EP2996471A2 - Aminoglycoside and azole compositions and methods - Google Patents
Aminoglycoside and azole compositions and methodsInfo
- Publication number
- EP2996471A2 EP2996471A2 EP14797052.9A EP14797052A EP2996471A2 EP 2996471 A2 EP2996471 A2 EP 2996471A2 EP 14797052 A EP14797052 A EP 14797052A EP 2996471 A2 EP2996471 A2 EP 2996471A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- alkyl
- group
- aminoglycoside
- compound
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 229940126575 aminoglycoside Drugs 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 36
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims description 38
- 239000000203 mixture Substances 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 208000031888 Mycoses Diseases 0.000 claims abstract description 18
- 230000000855 fungicidal effect Effects 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 206010017533 Fungal infection Diseases 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- -1 chlotirmazole Chemical compound 0.000 claims description 7
- 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 6
- 229960004884 fluconazole Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 6
- 229960004740 voriconazole Drugs 0.000 claims description 6
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 claims description 5
- 239000005868 Metconazole Substances 0.000 claims description 5
- 239000005869 Pyraclostrobin Substances 0.000 claims description 5
- XWPZUHJBOLQNMN-UHFFFAOYSA-N metconazole Chemical compound C1=NC=NN1CC1(O)C(C)(C)CCC1CC1=CC=C(Cl)C=C1 XWPZUHJBOLQNMN-UHFFFAOYSA-N 0.000 claims description 5
- 229960001589 posaconazole Drugs 0.000 claims description 5
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 claims description 5
- HZRSNVGNWUDEFX-UHFFFAOYSA-N pyraclostrobin Chemical compound COC(=O)N(OC)C1=CC=CC=C1COC1=NN(C=2C=CC(Cl)=CC=2)C=C1 HZRSNVGNWUDEFX-UHFFFAOYSA-N 0.000 claims description 5
- 229960004214 tioconazole Drugs 0.000 claims description 5
- PXMNMQRDXWABCY-UHFFFAOYSA-N 1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol Chemical compound C1=NC=NN1CC(O)(C(C)(C)C)CCC1=CC=C(Cl)C=C1 PXMNMQRDXWABCY-UHFFFAOYSA-N 0.000 claims description 4
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000005839 Tebuconazole Substances 0.000 claims description 4
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 claims description 3
- VHVPQPYKVGDNFY-ZPGVKDDISA-N itraconazole Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-ZPGVKDDISA-N 0.000 claims description 3
- 230000000843 anti-fungal effect Effects 0.000 abstract description 20
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 abstract description 20
- 150000003851 azoles Chemical class 0.000 abstract description 19
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 29
- 229960004130 itraconazole Drugs 0.000 description 29
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- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 9
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 150000002337 glycosamines Chemical class 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
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- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
-
- 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 present disclosure relates to active chemical combinations. More particularly, the present disclosure relates to aminoglycoside and azole combinations and their antibiotic activities.
- Aminoglycoside antibiotics have been commonly used as a medical treatment against infectious diseases for over 60 years, although the prevalence of aminoglycoside resistant bacteria has significantly reduced their effectiveness.
- Aminoglycosides have two or more amino sugars bound to an aminocyclitol ring through glycosidic bonds.
- Naturally occurring aminoglycosides are widely used as antibiotics against bacterial infections of animals and humans. These include the well-known antibiotics kanamycin, streptomycin, and neomycin. Aminoglycoside antibiotics are believed to act on the bacterial protein synthesis machinery, leading to the formation of defective cell proteins.
- Kanamycin is a known aminoglycoside antibiotic.
- the antibiotic function of kanamycin may be related to its ability to affect the 30S ribosomal subunit of bacteria, causing frameshift mutations or preventing the translation of RNA. Either frameshift mutations or a lack of RNA translation can lead to a reduction or absence of bacterial protein synthesis and, ultimately, to bacterial death.
- kanamycin has been rendered all but obsolete for clinical use due to the emergence of resistant bacteria.
- antimicrobial compounds it would be desirable for new antimicrobial compounds to be selective against either bacteria or fungi, so treatment for one of either bacterial or fungal disease does not contribute to the buildup of antimicrobial resistance in the other.
- Selective antimicrobial activity is especially desirable for antifungals used to treat crop disease, such as Fusarium head blight, due to the possibly large amounts of antimicrobial agent released into the environment when crops are treated.
- the present invention provides for novel
- aminoglycoside antimicrobials that are effective, have relatively low levels of toxicity, and are selective against fungal pathogens.
- the present disclosure in aspects and embodiments addresses these various needs and problems by providing an azole-aminoglycoside compound with biocidal effects.
- the fungicidal compound comprises an aminoglycoside compound, or salt thereof having the formula:
- X is a member selected from the group consisting of O, S, and NR 2 ;
- R 1 is a member selected from the group consisting of R 3 , C(0)OR 3 ,
- phenyl wherein phenyl groups may be Ci to C 6 alkyl substituted;
- R 2 is H or Ci to C 6 alkyl
- R 3 is a straight or branched chain C 4 to Ci 2 alkyl group
- R 4 is phenyl or Ci to C 6 alkyl substituted phenyl
- an azole is a straight or branched chain C 4 to Ci 2 alkyl group
- X is O, S or NH;
- R 1 is a member selected from the group consisting of C(0)R 3 , S(0) 2 R 3 , S(0) 2 R 4 , wherein: R 3 is C 4 to C 12 straight or branched chain alkyl and R 4 is phenyl or Ci to C 6 alkyl substituted phenyl.
- X is O and R 1 is C(0)R 3 . In some of these
- R 3 is n-CyHis or n-CgHn.
- X is O and R 1 is S(0) 2 R 3 .
- R 3 is C 6 Hi3 or R 3 is CsHn.
- X is O and R 1 is S(0) 2 R 4 . In some of these embodiments, R 4 is /?-tolyl.
- X is NH and R 1 is R 3 . In some of these embodiments,
- R 3 is CsHiv.
- the azole is selected from the group consisting of intraconazole, fluconazole, voriconazole, posaconazole, chlotirmazole, tioconazole, ketocaonazole, metconazole, tebuconazole, and pyraclostrobin.
- the above compounds may be used as a method of treating or preventing a fungal infection which comprises administering to a host in need thereof an effective amount of a fungicidal compound is disclosed, the compound comprising: an aminoglycoside compound, or salt thereof having the formula:
- X is a member selected from the group consisting of O, S, and NR 2 ;
- R 1 is a member selected from the group consisting of R 3 , C(0)OR 3 , NH(CO)R 3 , S(0) 2 R 3 , S(0) 2 R 4 , S(0)R 3 , P(0) 2 R 3 , C(0)R 3 , and phenyl, wherein phenyl groups may be Ci to C 6 alkyl substituted;
- R 2 is H or Ci to C 6 alkyl
- R 3 is a straight or branched chain C 4 to C 12 alkyl group; and R 4 is phenyl or Ci to C 6 alkyl substituted phenyl; and an azole.
- aminoglycoside analogs are derived from the parent molecule of kanamycin A.
- a still further object of the present invention is to provide method of synthesizing aminoglycoside analog compounds of Formula I.
- Yet another object of the present invention is to provide methods of using aminoglycoside analog compounds of Formula I as biocides having improved fungicidal activity.
- the compounds of the present invention unexpectedly demonstrate increased specificity for fungal pathogens and a lack of activity against some common bacterial pathogens.
- the synergistic effects of the added azole exhibit drastically improved biocidal effects.
- Figure 1 illustrates an exemplary method to synthesize an exemplary aminoglycoside.
- Figure 2 illustrates itraconazole and K20 synergistic inhibition of Candida albicans AT CC 10231
- Figure 3 illustrates the time kill curves of itraconazole and K20 synergistic inhibition of Candida albicans ATCC 10231.
- Figure 4 illustrates cytotoxicity of itraconazole and K20 mixtures on Chinese
- compositions, kits, reagents, and associated methods for active compounds that include aminoglycosides and azoles are provided for a thorough understanding of specific preferred embodiments. However, those skilled in the art will recognize that embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In some cases, well-known structures, materials, or operations are not shown or described in detail in order to avoid obscuring aspects of the preferred embodiments. Furthermore, the described features, structures, or characteristics may be combined in any suitable manner in a variety of alternative embodiments. Thus, the following more detailed description of the embodiments of the present invention, as illustrated in some aspects in the drawings, is not intended to limit the scope of the invention, but is merely representative of the various embodiments of the invention.
- circumstance occurs and instances in which the circumstance does not occur.
- the terms "one or more” and “at least one” refer, for example, to instances in which one of the subsequently described circumstances occurs, and to instances in which more than one of the subsequently described circumstances occurs.
- Host The term "host” is defined herein as any living organism infected or at least somewhat likely of being infected by a fungal pathogen, where said pathogen and any infection caused by said pathogen, or potential infection caused by said pathogen, are susceptible to treatment with one or more of the compounds of Formula I as claimed herein, where said treatment is likely to result in the elimination, avoidance, or alleviation of the infection caused by said pathogen.
- Kanamycin A has the structure:
- Fungal Infection is defined herein as an association of a fungal organism with a host, whether said association is actual or potential.
- an actual associate occurs when a fungi is physically present on or within a host.
- potential associations include fungi on or within the environment surrounding a host, where the fungi is at least somewhat likely to be actively or passively transferred to the host.
- examples of the association of the fungal organism with the host include biological associations that may be pathogenic or non-pathogenic, parasitic or nonparasitic, symbiotic or non-symbiotic, mutualistic or non-mutualistic, commensal, naturally occurring or man-made, or any other biological interaction.
- Host in need thereof is defined herein as any host associated or potentially associated with a fungal organism, where said host may actually or potentially benefit from elimination, prevention, or alleviation of a fungal infection.
- Fusarium Head Blight The phrase "fusarium head blight" is defined herein as any fungal disease caused by the fungus Fusarium graminearum.
- Surfactant is used to indicate the common laboratory surfactant C58H114O26. All uses of the term “surfactant” refer to C58H114O26, unless otherwise indicated.
- Prophylactically The term “prophylactically” is used herein to refer to the administration of an antimicrobial compound for the prevention of disease.
- N/A As used herein to describe data points, the abbreviation "N/A" means not tested.
- Adjuvant is defined herein as a substance that helps and enhances the pharmacological effect of a drug or increases the ability of an antigen to stimulate the immune system.
- Excipient is defined herein as an inactive substance used as a carrier for the active ingredients of a medication.
- Diluent The term “diluent” is defined herein as any liquid or solid material used to dilute or carry an active ingredient.
- Antifungal Amount or antifungal effective Unless otherwise specified, the phrases "antifungal amount” or “Antifungal Effective” are used herein to describe an amount of an antifungal agent sufficient to reduce, eliminate, or alleviate a fungal infection or the symptoms of a fungal infection on or within a host.
- MIC means the minimal inhibitory concentration or lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after 24, 48, or 72 hours of incubation.
- Admixed The term "admixed" is used herein to describe a chemical or compound in a mixture or combination with other chemicals or compounds.
- Administering is defined herein to describe the act of providing, exposing, treating, or in any way physically supplying or applying a chemical or compound to any living organism or inanimate object associated with a living organism, where said organism will actually or potentially benefit for exposure, treatment, supplying or applying of said chemical or compound.
- Topical is defined herein as pertaining to the surface of a body part, surface part of a plant, or surface of an inanimate object or composition, such as soil.
- a topical medication is applied to body surfaces such as the skin or mucous membranes, for example throat, eyes and ears.
- Carrier is defined herein as any substance that serves to improve the delivery and the effectiveness of a drug or antimicrobial agent and is inclusive of excipients as defined above. Examples include: microspheres made of biodegradable polymer poly(lactic-co-glycolic) acid, albumin microspheres, synthetic polymers (soluble), protein- DNA complexes, protein conjugates, erythrocytes, nanoparticles, and liposomes
- Grain head The phrase "grain head” as used herein is meant to include both small and large grains.
- Warm-blooded animal Used herein the phrase "warm-blooded animal” means an animal characterized by the maintaining of a relatively constant and warm body temperature independent of environmental temperature; homeothermic.
- PDB-CA refers to potato dextrose broth + casamino acids medium used for fungal growth and as diluent in MIC tests.
- PDB - CA To make 1L of PDB - CA, 200 g of diced fresh potatoes were boiled in 500 mL of distilled water for 30 min. The broth was filtered through 2 layers of cheesecloth, and the volume was brought up to 1 L. After addition of 20 g of glucose (2 %, w/v) and 4 g of casamino acid (0.4 %, w/v), the mixture was stirred with a magnetic bar until all solids were dissolved. The pH was adjusted with HC1 and NaOH to 5.1. Then, the medium was sterilized by autoclaving for 30 min.
- PDA-CA refers to a solid growth medium composed of
- RPMI 1640 refers to a chemically defined cell growth medium composed of twenty amino acids, eleven vitamins, calcium nitrate (Ca(N0 3 ) 2 4H 2 0), magnesium sulfate (MgS0 4 ) (anhyd.), potassium chloride (KC1), sodium chloride (NaCl), sodium phosphate dibasic (Na 2 HP0 4 ) anhydrous, dextrose, glutathione (reduced) and buffered to a pH of 7.0 with 0.165 M morpholinepropanesulfonic acid (MOPS) buffer (as described by Moore, G.E., Gerner, R.E. and Franklin, H.A. (1967) J. Amer. Med. Assoc. 199:51
- the present invention relates to antimicrobial compounds comprising aminoglycosides and azoles.
- exemplary aminoglycosides include the compound of Formula I as follows:
- X is a member selected from the group consisting of O, S, and NR 2 ;
- R 1 is a member selected from the group consisting of R 3 (alkyl), C(0)OR 3
- R 2 is H or Ci to C 6 branched or straight chained alkyl
- R 3 is a straight or branched chain C 4 to Ci 2 alkyl group
- R 4 is phenyl or Ci to C 6 alkyl substituted phenyl.
- the phenyl group in R 1 may be substituted with a branched or straight chain Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl group;
- R 2 may be a branched or straight chain Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl group;
- R 3 may be a branched or straight chain Ci, C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , Cs, C9, Cio, C11, or C 12 alkyl group;
- R 4 may be a Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl (straight or branched) substituted phenyl.
- These compounds are substituted analogs of kanamycin A.
- the present invention also relates to methods for the synthesis of such analogs and the utilization of them as antifungal agents.
- the compounds related to the present invention are analogs of parent molecule kanamycin A.
- the structure related to the present invention is distinguished from the parent molecule kanamycin A by the presence of functional groups terminating in either an alkyl or phenyl group in the 6 position of ring III.
- the functional groups at the 6 position of ring III are identified as XR 1 wherein X is a member selected from the group consisting of O, S, and NR 2 , where R 2 is H or Ci to C 6 alkyl and R 1 is a member selected from the group consisting of R 3 (alkyl), C(0)OR 3 (alkoxycarbonyl), NH(CO)R 3
- R 3 alkylsulfmyl
- P(0) 2 R 3 alkylphosphonyl
- C(0)R 3 alkanoyl
- phenyl groups may be Ci to C 6 alkyl substituted
- R 2 is H or Ci to C 6 branched or straight chained alkyl
- R 3 is a straight or branched chain C 4 to C 12 alkyl group
- R 4 is phenyl or Ci to C 6 alkyl substituted phenyl.
- R 3 is preferable n-alkyl.
- X is O or S with O being particularly preferred, but can also be NR 2 with R 2 being preferably H.
- R 1 is preferably a member selected from the group consisting of C(0)OR 3 (alkoxycarbonyl), S(0) 2 R 3 (alkylsulfonyl), S(0) 2 R 4 (phenylsulfonyl), and C 4 to C 12 straight or branched chain alkyl.
- R 3 is also C 4 to C 12 straight or branch chain alkyl.
- R 4 is phenyl or Ci to C 6 alkyl substituted phenyl.
- R 1 is C 4 to C 12 straight or branch chain alkyl.
- aminoglycosides may be used as illustrated above, as salts, or any other suitable form for delivery to a target organism.
- the aminoglycosides as described above and as set forth in Formula I may be combined with one or more of suitable azole.
- Azoles include compounds having a five- membered nitrogen heterocyclic ring containing at least one other non-carbon atom of either nitrogen, sulfur, or oxygen, such as azoles that include 1 nitrogen atom, 2 or more nitrogen atoms, 1 nitrogen atom and 1 oxygen atom, and 1 nitrogen atom and 1 sulfur atom.
- the five- membered nitrogen heterocyclic ring may be additionally substituted.
- suitable azoles include those that have at least some desired biocidal effect.
- exemplary azoles include pyrroles, pyrazoles, imidazoles, triazoles, tetrazoles, pentazoles, oxazoles, isoxazoles, thiazoles, and isothiazoles.
- the azole may be selected from one or more of the following: itraconazole, fluconazole, voriconazole, posaconazole, chlotrimazole, tioconazole, ketocaonazole, metconazole, tebuconazole, and pyraclostrobin.
- the azoles may be used as illustrated above, as salts, or any other suitable form for delivery to a target organism.
- the aminoglycosides and azoles may be used in any suitable ratio or combination.
- the ratio of azole to aminoglycoside may be from about 1 : 1 to about 1 : 1000, from about 1 :5 to about 1 :600, from about 1 :20 to about 1 :500, from about 1 :30 to about 1 :200, and from about 1 :50 to about 1 : 100.
- the ratio of azole aminoglycoside may be about 1 :5, 1 :21, 1 :32, 1 :53, 1 : 180, and 1 :533.
- One preferred embodiment of the present invention is the treatment of fungal infection in a host in need thereof, where the elimination or reduction of bacteria associated with said host is undesirable.
- one such use could occur in human or non-human mammals, where treatment of a fungal infection with and aminoglycoside of the invention such as K20 would eliminate or alleviate the fungal infection, but not affect the integrity of the intestinal flora of the host.
- a second example is the treatment or prevention of fungal disease in a host crop, where it is undesirable to affect the diversity or abundance of bacteria of said host crop.
- the present invention is drawn to novel antifungal compounds, a method to synthesize said novel antifungal compounds, and methods to use said novel antifungal compounds to treat humans, animals, soil, or plants to eliminate fungal growth and activity.
- the structure related to the present invention is derived from a parent aminoglycoside molecule other than kanamycin A that is capable of being modified by the addition of a variety of substituents on ring III equivalent of the ring III of kanamycin A. Particularly preferred is the addition of a carbon alkyl chain as designated herein on ring III.
- the present invention is derived from the parent aminoglycoside molecule by the synthesis method shown herein, but the substituent, such as the carbon alkyl chain on ring III of the structure related to the present invention varies in the number of carbon atoms and hydrogen atoms.
- the present invention is used to treat a variety of fungal pathogens related to human, crop, or animal disease.
- the compound of the present invention is administered by spraying, direct injection, topical application, ingestion (including pharmaceutical compositions that include the structure related to the present invention), or by inclusion in the water supply, to either a human, an animal, or a crop immediately threatened by, or potentially threatened by, a fungal pathogen, where fungal pathogen is causing or may cause fungal disease, and administration of the compounds of the present invention will reduce, eliminate, or avoid fungal disease.
- PDB - CA and PDA-CA growth media were used throughout. However, in embodiments RPMI 1640, or any other suitable growth media, may be used. [0084] Bacterial and fungal organisms
- Escherichia coli TGI Escherichia coli B
- Staphylococcus aureus ATCC 6538 Staphylococcus aureus ATCC 6538
- Micrococcus luteus, and Candida. albicans ATCC 10231 were obtained from the American Type Culture Collection (Manassas, VA, USA). Fusarium graminearum strain B-4-5A was obtained from the Small Grain Pathology Program, University of Minnesota, Minneapolis MN, USA. Saccharomyces cerevisiae W303C and Rhodotorula pilimanae were obtained from Dr. J.Y. Takemoto, Utah State University, Logan, Utah , USA). Aspergillus flavus, Fusarium oxysporum, Fusarium culmorum, Microdochium nivale, Mucor haemalis,
- Ulocladium spp., Penicillium spp., Rhizopus stolonifer and Cladosporium cladosporioides were obtained from Dr. B. Kropp (Utah State University, Logan, Utah, USA) and Aspergillus niger was obtained from Dr. C. Nischwitz (Utah State University, Logan, Utah, USA).
- Filamentous fungi and yeasts were cultivated at 35°C in PDB-CA. Bacterial strains were grown at 37°C for 24 h on Luria-Bertani medium (14) except for Staphylococcus aureus ATCC6538 which was grown on Mueller-Hinton medium (Difco, BD, Franklin Lakes, NJ, USA).
- NCLS Clinical and Laboratory Standards Institute
- M38-A National Committee for Clinical Laboratory Standards, Wayne, PA, 2002
- MIC tests Fusarium graminearum, Rhodotorula pilimanae, and Aspergillus flavus were grown in PDB-CA medium for 48 h at 28° C with aerobic shaking.
- various fungal species were inoculated in the middle of PDA-CA medium plate surfaces. Sterilized paper disks (0.5 cm diameter) were placed on the inoculated agar medium surfaces equidistant and around the fungal inoculum.
- test solutions (10 mg mL "1 ) were applied to the disks, and the plates were incubated for 24 to 48 h at 28°C before examination of the inhibition patterns seen as cleared zones of growth inhibition surrounding the disks.
- Assays for determination of MICs were conducted in sterile, flat-bottomed 96-well microtiter plates (Corning Costar, Corning, NY) in the range of 500 to 1 ⁇ g mL "1 .
- Stock solutions of analogs were prepared at concentrations of 2 mg mL "1 in water. In microtiter plates, 50 aliquots of stock solutions were added in the third column and 10 consecutive two-fold serial dilutions were made in each row with sterile distilled water.
- Tetra-Boc protected kanamycin (B4K) can be prepared with reported method (J. Med. Chem. 1991, 34, 1468-1476).
- a solution of B4K (90 g), octanesulfonyl chloride (64 mL) in anhydrous pyridine (800 mL) was stirred at 0°C overnight allowing the temperature to warm up to room temperature.
- the clear brownish mixture was stirred for another 6 days at room temperature and one day at 40°C, and then concentrated to an oily crude product. Water (500 mL) was added and the mixture was stirred for another day. The mixture was transferred to a separatory funnel with more water and EtOAc (2 L).
- the organic layer was washed with 0.5 N HCl (aq) (x2) and water. The washing sequence was repeated 3-4 times. If solid precipitation (mostly unreacted B4K) occurred, the organic layer was filtered first to remove the solid. After completion of the washing, the EtOAc solution was filtered through a Frit funnel and the EtOAC was evaporated. The brownish crude product was treated with a solution of TFA/DCM (1/4) (200 mL). After being stirred overnight, the solvents were removed. Water was added and evaporated to ensure the removal of residual acid. The crude product was dissolved in water and washed with EtOAc until the color in EtOAc was clear. The aqueous solution was evaporated and passed through a column packed with DowexlX-8 (CI- form). After removal of solvent, the desired K20 was afforded as a yellowish solid.
- K20 analogs i.e. K05, K07, K17, K18, K19 and K22 can be prepared in a similar manner using appropriate reactants in the place of octanesulfonyl chloride.
- EXAMPLE 2 Relative growth inhibitory activities of K20 against bacteria and fungal species.
- Table 1 there is shown the relative growth inhibitory activities of K20 against various species of bacteria and fungi as determined by disk diffusion agar plate assays. Table 1.
- Fusarium graminarum is a fungus that infects wheat and the disease is also known as head scab or Fusarium Head Blight and is a serious deterrent to the harvesting of good quality wheat and often results in farmers being forced to discard their crop. Consistent with the disk diffusion assay data shown in Table 1, the MIC testing of K20 against
- Fusarium graminarum resulted in MIC's of between 7.8 and 15.6 ⁇ g mL "1 using PDB-CA growth medium.
- EXAMPLE 3 Antifungal activities of K20 analogues against Fusarium graminearum and/or Rhodotorula pilimanae.
- the MICs of K20 were determined for selected bacterial pathogens. For purposes of the experiments discussed in this paragraph, the MIC is defined as the lowest concentration of compound needed to inhibit the growth of bacteria.
- a solution of a selected bacterium was inoculated into trypticase soy broth (Difco, BD, Franklin Lakes, NJ, USA), at 35°C and incubated for 1 - 2 hours. Following incubation, the bacterial concentrations were determined, and diluted with broth, if necessary, to an absorption value of 0.08 to 0.1 at 625nm. The adjusted inoculated medium (100 mL) was diluted with 10 mL broth, and then applied to a 96-well microtiter plate (50 mL).
- MIC values ⁇ g mL "1 ) for K20 were 250 for Escherichia coli B and 62.5 for Micrococcus luteus.
- Corresponding MIC values for kanamycin A and B were 0.98 ⁇ g mL "1 for Micrococcus luteus and 1.95 ⁇ g mL "1 for Escherichia coli B.
- the bacterial MIC values determined for K20 exceed the values that typically prompt consideration of candidate compounds as effective antibacterial
- the aminoglycoside analogs of the present invention demonstrate insufficient or no antibacterial activity and are structurally distinct from kanamycin A due to the presence of a carbon alkyl chain or aryl ring on ring III.
- the fungal specificity of the present invention will benefit crop protection strategies because use of the present invention will not promote bacterial resistance, whereas conventional aminoglycosides do promote bacterial resistance.
- EXAMPLE 5 Disk diffusion tests to determine synergistic inhibition of azole-resistant Candida albicans ATCC 10231 by itraconazole and K20
- Candida albicans ATCC 10231 yeast cells were grown in PDB-CA medium for 48h at 30°C with aerobic shaking. The culture densities were adjusted to ⁇ 5 x 10 5 c.f.u. mL "1 , and the fungal cultures were spread-plated on PDB-CA agar plate medium surfaces. Sterilized paper disks (0.5 cm diameter) were placed on the inoculated agar medium surfaces.
- EXAMPLE 6 Checkerboard assay to determine synergistic inhibition of azole-resistant Candida albicans ATCC 10231 by azoles and K20
- the final concentrations of the drugs ranged from 0.04 to 3 ⁇ g mL "1 for itraconazole (ITC); 0.3 to 48 ⁇ g mL “1 for fluconazole (FLC); 0.01 to 1 ⁇ g mL “1 for voriconazole (VRZ); 0.07 to 2.5 ⁇ g mL “1 for metconazole; 0.04 to 3 ⁇ g mL “1 for pyraclostrobin; 0.07 to 2.5 ⁇ g mL “1 for chlotrimazole; 0.005 to 0.5 ⁇ g ml "1 for tioconazole; 0.005 to 2 ⁇ g mL-1 for posaconazole; 0.3 to 24 ⁇ g mL "1 for ketoconazole and 2 to 256 ⁇ g mL "1 for K20.
- Negative (190 ⁇ of growth medium and 10 ⁇ , of water) and positive (190 ⁇ of growth medium and 10 ⁇ of organism) controls were placed in separate wells. The plates were incubated at room temperature or 30°C and visually inspected and scored every 24 to 48 h. Checkerboard microbroth dilution assays in a single test were replicated three times, and each test repeated at least twice. The analysis of the combination of K20 and azoles was obtained by calculating the Fractional Inhibitory
- FICI Concentration Index
- EXAMPLE 7 Time-kill curves to observe synergistic interaction of itraconazole and K20 against azole-resistant Candida albicans ATCC 10231 growing in PDB-CA medium
- Method Strain Candida albicans ATCC 10231 was prepared at an inoculum size of 10 5 c.f.u. mL "1 in PDB-CA medium. The drug concentrations used were 32 ⁇ g mL "1 for K20 and 0.18 ⁇ g mL "1 for itraconazole. At designated times (0, 3, 6, 9, 24 and 48 h after incubation), 100 aliquots were removed from each solution and serially diluted 10-fold in sterile water. One hundred volumes of each dilution were streaked on agar surfaces of potato dextrose agar plates to allow growth. Colony counts were determined after incubation for 48 h. The experiment was performed triplicate.
- EXAMPLE 8 Cytotoxicity of mixtures of itraconazole and K20 on Chinese Hamster Ovary cells.
- Method Chinese Hamster Ovary (CHO) cells (line 1-15) were maintained and suspended in HyCell CHO Growth Medium (Thermo Fisher Scientific) at approximately 50-100 rpm in reciprocal shaking flasks for 48 h under standard animal cell culture conditions (5% C0 2 , 37°C). The cells were transferred into sterile 50 mL Falcon conical plastic tubes containing 10 mL of the medium at a cell density of 2.5 x 10 5 cells mL "1 .
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