WO2013160670A1 - Compounds for use as inhibitors of alternative oxidase or cytochrome bc1 complex - Google Patents

Compounds for use as inhibitors of alternative oxidase or cytochrome bc1 complex Download PDF

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Publication number
WO2013160670A1
WO2013160670A1 PCT/GB2013/051030 GB2013051030W WO2013160670A1 WO 2013160670 A1 WO2013160670 A1 WO 2013160670A1 GB 2013051030 W GB2013051030 W GB 2013051030W WO 2013160670 A1 WO2013160670 A1 WO 2013160670A1
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WIPO (PCT)
Prior art keywords
group
compound
aox
atoms
use according
Prior art date
Application number
PCT/GB2013/051030
Other languages
English (en)
French (fr)
Inventor
Anthony Lennox MOORE
Mary Susan ALBURY
Luke Edward YOUNG
Catherine ELLIOTT
Original Assignee
The University Of Sussex
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1207213.8A external-priority patent/GB201207213D0/en
Priority to US14/397,164 priority Critical patent/US10851047B2/en
Priority to CN201710744009.7A priority patent/CN107691443B/zh
Priority to HRP20221493TT priority patent/HRP20221493T1/hr
Priority to PL13719143.3T priority patent/PL2841409T3/pl
Priority to EP13719143.3A priority patent/EP2841409B1/en
Priority to CN201380027565.2A priority patent/CN104334518B/zh
Priority to AU2013254493A priority patent/AU2013254493B2/en
Application filed by The University Of Sussex filed Critical The University Of Sussex
Priority to IN9924DEN2014 priority patent/IN2014DN09924A/en
Priority to KR1020147033032A priority patent/KR102209338B1/ko
Priority to ES13719143T priority patent/ES2932988T3/es
Priority to BR112014026551-8A priority patent/BR112014026551B1/pt
Priority to JP2015507594A priority patent/JP2015521163A/ja
Priority to MX2014012949A priority patent/MX2014012949A/es
Publication of WO2013160670A1 publication Critical patent/WO2013160670A1/en
Priority to PH12014502383A priority patent/PH12014502383B1/en
Priority to US17/060,013 priority patent/US11565996B2/en

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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10S424/00—Drug, bio-affecting and body treating compositions
    • Y10S424/10—Insect repellent

Definitions

  • the present invention relates to alternative oxidases (AOXs) and, in particular, to inhibitors of alternative oxidases.
  • AOXs alternative oxidases
  • the invention also relates to inhibitors of the cytochrome bci complex.
  • the invention is especially concerned with dual inhibitors of both AOXs and the cytochrome bci complex.
  • the invention extends to the use of such inhibitors in agrochemicals and in pharmaceuticals, for treating microbial infections, including fungal infections, as well as to agrochemical and pharmaceutical
  • Fungicides have long been used to control crop losses.
  • the most successful class of agricultural fungicides are a set of specific inhibitors which specifically target the mitochondrial respiratory chain. Mitochondria are the power-house of the cell and, hence, inhibition of the processes that result in an organism's energy conservation have a major impact on their capability to survive.
  • inhibitors known as strobilurins which target the oxidation of ubiquinol, a pivotal respiratory chain component, have improved the standards of disease control in plants (see Figure l).
  • Strobilurins inhibit fungal respiration and, hence, ATP synthesis by binding to the ubiquinol binding site of Complex III (the bci complex), which is essential for fungal respiration.
  • resistance was considered to be due to modification of the target site of the strobilurin, i.e. the apocytochrome b encoded by the mitochondrial genome.
  • AOX alternative oxidase
  • the AOX is a mitochondrial terminal oxidase, which, when engaged, by-passes the Qo (quinone-outside) site, and increases resistance of the plasma membrane efflux transporters to the fungicide.
  • Efflux transporters enable fungi to survive exposure to toxic compounds by preventing their accumulation to toxic concentrations within fungal cells.
  • the AOX is a terminal mitochondrial respiratory chain complex that branches from the main respiratory chain at the level of ubiquinone and, hence, bypasses the bci complex and cytochrome c oxidase, as shown in Figure l.
  • AOX is not only relevant to plant fungal pathogens, because it is also present in human parasites including
  • trypanosomes which is the cause of African sleeping sickness.
  • Cryptosporidium parvum and Blastocystis hominis which are intestinal parasites.
  • AOX In plants and fungi, expression of AOX is induced under conditions of oxidative stress, for instance when the main respiratory pathway is inhibited.
  • Currently available inhibitors of the AOX include salicylhydroxamic acids and octylgallates.
  • neither of these two classes of inhibitors is either a potent or specific target of AOX in cells, and they are therefore unsuitable for agrochemical (i.e. crop) or pharmaceutical applications.
  • the inventors have elucidated the molecular structure and catalytic mechanism of the alternative oxidase enzyme (AOX) in the plant, Sauromatum guttatum, and
  • AOX alternative oxidase
  • R 1 is selected from a nitrile group, an alkyl, alkenyl, amine group with l to 4 C- atoms that is optionally mono- or polysubstituted by F, O, NH 2 or CN, and in which one or more non-adjacent CH 2 groups are optionally replaced, in each case independently from one another, by -0-, -NH-, -CO-, -COO-, or -OCO-;
  • R 2 is hydrogen or a hydroxy or alkoxy group with 1 to 3 C atoms
  • R3 is a straight chain or branched alkyl or alkylene with 4 to 20 C atoms, that is optionally mono- or polysubstituted by a Ci to C 4 alkyl group;
  • R 4 is hydrogen or a hydroxy or alkoxy group with 1 to 3 C atoms
  • R 5 is a halogen group
  • R 6 is H or a Ci to C 4 alkyl group
  • R 2 and R 4 is a hydroxy or alkoxy group with 1 to 3 C atoms.
  • any group is an alkyl group, it may be a Ci, C 2 , C 3 or C 4 alkyl, for example a methyl, ethyl, propyl or butyl group.
  • the alkyl group may be substituted with one or more heteroatoms, for example nitrogen, oxygen, sulphur, phosphorous or a halogen.
  • R 1 may be a group selected from: CHO; CH 2 0H; CN; CH 3 ; C(0)NH 2 ; C(0)NHCH 3 ; C(0)CH 3 ; CF 2 CH 3 ; CH 2 CH 3 ; CH 2 0Ac; COOH; and COOCH 3 .
  • R 2 maybe a short-chain alkyl, for example a methyl, ethyl or propyl group. However, preferably R 2 is a hydroxyl group.
  • R3 maybe a straight chain or branched alkyl or alkylene with 6 to 15 C atoms, 8 to 12 C atoms or 8 to 10 C atoms, that is optionally mono- or polysubstituted by a Ci to C 4 alkyl group.
  • R 3 maybe branched diene having 6 to 15 C atoms that is substituted with at least one, and preferably two, methyl groups.
  • R 4 maybe a methyl, ethyl or propyl group. However, preferably R 4 is a hydroxyl group.
  • R 5 maybe a chlorine, bromine, fluorine or iodine group.
  • R 5 is a chlorine group.
  • R 6 maybe a methyl, ethyl or propyl group. However, preferably R 4 is a methyl group.
  • the AOX inhibitor comprises a compound of formula I, wherein:- R ! is selected from CHO; CH 2 0H; CN; CH 3 ; C(0)NH 2 ; C(0)NHCH 3 ; C(0)CH 3 ; CF 2 CH 3 ; CH 2 CH 3 ; CH 2 0Ac; COOH; and COOCH 3 ; and wherein
  • R 2 is a hydroxyl group
  • R 3 is a straight chain or branched alkyl or alkylene with 4 to 20 C atoms, that is optionally mono- or polysubstituted by a Ci to C 4 alkyl group;
  • R 4 is a hydroxyl group
  • R 5 is a chlorine atom
  • R 6 is H or a Ci to C 4 alkyl group.
  • the AOX inhibitor comprises a compound of formula I, wherein:- R ⁇ s selected from CHO; CH 2 0H; CN; CH 3 ; C(0)NH 2 ; C(0)NHCH 3 ; C(0)CH 3 ; CF 2 CH 3 ; CH 2 CH 3 ; CH 2 0Ac; COOH; and COOCH 3 ; and wherein
  • R 2 is a hydroxyl group
  • R 3 is a straight chain or branched alkyl or alkylene with 6 to 15 C atoms, that is optionally mono- or polysubstituted by a Ci to C 2 alkyl group;
  • R 4 is a hydroxyl group
  • R 5 is a chlorine atom
  • R 6 is H or a Ci to C 4 alkyl group.
  • the AOX inhibitor comprises a compound of formula I, wherein:- R s selected from CHO; CH 2 0H; CN; CH 3 ; C(0)NH 2 ; C(0)NHCH 3 ; C(0)CH 3 ; CF 2 CH 3 ; CH 2 CH 3 ; CH 2 0Ac; COOH; and COOCH 3 ; and wherein
  • R 2 is a hydroxyl group
  • R3 is an alkylene chain having 8 to 10 C atoms, and is substituted with at least one methyl group, preferably two methyl groups;
  • R 4 is a hydroxyl group
  • R 5 is a chlorine atom
  • R 6 is a methyl group.
  • the hydrophobic side chain which may be a geranyl group, may also be important.
  • the aldehyde group present in a known compound, ascofuranone may be problematic for anti- parasitic drug design for several reasons. Besides their ability to function as hydrogen bond acceptor and to undergo dipole-dipole interaction with AOX, aldehyde groups are chemically reactive enough to undergo reversible covalent modifications and would be generally unsuited to standard pharmaceutical formulations.
  • aldehydes are prone to metabolic oxidation to the respective carboxylic acid with the concomitant non-specific binding to basic transport proteins.
  • the inventors therefore believe that in some embodiments, it may be beneficial for there not to be an aldehyde group present.
  • R 1 is not a CHO group.
  • the inhibitor of the first aspect is capable of inhibiting a microbial AOX.
  • the inhibitor is capable of inhibiting a fungal, bacterial or protist AOX. Examples of such micro-organisms which may be inhibited are provided herein.
  • the inhibitor may be capable of inhibiting an AOX from any of the organisms represented in Figure 4.
  • the inhibitor is capable of binding with any of the amino acid residues shown in the boxes in Figure 4, as they represent conserved AOX residues which are believed to be involved in inhibitor binding.
  • the inhibitor can be synthesised using only a two-step process.
  • one embodiment of such a process is shown in Figure 7.
  • the compound of formula I is a specific inhibitor of the cytochrome b& complex as well as being a potent inhibitor of AOX.
  • the compound of formula I may be capable of inhibiting the cytochrome b& complex.
  • compounds of formula I can act as a specific and potent dual function fungicide, as not only do they inhibit the alternative oxidase (AOX), but also the cytochrome b& complex. This makes the compound a very potent inhibitor of respiration even in the absence of an alternative oxidase.
  • the compound inhibits the cytochrome b& complex at both the Qo (Quninone outside) and Qi (Quinone inside) binding sites of the Cytochrome bd complex.
  • the compound of formula I may inhibit the Qo and/or Qi binding site of the Cytochrome b& complex.
  • the compound of formula I inhibits the Qo and Qi binding sites of cytochrome bd complex.
  • commercially available fungicides such as azoxystrobin, inhibit only one site (Qo) within the bci complex.
  • the invention provides a use of the compound of the first aspect, for inhibiting an alternative oxidase (AOX).
  • AOX alternative oxidase
  • AOX microbial alternative oxidase
  • cytochrome b& complex wherein the compound is represented by formula I:-
  • R 1 is selected from a nitrile group, an alkyl, alkenyl, amine group with l to 4 C- atoms that is optionally mono- or polysubstituted by F, O, NH 2 or CN, and in which one or more non-adjacent CH 2 groups are optionally replaced, in each case independently from one another, by -0-, -NH-, -CO-, -COO-, or -OCO-;
  • R 2 is hydrogen or a hydroxy or alkoxy group with l to 3 C atoms
  • R3 is a straight chain or branched alkyl or alkylene with 4 to 20 C atoms, that is optionally mono- or polysubstituted by a Ci to C 4 alkyl group;
  • R4 is hydrogen or a hydroxy or alkoxy group with 1 to 3 C atoms
  • R 5 is a halogen group
  • R 6 is H or a Ci to C 4 alkyl group
  • R 2 and R 4 is a hydroxy or alkoxy group with 1 to 3 C atoms.
  • the compound that is used maybe the inhibitor as defined herein.
  • the use maybe carried out in vitro or in vivo.
  • the use may comprise inhibiting a microbial AOX, which may be a fungal, bacterial or protist AOX, as defined herein.
  • the use may comprise inhibiting the cytochrome b& complex, preferably the Qo and/ or Qi binding site of the cytochrome bd complex. The inventors believe that this is an important feature of the invention.
  • the invention provides a use of a compound of formula I, for inhibiting the cytochrome bd complex, wherein the compound of formula I is represented as:-
  • R 1 is selected from a nitrile group, an alkyl, alkenyl, amine group with 1 to 4 C- atoms that is optionally mono- or polysubstituted by F, O, NH 2 or CN, and in which one or more non-adjacent CH 2 groups are optionally replaced, in each case independently from one another, by -0-, -NH-, -CO-, -COO-, or -OCO-;
  • R 2 is hydrogen or a hydroxy or alkoxy group with 1 to 3 C atoms
  • R3 is a straight chain or branched alkyl or alkylene with 4 to 20 C atoms, that is optionally mono- or polysubstituted by a Ci to C 4 alkyl group;
  • R4 is hydrogen or a hydroxy or alkoxy group with 1 to 3 C atoms
  • R 5 is a halogen group
  • R 6 is H or a Ci to C 4 alkyl group
  • R 2 and R 4 is a hydroxy or alkoxy group with 1 to 3 C atoms.
  • R 1 to R 6 may be defined as above.
  • the use may comprise inhibiting the Qo and/or Qi binding site of the cytochrome b& complex, and preferably both the Qo and Qi binding sites.
  • the inventors have found that the AOX inhibitors of the invention can be effectively used to treat infections of plant pathogens which comprise an AOX enzyme.
  • an agrochemical composition comprising the compound of formula I, which may be alternative oxidase (AOX) inhibitor of the first aspect.
  • AOX alternative oxidase
  • agrochemical composition of the seventh aspect for treating an agrochemical disease or infection.
  • An agrochemical disease which may be treated, may be caused by an organism selected from a group of organisms consisting of: Chalara fraxinea; Septoria tritici;
  • Rhizoctonia solani Botrytis cinerea; Fusicladium effusum syn. Cladosporium caryigenum and Fusicladosporium effusum; Carya illinoinensis; Podosphaerafusca;
  • Microdochium nivale Microdochium majus; Septoria nodoum; Tapesia acuformis; and Metarhizium anisopliae.
  • Septoria ritici and Gaeumannomyces gramminis var titici are wheat pathogens (take-all); Magnaporthe grisea and Magnaporthe oryzae may cause rice blast and grey leaf spot of rye grass; Rhizoctonia solani may cause black scurf of potato, Botrytis cinerea may cause grey mold - a necrotrophic fungus that affects many plant species, although its most notable hosts are wine grapes; Fusicladium e usum (syn.
  • Cladosporium caryigenum and Fusicladosporium e usum is known as the Pecan scab and is the most devastating disease of the commercial pecan; Carya illinoinensis is involved in the production in South Eastern United States; Podosphaera fiisca is the main causal agent of cucurbit powdery mildew in Spain and one of the most important limiting factors for cucurbit production worldwide; Microdochium nivale & majus may attack barley, durum wheat and soft wheat and is present in all areas of France; Septoria nodoum may cause leaf and glume blotch; and Tapesia acuformis may cause eyespot. In addition, there is growing agrochemical interest in Metarhizium anisopliae which is an entomopathogenic fungus as an alternative for the management of pest insects.
  • Chalara fraxinea causes Chalara ash dieback disease.
  • the first DNA sequence for Chalara fraxinea has been published, as follows:- TTTATATATCCGATGTTTGGTGACAGCATTCTTGGTGCATGAAAAGTTACTCCCGGCGGCGAG GAACCGGTGACTTGGGAGAAGGGAGCGTTTGTTAATTGAAGGACTGGTACATGGATACCTGCGT ACTTCATGCGGTCCTTTCTCGTGGTGGTAGGCCTGCATTTAGGTTTCTTTGATGTTTGACGCCG CAGTTACACAGGCTGAGGCTGACTTGGATTTCGTGTGTCCCGATAAGACATCGTGAACGAGTTA TTTCCATCCCTTCTTTGTTCTCTTTTAGTTTGCTTAGAAGACGTTGCCGGCTTTTTCT TGACTGAGGTTGCTCGGGCTTTTATTCATTCACCTCTTCTTAGAGTTACCCGTTGCTTGCCGTG TTTCTTTGCTAGTGGCAATTGAAATACAACACCTACCTACTGTACCTTCACACACCTACACACCTACA
  • the DNA sequence for C.fraxinea encodes an AOX. Accordingly, the AOX inhibitors of the invention, as defined herein, will be effective against this fungus, especially its AOX encoded by SEQ ID No:l.
  • the agrochemical composition may comprise one or more solvents in which the AOX inhibitor is mixed.
  • the amount of solvents in the composition may range from 1% to 99%, or from 30% to 80%.
  • Suitable solvents include, for example, a non-polar water- immiscible solvent, or a polar aprotic water miscible organic solvent.
  • Non-polar solvents include, for example substituted or unsubstituted aliphatic or aromatic hydrocarbons and esters of plant oils or mixtures thereof.
  • Non-limiting examples of aromatic hydrocarbons include benzene or substituted benzene derivatives such as toluene, xylene, 1,2,4-trimethylbenzene, naphthalene or mixtures thereof.
  • a solvent includes a mixture of napthalen and 1,2,4-trimethylbenzene.
  • a solvent is Aromatic 150, a heavy aromatic naptha solvent containing ⁇ io% naphthalene and ⁇ i.7% 1,2,4-trimethylbenzene.
  • Alkyl esters can also be used as non-polar, water immiscible solvents.
  • Plant oils may be esterified with various alcohols to form alkyl esters of plant oils. Fatty acids of these plant oils have 5 to 20, or 6 to 15 carbon atoms.
  • Alkyl esters of plant oils include, without limitation, methyl, ethyl and butyl esters of canola (B. napus), linseed, safflower (Carthamus tinctorius L), soybean and sunflower oils.
  • the solvent is a mixture of methyl esters.
  • a specific non-limiting example of methyl esters is Agent 2416-21 manufactured by Stepan Company (22 W. Frontage Road, Northfield, Illinois).
  • Water-miscible polar aprotic solvents can include, for example, alkyl lactates, isopropyl lactate, alkyl carbonates, polyethylene glycols, polyethylene glycol alkyl ethers, polypropylene glycols, and polypropylene glycol alkyl ethers, or mixtures thereof.
  • the composition may comprise one or more adjuvants.
  • An adjuvant may enhance or improve herbicidal performance, for example.
  • Adjuvants may be added to the composition at the time of formulation, or by the applicator to a mix prior to treatment.
  • Adjuvants include, for example surfactants (emulsifier), crop oil, fertilizers, dispersing agents, compatibility agents, foaming activators, foam suppressants, correctives, and spray colorants (dyes).
  • An adjuvant may be present in any desired amount.
  • a formulation may contain i% to 3% adjuvant, 3% to 8% of adjuvant, 8% to 16% adjuvant, 17% to 30% adjuvant, or 30% or (e.g. 40% or more) more adjuvant.
  • the composition may comprise one or more surfactant.
  • a surfactant may increase solubility of the AOX inhibitor in a solution.
  • a surfactant may also affect spray retention, droplet spreading, and dry rates.
  • a surfactant may be anionic or non-ionic. Examples of anionic surfactants include phosphoric mono- and di- esters of long-chain alcohols having 14 to 22 carbon atoms and the salts thereof; phosphoric mono-and di- esters of alkylene oxide addition products of long-chain alcohols having 14 to 22 carbon atoms and the salts thereof; alkylsulphates having 14 to 22 carbon atoms;
  • Suitable non-ionic surfactants include, for example, ethoxylated fatty acids, alcohol ethoxylates, tristyrylphenol ethoxylates, ethoxylated sorbitan fatty acid esters or mixtures thereof.
  • Ethoxylated fatty acids include castor or canola oil ethoxylates having at least 25, preferably 27 to 37 ethoxy units, such as Sunaptol RTM CA350 (castor oil ethoxylate with 35 ethoxy units) of Uniqema (formerly ICI Surfactants), Mergital RTM EL33 (castor oil ethoxylate with 33 ethoxy units) of Henkel KGaA, Eumulgin RTM C03373 (canola oil ethoxylate with 30 ethoxy units) of Henkel KGaA and Ukanil RTM 2507 (castor oil ethoxylate) of Uniqema.
  • Sunaptol RTM CA350 castor oil ethoxylate with 35 ethoxy units
  • Uniqema now ICI Surfactants
  • Mergital RTM EL33 castor oil ethoxylate with 33 ethoxy units
  • Eumulgin RTM C03373 canola oil e
  • Surfactants may be present in any desired amount.
  • a surfactant may be present in an amount of about o.i to about 30% by weight in the formulation.
  • a surfactant is present in an amount of about 1 to about 9 % by weight in the formulation.
  • a surfactant is present in an amount of about 10 to about 20 % by weight in the formulation.
  • the composition may comprise one or more emulsifier.
  • An emulsifier is a type of surfactant typically used to keep emulsion well-dispersed.
  • Non-limiting examples of the emulsifier include Agent 2201-76, Agent 2416-20, Emulpon CO-360, T-Det C-40(R), and Agnique(TM) SBO-IO.
  • Agent 2201-76 is manufactured by Stepan Company (22 W. Frontage Road, Northfield, Illinois), which is a blend of nonionic and anionic surfactants (82%).
  • the ingredients in Agent 2201-76 are alkylbenzene sulfonate and fatty acid ethoxylate, aromatic petroleum hydrocarbon, i-hexanol and naphthalene.
  • Agent 2416-20 is also manufactured by Stepan Company (22 W. Frontage Road, Northfield, Illinois), which is a blend of nonionic and anionic surfactants (35-37%). Agent 2416-20 also includes aromatic petroleum hydrocarbon (57-58%), and naphthalene (6-7%).
  • Emulpon CO- 360 is manufactured by Akzo Nobel Chemicals Ltd. (525 West Van Buren, Chicago, Illinois), which contains ethoxylated castor oil (100% by weight) and oxirane ( ⁇ o.ooi% by weight).
  • T-Det C-4o(R) maybe purchased from Harcros Organics (5200 Speaker Road., P.O. Box 2930, Kansas City, Kansas), or from Akzo Nobel Chemicals Ltd.
  • a crop oil, or a crop oil concentrate may be used to increase the efficacy of a herbicide formulation.
  • a crop oil is believed to keep the leaf surface moist longer than water, which in turn allows more time for the herbicide to penetrate, thereby increasing the amount of herbicide that will enter the plant (e.g. weed).
  • a crop oil can improve uptake of herbicide by plant (e.g. weed).
  • a crop oil can therefore improve, enhance, increase or promote herbicidal efficacy or activity.
  • Crop oils may contained from 1% to 40% by weight, or 1% to 20% by weight in the formulation.
  • a crop oil can be derived from either petroleum oil or vegetable oil.
  • Non-limiting examples of crop oil include soybean oils and petroleum based oils.
  • the agrochemical composition of the invention may be in customary formulations.
  • Non-limiting examples include solutions, emulsions, suspensions, wettable powders, powders, dusts, pastes, soluble powders, granules, pellets, emulsifiable concentrate, oil spray, aerosol, natural and synthetic materials impregnated with active compound, and very fine capsules (e.g. in polymeric substances).
  • the composition is in a form of an emulsifiable concentrate, wettable powder, granule, dust, oil spray or aerosol.
  • the composition may optionally include adherent coatings.
  • adherent coatings include those that aid the AOX/bci inhibitor to adhere to the intended environment, for example, a plant being treated.
  • Adherent coatings include carboxymethylcellulose, natural and synthetic polymers in various forms, such as powders, granules or latexes.
  • Other adherent coatings include gum arabic, polyvinyl alcohol and polyvinyl acetate.
  • Phospholipids such as cephalins and lecithins, and synthetic phospholipids are also examples of adherent coatings. Further additives may be mineral and vegetable oils.
  • Colourants can also be included in the compositions.
  • inorganic pigments such as iron oxide, titanium oxide and Prussian Blue
  • organic dyestuffs such as alizarin dyestuffs, azo dye-stuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt,
  • compositions according to the invention can be applied in the form of ready mixes.
  • Herbicidal compositions can also be formulated individually and mixed upon use, i.e. applied in the form of tank mixes.
  • the compositions of the invention can be used as such or in the form of their formulations, and furthermore also as mixtures with herbicides, ready mixes or tank mixes.
  • the compositions may also be mixed with other active compounds, such as other fungicides, insecticides, acaricides, nematicides, bird repellents, growth substances, plant nutrients and agents which improve soil structure.
  • formulations such as mineral or vegetable oils which are tolerated by plants (for example the commercial product "Oleo DuPont l IE") or ammonium salts such as, for example, ammonium sulphate or ammonium thiocyanate, as further additives can be included.
  • the compositions can be used as such, in the form of their formulations or in the forms prepared therefrom by dilution of a concentrated form, such as ready-to-use or concentrated liquids, solutions, suspensions, emulsions, or solids, such as, powders, pastes, granules and pellets. They are dispersed in the customary manner, for example by watering, spraying, atomizing, dusting or scattering.
  • compositions of the invention can be produced by mixing or suspending one or more stabilizers, an active ingredient, and optionally an adjuvant, a diluent or a solvent.
  • compositions of the invention can be produced, for example by first mixing or suspending one or more AOX/bci inhibitor with a diluent or solvent. Next, the appropriate amount of adjuvant is combined to the resulting mixture containing the AOX/bci inhibitor. The AOX/bci inhibitor can be added at the end and blended until the formulation becomes mostly or entirely homogeneous.
  • Crop plants Plants that may be treated with the agrochemical composition are generally referred to herein as "crop plants”.
  • crop plants include floral and non- floral plants, trees, vegetable plants, turf, and ground cover.
  • Non-limiting specific examples of crop plants include canola, flax, peas, lentils, beans, linola, mustard, chickpeas, sunflowers, potatoes, seedling alfalfa, onions, soybeans and turf grass.
  • plants is meant to include germinant seeds, emerging seedlings, and established vegetation, including roots and above-ground portions (for example, leaves, stalks, flowers, fruits, branches, limbs, root, etc.).
  • roots and above-ground portions for example, leaves, stalks, flowers, fruits, branches, limbs, root, etc.
  • turf used herein refers to grass which grow in areas in which they are desired, or purposely planned for and
  • Turf also refers to a sod, where the surface layer of ground consisting of a mat of grass and grass roots.
  • the application rate of AOX/bci inhibitor varies depending, for example, on the crop being treated with the agrochemical composition. In general, the application rate may be from o.oi kg/ha to 5.ookg/ha or from 0.03 kg/ha to 3.ookg/ha of the AOX/bci inhibitor.
  • the inhibitors of the invention can be effectively used to treat infections of animal or human pathogens which comprise an AOX enzyme.
  • the compound of formula I which may be alternative oxidase (AOX) inhibitor of the first aspect, for use in therapy or diagnosis.
  • the compound of formula I which maybe alternative oxidase (AOX) inhibitor of the first aspect, for use in treating a microbial infection.
  • a method of treating, ameliorating or preventing a microbial infection in a subject comprising, administering to a subject in need of such treatment, a therapeutically effective amount of the compound of formula I, which may be alternative oxidase (AOX) inhibitor of the first aspect.
  • AOX alternative oxidase
  • a method of inhibiting activity of a microbial alternative oxidase (AOX) and/or cytochrome b& complex comprising contacting a microbial alternative oxidase (AOX) and/ or cytochrome b& complex with an effective amount of the compound of formula I, which may be alternative oxidase (AOX) inhibitor of the first aspect.
  • AOX microbial alternative oxidase
  • the AOX/bci inhibitor may be used to treat a bacterial infection, for example a Gram- positive or a Gram-negative bacterial infection.
  • the AOX/bci inhibitor is used to treat a fungal infection.
  • fungi against which the inhibitor is effective may include a filamentous fungus, such as an Ascomycete.
  • filamentous fungus such as an Ascomycete.
  • fungi against which the inhibitor is effective may be selected from a group of genera consisting of Aspergillus; Blumeria; Candida; Cryptococcus; Encephalitozoon; Fusarium; Leptosphaeria; Magnaporthe; Phytophthora;
  • Plasmopara Pneumocystis; Pyricularia; Pythium; Puccinia; Rhizoctonia;
  • fungi may be selected from a group of genera consisting of
  • the fungus may be selected from a group of species consisting of Aspergillus flavus; Aspergillus fiimigatus; Aspergillus nidulans;
  • Candida albicans Candida cruzei ; Candida glabrata; Candida par apsilosis; Candida tropicalis; Cryptococcus neoformans; Encephalitozoon cuniculi; Fusarium solani;
  • fungi include yeast, such as Saccharomyces spp, eg S. cerevisiae, or Candida spp, and Calbicans, which is know to infect humans.
  • the AOX/bci inhibitor may be used to treat a disease associated with human pathogens, such as intestinal disease; Leishmaniasis; Candidiasis; and diseases associated with contact lens usage.
  • AOX/bci inhibitors according to the invention may be used in a medicament, which may be used in a monotherapy, i.e. use of only the
  • AOX/bciinhibitor for treating, ameliorating, or preventing a microbial infection.
  • AOX/bci inhibitors may be used as an adjunct to, or in combination with, known therapies for treating, ameliorating, or preventing microbial infections, for example known antibacterial agents or antifungal agents.
  • the AOX/bci inhibitors according to the invention may be combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used.
  • the composition maybe in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment.
  • the vehicle of medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given.
  • Medicaments comprising AOX/bci inhibitors according to the invention may be used in a number of ways.
  • oral administration maybe required, in which case the inhibitors may be contained within a composition that may, for example, be ingested orally in the form of a tablet, capsule or liquid.
  • Compositions comprising inhibitors of the invention may be administered by inhalation (e.g. intranasally).
  • Compositions may also be formulated for topical use. For instance, gels, creams or ointments maybe applied to the skin, for example, adjacent the treatment site.
  • Inhibitors according to the invention may also be incorporated within a slow- or delayed-release device.
  • Such devices may, for example, be inserted on or under the skin, and the medicament maybe released over weeks or even months.
  • the device may be located at least adjacent the treatment site.
  • Such devices may be particularly advantageous when long-term treatment with modulators used according to the invention is required and which would normally require frequent administration (e.g. at least daily injection).
  • inhibitors and compositions according to the invention may be administered to a subject by injection into the blood stream or directly into a site requiring treatment. Injections maybe intravenous (bolus or infusion) or subcutaneous (bolus or infusion), or intradermal (bolus or infusion).
  • the amount of the AOX/bci inhibitor that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the inhibitor and whether it is being used as a monotherapy or in a combined therapy.
  • the frequency of administration will also be influenced by the half-life of the inhibitors within the subject being treated.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular inhibitors in use, the strength of the pharmaceutical composition, the mode of administration, and the advancement of the disease being treated. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • a daily dose of between o.o ⁇ g/kg of body weight and o.5g/kg of body weight of the inhibitors according to the invention may be used for treating, ameliorating, or preventing the microbial infection, depending upon which inhibitor is used. More preferably, the daily dose of inhibitor is between o.oimg/kg of body weight and 500mg/kg of body weight, more preferably between o.img/kg and 200mg/kg body weight, and most preferably between approximately lmg/kg and loomg/kg body weight.
  • the inhibitors may be administered before, during or after onset of the microbial infection. Daily doses may be given as a single administration (e.g. a single daily injection).
  • the inhibitors may require administration twice or more times during a day.
  • inhibitors may be administered as two (or more depending upon the severity of the disease being treated) daily doses of between 25mg and 7000 mg (i.e. assuming a body weight of 70 kg).
  • a patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3- or 4-hourly intervals thereafter.
  • a slow release device may be used to provide optimal doses of inhibitors according to the invention to a patient without the need to administer repeated doses.
  • an antimicrobial composition comprising the compound as represented by formula I, which may be an AOX inhibitor according to the first aspect, and a pharmaceutically acceptable vehicle.
  • antimicrobial composition can mean a pharmaceutical formulation used in the therapeutic amelioration, prevention or treatment of any microbial infection, for example a fungal, bacterial or pathogenic infection.
  • the invention also provides in an fourteenth aspect, a process for making the antimicrobial composition according to the thirteenth aspect, the process comprising contacting a therapeutically effective amount of the compound of formula I, which may be an AOX inhibitor according to the first aspect, and a pharmaceutically acceptable vehicle.
  • a “subject” may be a vertebrate, mammal, or domestic animal.
  • inhibitors, compositions and medicaments according to the invention may be used to treat any mammal, for example livestock (e.g. a horse), pets, or may be used in other veterinary applications. Most preferably, however, the subject is a human being.
  • a "therapeutically effective amount" of the AOX/bci inhibitor is any amount which, when administered to a subject, is the amount of medicament or drug that is needed to treat the microbial infection, or produce the desired effect.
  • the therapeutically effective amount of AOX/bci inhibitor used may be from about o.oi mg to about 8oo mg, and preferably from about o.oi mg to about 500 mg. It is preferred that the amount of inhibitor is an amount from about 0.1 mg to about 250 mg, and most preferably from about 0.1 mg to about 20 mg.
  • a "pharmaceutically acceptable vehicle” as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions.
  • the pharmaceutically acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet.
  • a solid pharmaceutically acceptable vehicle may include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet- disintegrating agents.
  • the vehicle may also be an encapsulating material.
  • the vehicle is a finely divided solid that is in admixture with the finely divided active agents according to the invention.
  • the active agent e.g. the modulator
  • the vehicle may be mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active agents.
  • Suitable solid vehicles include, for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like.
  • the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution.
  • Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the inhibitor according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators.
  • liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration.
  • the liquid vehicle for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and particularly subcutaneous injection.
  • the inhibitor may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • the inhibitor and pharmaceutical compositions of the invention may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 8o (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • the inhibitors according to the invention can also be administered orally either in liquid or solid composition form.
  • Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • FIG. l is a schematic drawing showing the mitochondrial respiratory chain, in which I-IV: Respiratory chain complexes; V: ATP synthase; Q: Ubiquinone; N ex t/int : NADH dehydrogenases; Stb: Strobilurin site of action; SHAM: salicylhydroxamic acid site of action; CN/CO: Cyanide/Carbon monoxide inhibition site; AO: Alternative oxidase; IMS/IM/M: Inter-membrane space/inner membrane/matrix of mitochondria;
  • Figure 2 shows a crystal structure of an alternative oxidase (AOX) protein from Trypanosoma brucei in the presence of a stoichiometric inhibitor
  • Figure 3 is a schematic figure showing the hydrophobic pocket and hydrogen-bonding of the inhibitor to the di-iron site of the alternative oxidase (AOX) using Sauromatum numbering;
  • Figure 4 is a sequence alignment of various alternative oxidases (AOX) of various species showing a consensus sequence.
  • AXIB-APvATH is the AOX enzyme from
  • AOXi_SOYBN is the AOX enzyme from soybean (SEQ ID No:3)
  • AOXi_TOBAC is the AOX enzyme from tobacco (SEQ ID No:4)
  • AOXiA_OPvYS is the AOX enzyme from Oryza sativa-ri ' ce (SEQ ID No:5)
  • AOXi_SAUGU is the AOX enzyme from Sauromatum guttatum (SEQ ID No:6)
  • AOX_CATRO is the AOX enzyme from Catharanthus roseus (SEQ ID No:7)
  • AOXi_MANIN is the AOX enzyme from Mangifera indica (SEQ ID No:8),
  • AOX_ZEAMA is the AOX enzyme from Maize (SEQ ID No: 9)
  • AOXi_CHLRE is the AOX enzyme from Chlamydomonas reinhardtii (SEQ ID No: 10)
  • AOX_NEUCR is the AOX enzyme from Neuropsora crassa (SEQ ID No: 11)
  • AOX_HANAN is the AOX enzyme from Hansenula anomola (SEQ ID No: 12)
  • AOX_TRYBB is the AOX enzyme from Trypanosoma brucei (SEQ ID No: 13)
  • AOX_CHLSP is the AOX enzyme from Chlamydomonas species (SEQ ID No:i4);
  • Figure 5 represents the chemical formula of Ascofuranone (left-hand side) and various embodiments of the AOX inhibitor according to the invention
  • Figure 6 represents the chemical formula of Colletochlorin B
  • Figure 7 shows the chemical synthesis of Colletochlorin B
  • Figure 8 is a graph showing IC 50 values for Colletochlorin B.
  • Figure 9 is a graph showing the effects of Colletochlorin B on cytochrome bci activity. Examples
  • the alternative oxidase (AOX) protein was purified and crystallized according to the techniques outlined in Kido, Y. et al (2010) Biochim. Biophys. Acta 1797, 443-450, and in Kido, Y. et al (2010) Acta, Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 66, 275- 278.
  • the crystal structure of the protein was obtained both in the presence and absence of an inhibitor using the vapour hanging-drop technique, as outlined in the papers given above.
  • the inhibitor-binding site was identified from the crystal structure.
  • FIG. 3 there is shown the fully characterised quinone-binding site or pocket of the alternative oxidase enzyme (AOX) of the plant, Sauromat m guttatum (Voodoo Lily).
  • AOX alternative oxidase enzyme
  • FIG. 3 shows the fully characterised quinone-binding site or pocket of the alternative oxidase enzyme (AOX) of the plant, Sauromat m guttatum (Voodoo Lily).
  • the Figure also shows a representative inhibitor (Colletochlorin B) positioned inside the pocket.
  • the six-membered ring of the inhibitor tightly interacts with the hydrophobic residues of the pocket, and the isoprenyl tail of the inhibitor interacts with Argi73, GIU270 and Ser274 residues of the pocket.
  • Figure 3 also shows that the inhibitor binding pocket (R173, L177, E178, L267, E270, A271, S274 & Y275) is located near the membrane surface, and is within 4 A of the active-site of the protein.
  • the numbering on Figure 3 refers to the plant (i.e. Sauromatum guttatum) AOX protein, as all AOXs tend to be compared with this protein.
  • the head group aldehyde oxygen is hydrogen-bonded by GIUI78 and Tyr275. Although not wishing to be bound by theory, these hydrogen bonds are believed to be important for the potent inhibitory activity of these compounds.
  • the inventors have confirmed that the quinone- binding site of the AOX shown in Figure 4 is a promising target in the treatment of fungal pathogens.
  • the inventors have prepared a sequence alignment of a number of AOX enzymes, which is shown in Figure 4, and it can be seen that the architecture of the AOX binding-site is highly conserved across all AOXs, irrespective of the species from which they are derived.
  • the boxed residues in Figure 4 represent AOX residues which are involved in inhibitor binding.
  • the Argi73, GIU270 and Ser274 residues shown in Figure 3 are less conserved. However, as these residues are only involved in the binding of the tail, variation is believed to be less significant with respect to inhibitor sensitivity.
  • guttatum is important, as it has revealed that there is a common architecture that can be applied to quinol-binding sites in general, and hence provides further insight into the mechanism of binding. More importantly, this information has assisted in the rational design of phytopathogenic fungicides and human parasites that are specifically targeted to the alternative oxidase.
  • the inventors set out to design and synthesize a new library of AOX inhibitors, and also to gain further detailed structural knowledge of the nature of the protein-ligand interaction and kinetics. They also tested the extent to which structurally modified inhibitors targeted at the AOX could also inhibit the fungal Qo site, thereby providing a new generation of dual-mode fungicides.
  • the inventors have designed and synthesised a number of AOX inhibitors based on the compound, ascofuranone, the chemical structures of which are illustrated in Figure 5.
  • Ascofuranone has a complex synthetic route, and has a reactive aldehyde group (- CHO).
  • Ascofuranone derivatives were synthesised, namely Colletochlorin B (labelled structure "2" in Figure 5, where R is CHO), compound "3" shown in Figure 5, where R is CH 2 0H, and 4a-4h, where R is as shown in Figure 5.
  • the inhibitory effects of some of these compounds were assessed, and the results are summarised in Table 1.
  • Table 1 summarises the concentration of inhibitor required to reduce the respiration of purified recombinant AOX protein by 50%. Respiration was measured as the rate of oxygen consumption in the presence of imM NADH as substrate and the numbers represent the final I 50 concentration of the inhibitor.
  • Colletochlorin B was one of the most promising candidates, because it has an IC 50 value of approx i65pM (IC 50 for
  • Ascofuranone 58pM when tested upon recombinant AOX proteins. This inhibitor was specific for membrane-bound and purified AOX, and did not appear to inhibit other quinol oxidases. Furthermore, Colletochlorin B can also be synthesized by a simple two-step process, which is a significant advantage over ascofuranone.
  • Orcinol (5g, 40mmol) and Zn(CN) 2 (7-ig, 6ommol) were placed into a 3 necked flask with mechanical stirrer under N 2 . 50ml of Ether was added, and the reaction was saturated with HC1 gas. After 2 hours, the Ether was decanted off and 50mls of water added to the reaction mixture. This was heated to ioo°C where the product crashed out of solution. The crude product was collected via buchner filtration, and recrystallised from water to yield the aldehyde (4.6g) in 76% yield.
  • Step 2 Compound (2) to compound (3)
  • Orcinol Aldehyde (527mg, 3.5 mmol) was put under N 2 and dissolved in anhydrous ether (60ml) on an ice bath. S0 2 C1 2 (1.35ml, 4.7mmol) was diluted in ether (15ml) and then added dropwise over isminutes. The reaction was left to stir overnight, and quenched with the addition of water. The Ether layer was washed with 0.1M NaHC0 3 and water, then dried over MgS0 4 and concentrated under vacuum. The crude solid was then purified via flash chromatography (Toluene: Ethyl acetate 2:1 -> 1:1) to obtain the product (459mg) in 75% yield.
  • Step 3 Compound (3) to compound (4)
  • aldehyde group present in ascofuranone (1) and Colletochlorin (2) is believed to represent a problem for anti-parasitic design for several reasons. Besides their ability to function as hydrogen bond acceptor and to undergo dipole-dipole interaction with AOX, aldehyde groups are chemically reactive enough to undergo reversible covalent modifications and would be generally unsuited to standard pharmaceutical formulations. Furthermore, aldehydes are prone to metabolic oxidation to the respective carboxylic acid with the concomitant non-specific binding to basic transport proteins. Therefore, the inventors set out to remove this aldehyde group using the reducing agent NaBH 4 , as shown in Figure 5.
  • the inventors have generated mutants of E123 and Y220, and have demonstrated that they are important for enzyme activity and inhibitor-binding. Site-directed mutagenesis and plasmid construction
  • Activity was measured as oxygen consumed/min/mg protein using NADH as substrate when isolated yeast mitochondria (Schizosaccharomyces pombe) containing the wild- type and mutant form of the AOX. Note that the inhibitor does not bind to the mutant forms of the oxidase.
  • Colletochlorin B and its derivatives have been demonstrated in Examples 1-5 to be a specific inhibitor of the alternative oxidase (AOX) in plants and fungi. Following on from this work, the inventors set out to test whether or not these compounds also have any effect on the respiratory activity of cytochrome bd complex. Mitochondria from two sources (rat liver and potato) were titrated with Colletochlorin B (CB), as indicated in typical data summarised in Figure 9. Both mitochondrial sources did not contain any alternative oxidase (AOX), and so the respiratory activity measured must have been from the cytochrome bd complex.
  • AOX alternative oxidase
  • Respiratory activity was measured in a medium containing 0.3M mannitol, lomM KCl, 5mM MgCl 2 , imM potassium phosphate and lomM MOPS (3-(N- morpholino)propanesulfonic acid) buffer PH7.4. Either o.9mg of rat liver mitochondria respiring on srnM succinate or o.3mg potato mitochondria respiring on imM NADH were used. Respiration was measured using a Rank oxygen electrode of 0.4ml volume at 25°C in the presence of ⁇ CCCP (Carbonyl cyanide m-chloromethoxy
  • Colletochlorin B was a promising candidate, because it has a lower IC 50 value (approx 5i5nM) than Azoxystrobin (approx 525nM) when tested on rat liver mitochondria.
  • the IC 50 value of Colletochlorin B was only ⁇ .75 ⁇ , which was half of the IC 50 of Azoxystrobin (approx ⁇ .4 ⁇ ), and significantly less than the IC 50 of Ascofuranone (approx 3 ⁇ ).

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MX2014012949A MX2014012949A (es) 2012-04-25 2013-04-24 Compuestos para utilizarse como inhibidores oxidasa alternativa o el complejo bc1 de citocromo.
IN9924DEN2014 IN2014DN09924A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2012-04-25 2013-04-24
HRP20221493TT HRP20221493T1 (hr) 2012-04-25 2013-04-24 Spojevi za uporabu kao inhibitora alternativne oksidaze ili citokromnog bc1 kompleksa
PL13719143.3T PL2841409T3 (pl) 2012-04-25 2013-04-24 Związki do zastosowania jako inhibitory alternatywnej oxydazy lub kompleksu cytochromu bc1
EP13719143.3A EP2841409B1 (en) 2012-04-25 2013-04-24 Compounds for use as inhibitors of alternative oxidase or cytochrome bc1 complex
CN201380027565.2A CN104334518B (zh) 2012-04-25 2013-04-24 用作交替氧化酶或细胞色素bc1复合物的化合物
AU2013254493A AU2013254493B2 (en) 2012-04-25 2013-04-24 Compounds for use as inhibitors of alternative oxidase or cytochrome bc1 complex
US14/397,164 US10851047B2 (en) 2012-04-25 2013-04-24 Compounds for use as inhibitors of alternative oxidase or cytochrome BC1 complex
ES13719143T ES2932988T3 (es) 2012-04-25 2013-04-24 Compuestos para uso como inhibidores de oxidasa alternativa o complejo de citocromo bc1
CN201710744009.7A CN107691443B (zh) 2012-04-25 2013-04-24 用作交替氧化酶或细胞色素bc1复合物的化合物
KR1020147033032A KR102209338B1 (ko) 2012-04-25 2013-04-24 AOX 또는 시토크롬 bc1 복합체의 저해제로서 이용을 위한 화합물
BR112014026551-8A BR112014026551B1 (pt) 2012-04-25 2013-04-24 uso de um composto para inibir uma oxidase alternativa (aox)
JP2015507594A JP2015521163A (ja) 2012-04-25 2013-04-24 オルタナティブオキシダーゼまたはシトクロムｂｃ１複合体の阻害剤として用いるための化合物
PH12014502383A PH12014502383B1 (en) 2012-04-25 2014-10-24 Compounds for use as inhibitors of alternative oxidase or cytochrome bc1 complex
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US10851047B2 (en) 2012-04-25 2020-12-01 The University Of Sussex Compounds for use as inhibitors of alternative oxidase or cytochrome BC1 complex
US11565996B2 (en) 2012-04-25 2023-01-31 Alternox Scientific Limited Compounds for use as inhibitors of alternative oxidase or cytochrome bc1 complex
WO2015032692A1 (de) * 2013-09-03 2015-03-12 Bayer Cropscience Ag Verwendung fungizider wirkstoffe zur kontrolle von chalara fraxinea an eschenbäumen
CN106413400B (zh) * 2014-01-23 2022-03-25 萨塞克斯大学 抗真菌组合物
KR102381669B1 (ko) * 2014-01-23 2022-03-31 유니버시티 오브 서섹스 항진균성 조성물
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AU2015208926B2 (en) * 2014-01-23 2018-08-30 Alternox Scientific Limited Antifungal composition
US10334847B2 (en) 2014-01-23 2019-07-02 The University Of Sussex Antifungal composition
WO2015110820A1 (en) * 2014-01-23 2015-07-30 The University Of Sussex Antifungal Composition
US20170006864A1 (en) * 2014-01-23 2017-01-12 The University Of Sussex Antifungal Composition
CN106413400A (zh) * 2014-01-23 2017-02-15 萨塞克斯大学 抗真菌组合物
KR20160111496A (ko) * 2014-01-23 2016-09-26 유니버시티 오브 서섹스 항진균성 조성물
JP7041129B2 (ja) 2016-06-20 2022-03-23 ユニバーシティ・オブ・ダンディー 抗感染剤
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JP2019522048A (ja) * 2016-06-20 2019-08-08 ユニバーシティ・オブ・ダンディー 抗感染剤
WO2021102568A1 (en) 2019-11-26 2021-06-03 Canopy Growth Corporation Cannabinoid derivatives
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