmaceutically acceptable salt thereof as active ingredient(s).
The present invention solves the problems of the related art by an antifungal agent, (lS,4aS,4bR,7S,8aR,10aR)-7-Ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl- 1-phenanthrenemethanol (ACI), also called 1-Phenanthrenemethanol, 7- ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, [lS-(lo,4ao,4bp,7P,8aa, 10aP)] - (ZCI) or Akhdardiol and with the CAS Registry Number, 41756-41-6. The IUPAC name for akhdardiol is (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)-l,4a,7- trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol.
In accordance with the purpose of the invention, as embodied and broadly described herein, the invention is broadly drawn to an anti-fungal composition for the growth reduction of one or more target fungi whose growth is reduced by an effective amount of 1-Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI).
In one aspect of the invention, is the use of 7-ethenyltetradecahydro-8a-hydroxy- l,4a,7-trimethyl-, [lS-(lo,4ao,4bp,7P,8aa,10aP)]- (ZCI) or an anti-fungal composition comprising the compound for use to prevent or treat a candidiasis in a human or animal subject.
Some embodiments of the invention are set forth in claim format directly below:
1. 1-Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7- trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI), or salts, ethers and esters; polymorphs; solvates, including hydrates; clathrates; stereoisomers; enantiomers; metabolites and pro-drugs; conjugates; pure forms; particle size; isomers and mixtures thereof; complexes thereof, for use in a prevention and/or treatment of a fungal infection in human and/or animal subject.
The IUPAC name for akhdardiol is (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)- l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol.
2. A antifungal agent comprising or consisting of 1-Phenanthrenemethanol, 7- ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI) or a pharmaceutically acceptable salt thereof, for use a prevention and/or treatment of a fungal infection in human and/or animal subject.
3. The antifungal for use according to any one of the embodiment 1 to 2, wherein the subject is not immunocompromised.
4. The antifungal for use according to any one of the embodiment 1 to 2, wherein the subject is immunocompromised.
5. The antifungal for use according to any one of the embodiment 1 to 2, wherein the subject is infected with Human Immunodeficiency Virus.
6. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is a skin infection.
7. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is a skin infection and the skin infection is athlete's foot.
8. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is a lung infection.
9. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is a lung infection and the lung infection is pneumonia.
10. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is nail fungus infection (onychomycosis).
11. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is an eye infection, oral infections or esophageal infections
12. The antifungal for use according to any one of the embodiment 1 to 2, wherein the fungal infection is candidaemia or is Candida sepsis.
13. The antifungal for use according to any one of the embodiment 1 to 2, wherein the use is prevention and/or treatment of a fungal infection caused by one or more pathogenic fungi selected from the group consisting of Candida albicans, Candida, dubliniensis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida parapsilosis, Malassezia spp., Aspergillus fumigatus, Aspergillus niger, Penicillium sp., Cladosporium sp, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Epidermophyton spp and Microsporum can is.
14. The antifungal for use according to any one of the embodiment 1 to 2, wherein the use is prevention and/or treatment of a fungal infection caused by one or more fungi selected from the group consisting of terbinafine-resistant Trichophyton rubrum, fluconazole-resistant Candida albicans, fluconazole-resistant Candida krusei and fluconazole-resistant Candida glabrata,
15. The antifungal for use according to any one of the embodiment 1 to 2, wherein the use is prevention and/or treatment of a candidiasis.
16. The antifungal for use according to any one of the embodiment 1 to 2, wherein the use is prevention and/or treatment of a vulvovaginal candidiasis.
17. The antifungal for use according to any one of the embodiment 1 to 2, wherein the use is prevention and/or treatment of vulvovaginitis or vaginosis caused by at least one pathogen selected from among Candida albicans, Candida glabrata and Gardenerella vaginalis.
18. An anti-fungal composition for the growth reduction of one or more target fungi whose growth is reduced by an effective amount of 1-Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI) or salts, ethers and esters; polymorphs; solvates, including hydrates; clathrates; stereoisomers; enantiomers; metabolites
and pro-drugs; conjugates; pure forms; particle size; isomers and mixtures thereof or complexes thereof.
19. The anti-fungal composition according to embodiment 18 that is formulated for topical or systemic administration.
20. The anti-fungal composition according to embodiment 18, wherein diluent medium is water-based, or is a particulate solid.
21. The anti-fungal composition according to embodiment 18, wherein the formulation is nanoformulation.
22. The anti-fungal composition according to embodiment 18, wherein the formulation is a polymeric nanoformulation or a lipidic polymeric nanoformulation.
23. An anti-fungal concentrate composition that upon dilution provides the antifungal composition of embodiment 18.
24. A method of controlling fungal diseases in a crop that is at risk of being diseased comprising the steps of: contacting at least a portion of a plant and/or an area adjacent to a plant with a composition according to any one of the embodiments 18 to 21.
25. The method according to embodiment 24, whereby the fungal pathogen is selected from the group consisting of the causal agents of: brown rust of corn {Puccinia polysora), grey leaf spot of corn {Cercospora zeae-maydis), rice panicle blast {Magnaporthe grisea), Cercospora leaf spot of sugar beet {Cercospora beticola), net blotch of barley {Pyrenophora teres), powdery mildew of barley {Blumeria graminis f. sp. tritici), Ramularia leaf spot of barley {Ramularia collo-cygni), powdery mildew of wheat {Blumeria graminis f. sp. tritici), white mould of peanut (Sclerotium rolfsii), early leaf spot of peanut /Cercospora arachidicola), late leaf spot of peanut {Cercosporidium personatum) , and frogeye leaf spot of soybean {Cercospora sojina).
26. The method according to embodiment 24, whereby the fungal pathogen is selected from the group consisting of Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora lini.
An aspect of the invention relates to compositions comprising (lS,4aS,4bR)-7- ethenyl-l-(hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a- decahydrophenanthren-8a-ol [Akhdardiol] or a pharmaceutically acceptable salt or ester thereof for use in the prevention and/or treatment of a fungal infection in a human and/or animal subject.
In embodiments thereof, the subject is immunocompromised, for example infected with Human Immunodeficiency Virus.
In embodiments thereof, the fungal infection is a skin infection, such as athlete's foot.
In embodiments thereof, the fungal infection is a lung infection, such as pneumonia. In embodiments thereof, the fungal infection is nail fungus infection.
In embodiments thereof, the fungal infection is an eye infection, an oral infection or an oesophageal infection.
In embodiments thereof, the fungal infection is candidaemia or is Candida sepsis.
In embodiments thereof, the fungal infection is caused by one or more selected from the group consisting of Candida albicans, Candida dubliniensis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida parapsilosis, Malassezia spp., Aspergillus fumigatus, Aspergillus niger, Penicillium sp., Cladosporium sp, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Epidermophyton spp and Microsporum canis, more particular, fungal infection is one or more selected from the group consisting of terbinafine-resistant Trichophyton rubrum, fluconazole-resistant Candida albicans, fluconazole-resistant Candida krusei and fluconazole-resistant Candida glabrata.
In embodiments thereof, the compositions are for the prevention and/or treatment of a candidiasis, for example vulvovaginal candidiasis or a vulvovaginitis or vaginosis caused by one or more of Candida albicans, Candida glabrata and Gardenerella vaginalis.
In embodiments thereof, compositions are formulated for topical or systemic administration and include nanoformulations, such as polymeric nanoformulations or lipidic polymeric nanoformulations.
Another aspect is the compounds (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)- l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a -decahydrophenanthren-8a-ol
[Akhdardiol] or a pharmaceutically salt or ester thereof for use as a medicament.
Another aspect of the inventions are methods of preventing or treating a fungal infection in a crop comprising the steps of contacting at least a portion of a plant and/or an area adjacent to a plant with a composition comprising (lS,4aS,4bR)-7- ethenyl-l-(hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a- decahydrophenanthren-8a-ol [Akhdardiol].
In embodiments thereof the fungal infection is caused by a fungus selected from the group consisting of brown rust of corn {Puccinia polysora), grey leaf spot of corn {Cercospora zeae-maydis), rice panicle blast {Magnaporthe grisea), Cercospora leaf spot of sugar beet {Cercospora beticola), net blotch of barley {Pyrenophora teres), powdery mildew of barley {Blumeria graminis f. sp. tritici), Ramularia leaf spot of barley Ramularia collo-cygni), powdery mildew of wheat {Blumeria graminis f. sp. tritici), white mould of peanut {Sclerotium rolfsii), early leaf spot of peanut {Cercospora arachidicola), late leaf spot of peanut {Cercosporidium personatum), and frogeye leaf spot of soybean {Cercospora sojina), more specific the fungal infection is caused by a fungus selected from the group consisting of Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora lini.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
Detailed Description
The following detailed description of the invention refers to the accompanying drawings. The same reference numbers in different drawings identify the same or similar elements. Also, the following detailed description does not limit the invention. Instead, the scope of the invention is defined by the appended claims and equivalents thereof.
Akhdardiol refers to (lS,4aS,4bR,7S,8aR,10aR)-7-Ethenyltetradecahydro-8a- hydroxy-l,4a,7-trimethyl-l-phenanthrenemethanol (ACI), and is also called 1-
Phenanthrenemethanol, 7-ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, [lS-(la,4aa,4bp,7P,8aa,10aP)]- (ZCI) or Pimar-15-ene-8,18-diol with the CAS Registry Number, 41756-41-6.
The IUPAC name for Akhdardiol is (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)- l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol and has the below formula
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., (1977) "Pharmaceutical Salts", J. Pharm. Sci 66, 1-19)
As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
It is submitted that structurally related compounds such as akhdarenol akhdartriol and isoakhdartriol, with the below structures, are equally suitable as antifungal compounds.
Akhdartriol Isoakhdartriol
EXAMPLES
Example 1 Materials and organisms
All chemicals, reagents, and solvents (HPLC grade) used are available at Acros Organics (Geel, Belgium) or Sigma-Aldrich (St. Louis, MO, USA).
The strains Candida auris (OS299), C. albicans strains SC5314, C. glabrata ATCC 2001 and C. parapsilosis ATCC 22019, C. utilis (ATCC 9950), and Saccharomyces cerevisiae (ATCC 7754), Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora Uni are used.
(lS,4aS,4bR,7S,8aR,10aR)-7-Ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-
1-phenanthrenemethanol (ACI) with CAS Registry Number, 41756-41-6, is available
from Ambinter, (France), ASW MedChem, Inc., New Brunswick, NJ, 08901 (United States) and Aurora Fine Chemicals LLC (United States).
Example 2 Single-crystal X-ray data and structure of akhdardiol
Crystals of akhdardiol were obtained from a hexane solution. Diffraction intensity data were collected on a Rigaku Oxford Diffraction SuperNova diffractometer equipped with an Eos detector using Mo Ka radiation ( = 0.71073 A) at 294(1) K. Using Olex2 [Dolomanov et al. (2009) J. Appl. Cryst. 42, 339-341], the structure was solved with the SHELXT (Sheldrick (2015) Acta Crystallogr A Found Adv 71, 3-8) structure solution program using intrinsic phasing and refined with the SHELXL (Sheldrick (2015) Acta Crystallogr C Struct Chem. 71, 3-8) refinement package using full-matrix least-squares minimization. The crystallographic data for akhdardiol reported in the present study have been deposited at the Cambridge Crystallographic Data Centre. Crystal Data for 2(C2oH3402), H2O (M = 630.96 g/mol): orthorhombic, space group P2i2i2i (no. 19), a = 7.49184(19), b = 11.5145(4), c = 44.4145(13) A, V = 3831.40(19) A3, Z = 4, T = 294(1) K, pt(MoKa) = 0.070 mm , Dcaic = 1.094 g/cm3, 36796 reflections measured (5.096° < 20 < 52.744°), 7841 unique (Rint = 0.0280, Rsigma = 0.0260) that were used in all calculations. The final Ri was 0.0499 (I > 2CT(I)), and WR2 was 0.1333 for all data.
A structure determination revealed that the asymmetric unit contains two akhdardiol molecules and a water molecule (Figure 2a). Both akhdardiol molecules are identical (r.m.s. deviation = 0.295 A, Figure 2b) and display disorder of the ethylene fragment over two positions with an occupancy ratio of 0.50(3) to 0.50(3) for the first molecule and 0.77(2) to 0.23(2) for the second one. In the crystal packing, the water molecule links three akhdardiol molecules by hydrogen bond formation (Figure 2C, Table 2). As akhdardiol only contains light atoms, the absolute configuration could not be determined and a meaningless negative Flack parameter of -0.5(3) was observed. However, the configuration is the same as previously determined for akhdardiol-19- o-bromobenzoate [Stierle et al. (1988) Phytochemistry 27, 517-522]
Example 3 Antifungal activity
The in vitro antifungal activity was evaluated against Candida auris (OS299), C. albicans strains SC5314, C. glabrata ATCC 2001, C. parapsilosis ATCC 22019, C. utilis (ATCC 9950), and Saccharomyces cerevisiae (ATCC 7754) using a 96-well microplate broth dilution method essentially as described before (Hu et al. (2021) Front Pharmacol 12, 761751). The (frozen) storage, maintenance and preparation of
working culture suspensions were carried out following established procedures described in a previous study (Hu et al., cited above). Miconazole (50 pg/mL) was used as positive control, while 2% DMSO served as negative (solvent) control.
Biofilm activity was determined in duplicate after 24 h of incubation in RPMI 1640 plus MOPS medium using a resazurin reduction assay. The antifungal concentration that caused 50% reduction in the metabolic activity of the biofilm compared with the control (incubated in the absence of the antifungal agent) was determined, and the concentration resulting in 50% reduction in the metabolic activity was considered as the biofilm IC50 (BICso). In addition, hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, cytotoxicity as well as overall toxicity class, and LDso values (mg/kg) were predicted using ProTox Sahoo et al. (2021) Biomedicines 9(11), 1505)
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
Drawing Description
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given herein below and the accompanying drawings which are given by way of illustration only, and thus are not limitative of the present invention, and wherein:
FIG. 1 shows (A) the asymmetric unit of akhdardiol with displacement ellipsoids drawn at the 30% probability level. Only one disordered position of the ethylene fragments is shown.
(B) Overlay of both akhdardiol molecules present in the asymmetric unit. The second molecule (atoms C23 to C44) is shown in green. (C) Partial crystal packing showing the hydrogen bonding (red dashed lines) between the akhdardiol and water molecules. Symmetry codes: (i) -1 + x, y, z; (ii) 1/2 + x, 3/2 -y, 1 - z; (iii) 1 + x, y, z; (iv) -1/2 + x, 3/2 - y, 1 - z.
FIG. 2 provides a structural formulation of 1-Phenanthrenemethanol, 7- ethenyltetradecahydro-8a-hydroxy-l,4a,7-trimethyl-, (lS,4aS,4bR,7S,8aR,10aR)- (9CI, ACI) or Akhdardiol.
Table 1: Antifungal activity of akhdardiol isolated from the leaves of T. riparia
Table 2: Hydrogen-bond geometry (A°).
Symmetry codes: (i) -1 + x, y, z; (ii) 1/2 + x, 3/2 -y, 1 - z.
Claims
Claims
1. A composition comprising (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)- l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a-decahydrophenanthren-8a-ol [Akhdardiol] or a pharmaceutically acceptable salt or ester thereof for use in the prevention and/or treatment of a fungal infection in a human and/or animal subject.
2. The composition for use according to claim 1, wherein the subject is immunocompromised.
3. The composition for use according to claim 1 to 2, wherein the subject is infected with Human Immunodeficiency Virus.
4. The composition for use according to any one of claims 1 to 3, wherein the fungal infection is a skin infection.
5. The composition for use according to claim 4, wherein the skin infection is athlete's foot.
6. The composition for use according to one of claims 1 to 3, wherein the fungal infection is a lung infection.
7. The composition for use according to claim 6, wherein the lung infection is pneumonia.
8. The composition for use according to any one of claims 1 to 3, wherein the fungal infection is nail fungus infection.
9. The composition for use according to any one of claims 1 to 3, wherein the fungal infection is an eye infection, an oral infection or an esophageal infection.
10. The composition for use according to any one of the claim 1 to 9, wherein the fungal infection is candidaemia or is Candida sepsis.
The composition for use according to any one of claims 1 to 9, wherein the fungal infection is caused by one or more selected from the group consisting of Candida albicans, Candida, dubliniensis, Candida krusei, Candida glabrata, Candida parapsilosis, Candida parapsilosis, Malassezia spp., Aspergillus fumigatus, Aspergillus niger, Penicillium sp., Cladosporium sp, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Epidermophyton spp and Microsporum canis. The composition for use according to any one of claims 1 to 9, wherein the a fungal infection is one or more selected from the group consisting of terbinafine-resistant Trichophyton rubrum, fluconazole resistant Candida albicans, fluconazole-resistant Candida krusei and fluconazole-resistant Candida glabrata. The composition for use according to any one of the claim 1 to 3, in the prevention and/or treatment of a candidiasis. The composition for use according to claim 13, wherein the candidiasis is a vulvovaginal candidiasis. The composition for use according to claim 13, in prevention and/or treatment of a vulvovaginitis or vaginosis caused by one or more of Candida albicans, Candida glabrata and Gardenerella vaginalis. The composition for use according to any one of claims 1 to 15, which is formulated for topical or systemic administration. The composition for use according to claim 16, wherein the formulation is a nanoformulation. The composition for use according to claim 17, wherein the formulation is a polymeric nanoformulation or a lipidic polymeric nanoformulation.
19. (lS,4aS,4bR)-7-ethenyl-l-(hydroxymethyl)-l,4a,7-trimethyl- 2,3,4,4b,5,6,8,9,10,10a -decahydrophenanthren-8a-ol [Akhdardiol] or a pharmaceutically salt or ester thereof for use as a medicament.
20. A method of preventing or treating a fungal infection in a crop comprising the steps of contacting at least a portion of a plant and/or an area adjacent to a plant with a composition comprising (lS,4aS,4bR)-7-ethenyl-l- (hydroxymethyl)-l,4a,7-trimethyl-2,3,4,4b,5,6,8,9,10,10a- decahydrophenanthren-8a-ol [Akhdardiol].
21. The method according to claim 20, whereby the fungal infection is caused by a fungus selected from the group consisting of brown rust of corn {Puccinia polysora), grey leaf spot of corn {Cercospora zeae-maydis), rice panicle blast {Magnaporthe grisea), Cercospora leaf spot of sugar beet {Cercospora beticola), net blotch of barley {Pyrenophora teres), powdery mildew of barley {Blumeria graminis f. sp. tritici), Ramularia leaf spot of barley {Ramularia collo-cygni), powdery mildew of wheat Blumeria graminis f. sp. tritici), white mould of peanut (Sclerotium rolfsii), early leaf spot of peanut /Cercospora arachidicola), late leaf spot of peanut {Cercosporidium personatum), and frogeye leaf spot of soybean {Cercospora sojina).
22. The method according to claim 20, whereby the fungal infection is caused by a fungus selected from the group consisting of Magnaporthe oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, Fusarium oxysporum, Blumeria graminis, Mycosphaerella graminicola, Colletotrichum spp., Ustilago maydis and Melampsora Uni .
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