WO2019088917A1 - Copolymères d'ammonium quaternaire-imidazolium utilisés en tant que nouveaux matériaux antibactériens et antifongiques - Google Patents

Copolymères d'ammonium quaternaire-imidazolium utilisés en tant que nouveaux matériaux antibactériens et antifongiques Download PDF

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WO2019088917A1
WO2019088917A1 PCT/SG2018/050495 SG2018050495W WO2019088917A1 WO 2019088917 A1 WO2019088917 A1 WO 2019088917A1 SG 2018050495 W SG2018050495 W SG 2018050495W WO 2019088917 A1 WO2019088917 A1 WO 2019088917A1
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group
polymer
optionally substituted
polymer according
range
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PCT/SG2018/050495
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English (en)
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Yugen Zhang
Yuan Yuan
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Agency For Science, Technology And Research
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Priority to CN201880069489.4A priority Critical patent/CN111344333A/zh
Priority to SG11202002936YA priority patent/SG11202002936YA/en
Publication of WO2019088917A1 publication Critical patent/WO2019088917A1/fr

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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
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A01N25/10—Macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0206—Polyalkylene(poly)amines
    • C08G73/0213—Preparatory process
    • C08G73/0226—Quaternisation of polyalkylene(poly)amines
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/0605—Polycondensates containing five-membered rings, not condensed with other rings, with nitrogen atoms as the only ring hetero atoms
    • C08G73/0616—Polycondensates containing five-membered rings, not condensed with other rings, with nitrogen atoms as the only ring hetero atoms with only two nitrogen atoms in the ring

Definitions

  • the present invention generally relates to a polymer of Formula (I) or a polymer of Formula (II).
  • the present invention also relates to a composition, a pharmaceutical composition, methods of producing the polymer of Formula (I) or the polymer of Formula (II), the uses and methods of uses thereof.
  • the cationic compounds such as quaternary ammonium compounds (QACs)
  • QACs quaternary ammonium compounds
  • the development and applications of QACs have been reduced due to the emergence of antimicrobial resistance and potential toxicity toward mammalian cells and the ecosystem.
  • imidazolium salts have emerged as new alternatives for antimicrobial applications.
  • Di-imidazolium salts showed good antimicrobial activity and low toxicity to mammalian cells.
  • the selectivity can be tuned by modifying the structure of imidazolium with different functional groups or changing the anions.
  • a series of main-chain imidazolium oligomers and polymers have been developed, which demonstrated high efficacy and high selectivity against a broad range of bacteria and fungi. These polymers and oligomers were designed to capture the essential features of antimicrobial peptides, such as amphiphilic structure of cationic hydrophilic groups and hydrophobic moieties.
  • polycationic materials provide a valid approach to address both of the resistance and toxicity problems.
  • Synthetic polymers that target the membranes of many pathogenic species are reported to have low susceptibility for developing resistance, unlike small molecular antibiotics and conventional low-molecular- weight QACs.
  • cationic polymers In topical applications, cationic polymers have limited residual toxicity since they are more difficult to permeate through skin.
  • cationic polymers Compared to low-molecular-weight QACs, cationic polymers have higher positive charge density which promotes initial adsorption onto the negatively charged bacterial surfaces and disruption of cellular membranes, resulting in significantly enhanced antibacterial activity.
  • a drawback for some of the cationic polymers is that they can lead to hemolysis, which is one of the more harmful side effects of many cationic polymers.
  • L 1 , L 2 and L 3 are independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkenylalkyl, optionally substituted alkylalkenyl, optionally substituted alkylalkenylalkyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted alkylaryl, optionally substituted alkenylaryl, and optionally substituted alkynyl aryl;
  • X is independently selected from a halogen
  • n, m and p are independentiy an integer of at least 1 ;
  • q is 0 or an integer of at least 1 ;
  • A has the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently selected from an optionally substituted alkyl, or any two of R 1 , R 2 , R 3 and R 4 may be taken together to form at least one bridging group, and
  • the ammonium-imidazolium copolymers as defined herein may display antimicrobial activity against a broad range of microbe or microorganism. More advantageously, the ammonium-imidazolium copolymer may also display antifungal activity a broad range of fungal species. Most of the ammonium-imidazolium copolymers may show much higher activity against fungi compared to single component imidazolium or ammonium polymers. More advantageously, the copolymer may be biocompatible and degradable with non-resistance property. These copolymers may be non-hemolytic.
  • composition comprising the polymer as defined herein or a salt or hydrate thereof, in association with a carrier.
  • the ammonium-imidazolium copolymers may not suffer from antimicrobial resistance. More advantageously, the ammonium-imidazolium copolymers may be used against microbe or microorganism that has developed a resistance to conventional antimicrobial drugs.
  • the polymer as defined herein or the composition as defined herein as a non-therapeutic agent for killing or inhibiting the growth of a microorganism.
  • a pharmaceutical composition comprising the polymer as defined herein or a pharmaceutically acceptable salt or hydrate thereof, in association with a pharmaceutically acceptable carrier.
  • a method for killing or inhibiting the growth of a microorganism comprising administering to a subject the polymer as defined herein or the pharmaceutical composition as defined herein.
  • a polymer as defined herein or a pharmaceutical composition as defined herein for killing or inhibiting the growth of a microorganism.
  • a method for treating a microbial infection comprising administering to a subject the polymer as defined herein or the pharmaceutical composition as defined herein.
  • a polymer as defined herein or a pharmaceutical composition as defined herein for use as an antibiotic is provided.
  • R 2 , R 3 and R 4 are independently selected from an optionally substituted alkyl, or any two of R 1 , R 2 , R 3 and R 4 is taken together to form at least one bridging group; and x is an integer of at least 1 ;
  • di-imidazole having the following structure:
  • ortho -phenylene group pcra-phenylene group, meia-phenylene group and ethenylene
  • L 5 is selected from the group consisting of orf/io-phenylene group
  • these copolymers may be easy and straightforward to synthesize with relatively low cost.
  • polymer refers to a large molecule, or macromolecule, composed of a number of repeating units, up to 30 in total of the same repeating units, whereby the repeating unit may be ammonium, imidazolium, any linkers (L 1 , L 2 and L 3 ) of Formula (I), any linkers (L 4 and L 5 ) of Formula (II) or any combinations thereof.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group to be interpreted broadly, having from 1 to 16 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon atoms, preferably a C 1 -C16 alkyl, C 1 -C 12 alkyl, more preferably a C 1 -C 10 alkyl, most preferably Ci-Ce alkyl unless otherwise noted.
  • Suitable straight and branched alkyl substituents include but is not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1 ,2-dimethylpropyl, 1, 1- dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3- dimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, undecyl, 2,2,3- trimethyl-undecyl, dodecyl, 2,2-dimethyl-dodecyl, tridecyl, 2-methyl-tridecyl, 2-
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2 to 16 carbon atoms, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 carbon atoms, preferably a Ci-C 16 alkenyl, Q-C ⁇ alkenyl, more preferably a C Ci 0 alkenyl, most preferably Cj-Cealkenyl in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • the bridging group may be ethenylene or vinylene.
  • the alkenyl may be optionally substituted with one or more groups as defined under the term "optionally substituted" below.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2 to 16 carbon atoms, e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 carbon atoms, preferably a Q-C16 alkynyl, Q-C 12 alkynyl, more preferably a Cj-Cio alkynyl, most preferably C 1 -C6 alkynyl in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • the alkynyl may be optionally substituted with one or more groups as defined under the term "optionally substituted" below.
  • Aryl as a group or part of a group to be interpreted broadly denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring, e.g. 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the optionally substitution can be di-substitution, or tri- substitution.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C 5 7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C 6 -Ci 8 aryl group.
  • the aryl may be optionally substituted with one or more groups as defined under the term "optionally substituted" below.
  • the groups may include orfAo-phenylene group, para-phenylene group and mefa-phenylene group where it is used interchangeably with o-phenylene group, /?-phenylene group and m-phenylene group.
  • Alkylaryl refers to an alkyl-aryl group in which alkyl and aryl moieties are as defined herein.
  • arylalkyl refers to an aryl-alkyl group in this sequence, in which aryl and alkyl moieties are as defined herein.
  • Preferred alkylaryl groups are Ci-C t -alkylaryl having 6 or 10 carbon atoms in the aryl.
  • Preferred arylalkyl groups are aryl-Ci-C 4 -alkyl having 6 or 10 carbon atoms in the aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkyl moiety of the alkylaryl or arylalkyl may also be the terminating molecule.
  • alkenylalkyl refers to an alkenyl-alkyl group in which alkenyl and alkyl moieties are as defined herein.
  • alkylalkenyl refers to an alkyl -alkenyl group in this sequence, in which alkyl and alkenyl moieties are as defined herein.
  • Preferred alkenylalkyl groups are C 2 -Ce ⁇ alkenylalkyl having 1 to 10 carbon atoms in the alkyl.
  • Preferred alkylalkenyl groups are alkyl-C 2 -C 6 -alkenyl having 1 to 10 carbon atoms in the alkyl.
  • the group may be a terminal group or a bridging group.
  • Alkylalkenylalkyl refers to alkyl-alkenyl-alkyl group in which alkenyl and alkyl moieties are as defined herein.
  • Preferred alkylalkenylalkyl groups are alkylC 2 -C 3 -alkenylalkyl having 1 to 10 carbon atoms in the alkyl.
  • Preferred alkylalkenylalkyl groups are alkyl-C 2 - Ce- alkenyl- alkyl having 1 to 10 carbon atoms in the alkyl.
  • the group may be a terminal group or a bridging group.
  • alkenylaryl refers to an alkenyl-aryl group in which alkenyl and aryl moieties are as defined herein.
  • arylalkenyl refers to an aryl-alkenyl group in this sequence, in which aryl and alkenyl moieties are as defined herein.
  • Preferred alkenylaryl groups are C 2 -C6-alkenylaryl having 6 or 10 carbon atoms in the aryl.
  • Preferred arylalkenyl groups are aryl-C2-C6-alkenyl having 6 or 10 carbon atoms in the aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkenyl moiety of the alkenylaryl or arylalkenyl may also be the terminating molecule.
  • Alkynylaryl refers to an alkynyl-aryl group in which alkynyl and aryl moieties are as defined herein.
  • arylalkynyl refers to an aryl-alkynyl group in this sequence, in which aryl and alkynyl moieties are as defined herein.
  • Preferred alkynylaryl groups are C 2 -C 6 - alkynylaryl having 6 or 10 carbon atoms in the aryl.
  • Preferred arylalkynyl groups are aryl-C 2 - C 6 -alkynyl having 6 or 10 carbon atoms in the aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkynyl moiety of the alkynylaryl or arylalkynyl may also be the terminating molecule.
  • a “bond” is a linkage between atoms in a compound or molecule.
  • the bond may be a single bond, a double bond, or a triple bond.
  • “Archaea” refers to a domain of single-celled microorganisms that do not have any cell nucleus or any other organelles inside their cells.
  • Bacteria refers to a member of a large group of unicellular microorganisms which have cell walls but lack a nuclear membrane or membrane-bound organelles and an organized nucleus, including some which can cause disease. Bacteria (plural) are categorized as gram-positive or gram-negative when a cell wall is present. While many bacteria are aerobic requiring the presence of oxygen to survive, others are anaerobic and are able to survive only in the absence of oxygen. Bacterium is any of a domain of chiefly round, spiral, or rod-shaped single-celled prokaryotic microorganisms that typically live in soil, water, organic matter, or the bodies of plants and animals, that make their own food especially from sunlight.
  • “Bridging group” refers to a group having from 2 to 50 atoms not counting hydrogen atoms, preferably 2 to 40 atoms, 2 to 30 atoms, 2 to 20 atoms, e.g. more preferably 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16 carbon atoms, a Q-Cie alkyl, Ci-C 12 alkyl, more preferably a Q-Cio alkyl, most preferably C -Ce alkyl in the normal chain.
  • the alkyl group may be divalent alkyl, alkenyl, alkynyl, aryl group but not limited to this.
  • Exemplary alkyl groups include, but are not limited to, ethenylene (-CH 2 CH 2 -) group, ortho-phenylene group, para-phenylene group or meta-phenylene group.
  • the bridging group may be optionally substituted with one or more groups as defined under the term “optionally substituted” below.
  • “Fungus” refers to any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds.
  • Halide or "halogen” represents chlorine, fluorine, bromine or iodine.
  • Microorganism or “microbe” being used interchangeably refers to an organism that is microscopic (too small to be visible to the naked eye). Microorganisms are often described as single-celled, or unicellular organisms.
  • Polydispersity index or value or “dispersity index (D)” refers is a measure of the distribution of molecular mass in a given polymer sample.
  • the dispersity indicates the distribution of individual molecular masses in a batch of polymers. D has a value equal to or greater than 1, but as the polymer chains approach uniform chain length, D approaches unity (1).
  • Protist refers to any eukaryotic organism or a diverse collection of organisms that is not an animal, plant or fungus.
  • the protists do not form a natural group, or clade, since they exclude certain eukaryotes; but, like algae or invertebrates, they are often grouped together for convenience. While exceptions exist, they are primarily microscopic and unicellular, or made up of a single cell.
  • the cells of protists are highly organized with a nucleus and specialized cellular machinery called organelles.
  • xylylene as used herein, is used interchangeably with “xylene”.
  • optionally substituted means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkenyl, heterocycloalkyl, cycloalkylheteroalkyl, cycloalkyloxy, cycloalkenyloxy, cycloamino, halo, carboxyl, haloalkyl, haloalkynyl, alkynyloxy, heteroalkyl, heteroalkyloxy, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyl, haloalkynyl, haloalkenyloxy, nitro, amino, nitroalkyl, cycloal
  • the group to which this term refers to may be substituted with one or more of the same groups mentioned above.
  • the word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.
  • the term "about”, in the context of concentrations of components of the formulations, typically means +/- 5% of the stated value, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1% of the stated value, and even more typically +/- 0.5% of the stated value.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • the polymer may have the following formula (I):
  • L 1 , L 2 and L 3 are independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkenylalkyl, optionally substituted alkylalkenyl, optionally substituted alkylalkenylalkyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted alkylaryl, optionally substituted alkenylaryl, and optionally substituted alkynyl aryl;
  • X is independently selected from a halogen
  • n, m and p are independently an integer of at least 1 ;
  • q is 0 or an integer of at least 1;
  • A has the following structure:
  • R 1 , R 2 , R 3 and R 4 are independently selected from an optionally substituted alkyl, or any two of R 1 , R 2 , R 3 and R 4 may be taken together to form at least one bridging group, and x and y are independently an integer of at least 1 , or
  • L 1 , L 2 and L 3 may be independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkenylalkyl, optionally substituted alkylalkenyl, optionally substituted alkylalkenylalkyl, optionally substituted arylalkyi, optionally substituted arylalkenyl, optionally substituted arylalkynyl, optionally substituted alkylaryl, optionally substituted alkenylaryl, and optionally substituted alkynylaryl.
  • the carbons atoms of alkyl group may be in the range of 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms or preferably 1 to 6 carbon atoms.
  • the carbons atoms of alkenyl group or alkynyl group may be in the range of 2 to 20 carbon atoms, 2 to 16 carbon atoms, 2 to 12 carbon atoms, 2 to 10 carbon atoms or preferably 2 to 6 carbon atoms.
  • the carbons atoms of aryl group may be in the range of 5 to 18 carbon atoms, 5 to 12 carbon atoms, 5 to 10 carbon atoms, 6 to 18 carbon atoms or preferably 6 to 12 carbon atoms.
  • the aryl group may be selected from the group consisting of o-xylylene, m-xylylene and /7-xylylene.
  • the alkenyl-alkyl group may be C 2 _ 6 alkenyl-Ci_ 6 alkyl group.
  • the alkyl-alkenyl group may be C h alky 1-C 2 _ 6 alkenyl group.
  • the alkyl-alkenyl-alkyl group may be Ci_ 6 alkyl-C 2 -6 a lk en yl-C 1 _ 6 alkyl group.
  • the aryl-alkyl group may be C6-i 2 aryl-Ci_6alkyl group.
  • the alkyl-aryl group may be C ⁇ alkyl-Ce- ⁇ aryl group.
  • the aryl-alkenyl may be C6-i 2 aryl-C 2 6 alkenyl group.
  • the alkenyl-aryl may be C 2 _6alkenyl-C6 i 2 aryl group.
  • the aryl-alkynyl may be C6 12 aryl-C 2 _ ealkynyl group.
  • the alkynyl-aryl may be C2-6alkynyl-C6 i 2 aryl group.
  • the alkyl- aryl- alkyl group may be CYealkyl-phenyl-C ⁇ alkyl.
  • the C 1 6 alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl.
  • the phenyl of the Ci_6alkyl-phenyl-Ci_6alkyl group may be selected from the group consisting of o-xylylene, m-xylylene, 7-xylylene.
  • X may be a halogen from Group VII of the periodic table.
  • X may be a halide or halogen selected from fluoride, chloride, bromide and iodide.
  • n, m and p may be independently an integer of at least 1, or an integer between 1 to 5,000, between 1 to 1,000, between 1 to 500, between 1 to 100, preferably between 1 to 50, that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50, more preferably between 1 to 10 or most preferably between 1 to 5.
  • p may preferably be an integer of 1.
  • q may be 0 or may be an integer of at least 1, or an integer from 1 to 10,000, from 1 to 5,000, from 1 to 1,000, from 1 to 500, from 1 to 100, from 1 to 50, preferably from 1 to 25, that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25. q may preferably be an integer of 1.
  • A may be of the following structure:
  • R 1 , R 2 , R 3 and R 4 may be independently selected from an optionally substituted alkyl, or any two of R 1 , R 2 , R 3 and R 4 may be taken together to form at least one bridging group, and x and y may independently be an integer of at least 1.
  • the optionally substituted alkyl may be optionally substituted Cusalkyl group, preferably optionally substituted Ci ⁇ alkyl group or more preferably, optionally substituted Q ⁇ alkyl group.
  • the any two of R 1 , R 2 , R 3 and R 4 may be taken together to form at least one bridging group.
  • R 1 and R 2 may be taken together to form at least one bridging group.
  • R 3 and R 4 may be taken together to form at least one bridging group.
  • the bridging group may be C 2 to C 10 bridging group, preferably C 2 to C5 bridging group or more preferably an ethenylene group.
  • the bridging group may be optionally substituted.
  • the x and y may independently be an integer of at least 1 or at least between 1 to 10, between 1 to 5, from 1, 2, 3, 4 or 5, or more preferably 1.
  • A may be selected from the group consisting of the following structures:
  • the molar ratio between A and L 1 may be in the range of 1 :5 and 5:1, in the range of 1:4 and 5:1, in the range of 1:3 and 5: 1, in the range of 1:2 and 5: 1, in the range of 1 : 1 and 5:1, in the range of 2: 1 and 5: 1, in the range of 3:1 and 5: 1, in the range of 4:1 and 5: 1, in the range of 1:5 and 4:1, in the range of 1 :5 and 3:1, in the range of 1 :5 and 2: 1 or in the range of 1:5 and 1:1, in the range of 1 :5 and 1 :2, in the range of 1 :5 and 1:3 or in the range of 1 :5 and 1:4.
  • the molar ratio between (L 1 + L 2 ) and L 3 is in the range of about 1:5 to about 5:1, in the range of 1:4 and 5:1, in the range of 1 :3 and 5: 1, in the range of 1:2 and 5: 1, in the range of 1: 1 and 5:1, in the range of 2: 1 and 5:1, in the range of 3: 1 and 5:1, in the range of 4:1 and 5: 1, in the range of 1:5 and 4:1, in the range of 1:5 and 3:1, in the range of 1:5 and 2:1 or in the range of 1 :5 and 1 :1, in the range of 1 :5 and 1 :2, in the range of 1 :5 and 1 :3 or in the range of 1 :5 and 1:4.
  • the polymer may have a molecular weight in the range of about 1,000 to about 20,000, about 1,000 to about 15,000, about 1,000 to about 10,000, about 1,000 to about 9,000, about 1,000 to about 8,000, about 1 ,000 to about 7,000, about 1,000 to about 6,000, about 1,000 to about 5,000, about 1,000 to about 4,000, about 1,000 to about 3,000, about 1,000 to about 2,000, about 2,000 to about 10,000, about 3,000 to about 10,000, about 4,000 to about 10,000, about 5,000 to about 10,000, about 6,000 to about 10,000, about 7,000 to about 10,000, about 8,000 to about 10,000, about 9,000 to about 10,000, about 10,000 to about 20,000, about 10,000 to about 15,000 or about 15,000 to about 20,000.
  • the polymer having the formula (I) may have a high molecular weight when the polymer is synthesized in dimethylformamide (DMF).
  • DMF dimethylformamide
  • the polymer may have a polydispersity value in the range of about 1.2 to about 3.2, about 1.4 to about 3.2, about 1.6 to about 3.2, about 1.8 to about 3.2, about 2.0 to about 3.2, about 2.2 to about 3.2, about 2.4 to about 3.2, about 2.6 to about 3.2, about 2.8 to about 3.2, about 3.0 to about 3.2, about 1.2 to about 3.0, about 1.2 to about 2.8, about 1.2 to about 2.6, about 1.2 to about 2.4, about 1.2 to about 2.2, about 1.2 to about 2.0, about 1.2 to about 1.8, about 1.2 to about 1.6 or about 1.2 to about 1.4.
  • the polymer having the formula (I) may be characterized by relatively low degree of polymerization (M w ⁇ 10,000) and high polydispersity values (1.3 ⁇ D ⁇ 3.1).
  • the polymer may have the following formula (II):
  • L 4 and L 5 are independently selected from optionally substituted alkenyl or optionally substituted aryl.
  • the optionally substituted alkenyl may be optionally substituted C 2 isalkenyl group, optionally substituted C 2 i 2 alkenyl group or preferably optionally substituted C 2 6 alkenyl group.
  • the optionally substituted alkenyl may be ethenylene.
  • the optionally substituted aryl may be optionally substituted Ce-isaryl group, optionally substituted Ce ⁇ aryl group or preferably optionally substituted Cearyl group.
  • the optionally substituted aryl may be selected from the group consisting of ort/zo-phenylene (o-phenylene) group, /3 ⁇ 43 ⁇ 4ra-phenylene (/7-phenylene) group and meto-phenylene (m-phenylene) group.
  • X may be a halogen from Group VII of the periodic table.
  • X may be a halide or halogen selected from fluoride, chloride, bromide and iodide.
  • polymer having the formula (II) be selected from the group consisting of the following structures:
  • p and q may be independently an integer between 1 to 20, between 1 to 10, between 1 to 5, from 1, 2, 3, 4 or 5, or more prelerably 1.
  • the polymer having the formula (I) or formula (II) may be selected from the group consisting of:
  • the distribution of molecular weights of the polymer having the formula (I) may be affected by the solubility of the polymer in solvents.
  • the polymer having the formula (I) may have higher solubility in DMF than in THF due to the higher polarity of DMF.
  • ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) may display synergistic effect when ammonium and imidazolium are combined together instead of the individual ammonium polymer or imidazolium polymer.
  • DABCO and imidazolium may be combined together as the ammonium-imidazolium copolymers.
  • the ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) may display antimicrobial activity against a broad range of microbe or microorganism. More advantageously, the ammonium-imidazolium copolymer may also display antifungal activity a broad range of fungal species. Most of the ammonium-imidazolium copolymers may show much higher activity against fungi compared to single component imidazolium or ammonium polymers.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against bacteria may be in the range of about 1 to about 200 ⁇ g/mL, about 1 to about 180 ⁇ g/mL or about 1 to about 160 ⁇ g/mL.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against bacteria (E. coli) may be in the range of about 10 to about 150 ⁇ g/mL, about 10 to about 125 ⁇ g/mL, about 10 to about 100 ⁇ g/mL, about 10 to about 80 ⁇ g/mL, about 10 to about 60 ⁇ g/mL, about 10 to about 40 ⁇ g mL, preferably about 10 to about 30 ⁇ g/mL or more preferably about 10 to about 16 ⁇ g/mL.
  • the ammonium-imidazolium copolymer may preferably be TMED-imidazolium copolymer with -phenylene linker or DMP -imidazolium copolymer with /?ara-phenylene linker. More preferably, the ammonium-imidazolium copolymer may be DABCO-imidazolium copolymer with irans-butene linker.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against bacteria may be in the range of about 5 to about 80 ⁇ g/mL, about 5 to about 60 ⁇ g/mL, about 5 to about 50 ⁇ g/mL, about 5 to about 40 ⁇ g/mL, about 5 to about 30 ⁇ g/mL, about 5 to about 20 ⁇ g/mL, preferably about 5 to about 16 ⁇ g/mL or more preferably about 8 ⁇ g mL.
  • the ammonium-imidazolium copolymer may preferably be TMED-imidazolium copolymer with ara-phenylene linker or DMP-imidazolium copolymer with £>ara-phenylene linker. More preferably, the ammonium- imidazolium copolymer may be DABCO-imidazolium copolymer with trans-b tene linker.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against bacteria (P. aeruginosa) may be in the range of about 10 to about 80 ⁇ g/mL, about 10 to about 60 ⁇ g/mL, about 10 to about 40 ⁇ g/mL, about 10 to about 30 pg/mL, about 10 to about 25 ⁇ g/mL, about 10 to about 20 ⁇ g mL, preferably about 31 ⁇ g/mL, or more preferably 16 ⁇ g/mL.
  • the ammonium-imidazolium copolymer may preferably be DMP-imidazolium copolymer with /jara-phenylene linker. More preferably, the ammonium-imidazolium copolymer may be DABCO-imidazolium copolymer with trans-butene linker.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against fungi species may be in the range of about 1 to about 200 ⁇ g/mL, about 1 to about 180 ⁇ g/mL, about 1 to about 160 ⁇ g/mL or about 1 to about 140 ⁇ g/mL.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against fungi species (C. albicans) may be in the range of about 1 to about 130 ⁇ g/mL, about 1 to about 115 ⁇ g/mL, about 1 to about 100 ⁇ g/mL, about 1 to about 70 ⁇ g/mL, about 1 to about 40 ⁇ g/mL, about 1 to about 20 ⁇ g/mL ) about 1 to about 10 ⁇ g/mL, preferably about 1 to about 8 ⁇ g/mL or more preferably about 2 ⁇ g/mL.
  • the ammonium-imidazolium copolymer may preferably be DMP based polymer with frares-butene linker. More preferably, the ammonium-imidazolium copolymer may be DABCO- imidazolium copolymer with fraras-butene linker.
  • the minimum inhibitory concentrations (MICs) of ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) against fungi species (F. solani) may be in the range of about 20 to about 130 ⁇ g mL, about 20 to about 100 ⁇ g/mL, about 20 to about 80 ⁇ g/mL, about 20 to about 60 ⁇ g/mL, about 20 to about 50 ⁇ g mL, about 20 to about 40 ⁇ g/mL, about 20 to about 35 ⁇ g/mL or more preferably about 31 ⁇ g/mL.
  • the ammonium- imidazolium copolymer may preferably be TMED-imidazolium copolymer with para- phenylene linker. More preferably, the ammonium-imidazolium copolymer may be DABCO- imidazolium copolymer with iraras-butene linker.
  • the ammonium-imidazolium copolymers may not suffer from antimicrobial resistance. More advantageously, the ammonium-imidazolium copolymers may be used against microbe or microorganism that has developed a resistance to conventional antimicrobial drugs. More advantageously, the DABCO-imidazolium copolymer with iraras-butene linker may have better minimum inhibitory concentrations (MICs) than conventional antimicrobial drugs.
  • the minimum inhibitory concentrations (MICs) may be in the range of about 1 to about 10 ⁇ g/mL, preferably about 1 to about 8 pg/mL or more preferably about 2 pg/mL.
  • the minimum fungicidal concentration (MFC) of DABCO-imidazolium copolymer with trans- butene linker may be in the range of about 50 to about 90 pg/mL, about 50 to about 80 ⁇ g mL, about 50 to about 70 ⁇ g/mL, preferably about 55 to about 65 pg/mL or more preferably 62 pg/mL.
  • the ammonium-imidazolium copolymers as defined by Formula (I) or Formula (II) may have better stability than the conventional antimicrobial drugs.
  • the copolymer may be biocompatible and non-hemolytic.
  • these copolymers may be easy and straightforward to synthesize and relatively low cost.
  • exemplary, non-limiting embodiments of a composition comprising the polymer as defined herein will now be disclosed.
  • composition may comprise of the polymer as defined herein, or a salt or hydrate thereof, in association with a carrier.
  • the use of the polymer as defined herein or the composition as defined herein may be as a non- therapeutic agent for killing or inhibiting the growth of a microorganism.
  • the polymer may be used as a therapeutic agent for killing or inhibiting the growth of a microorganism.
  • the pharmaceutical composition may comprise of the polymer as defined herein, or a pharmaceutically acceptable salt or hydrate thereof, in association with a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.
  • the polymer may be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • the amount of the polymer in the composition may be such that it is effective to measurably treat the microbial infection or disease.
  • the amount of polymer in the composition may be such that it is effective to measurably treat the disease, disorder or condition associated with microbial infection.
  • the amount of polymer in the composition may be such that it is effective to measurably treat the disease, disorder or condition associated with microbial infection that is from any of the microorganisms.
  • the composition may be formulated for administration to a subject in need of such composition.
  • the composition may be formulated for administration to a patient in need of such composition. In using the polymers, they may be administered in any form or mode which may make the polymer bioavailable.
  • the pharmaceutically acceptable carrier or pharmaceutically acceptable excipient may be a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the polymer with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the composition may include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene - polyoxypropylene-block polymers, polyethylene glycol or wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates,
  • compositions or pharmaceutical compositions as defined above may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions as defined above may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. If desired, and for more effective distribution, the polymers may be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • the injectable formulations may be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • compositions as defined above may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions as defined above may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations may be readily prepared for each of these areas or organs. Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds as defined above may include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers may include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions as defined above may also be administered by nasal aerosol or inhalation.
  • Such compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions as defined above may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions as defined above may be administered without food. In other embodiments, pharmaceutically acceptable compositions as defined above may be administered with food.
  • compositions may vary depending upon the host treated, the particular mode of administration.
  • the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a polymer of the present disclosure in the composition will also depend upon the particular compound in the composition.
  • the method for killing or inhibiting the growth of a microorganism may comprise of administering to a subject the polymer as defined herein, or the pharmaceutical composition as defined herein.
  • the subject may be a cell.
  • the subject may be a human or animal body.
  • the cell may be present in a cell culture in vitro.
  • the cell may be from a cell line.
  • the cell line may be an immortalized cell line, a genetically modified cell line or a primary cell line.
  • the cell may be from a tissue of a subject.
  • the cell may be in a subject.
  • the method of killing or inhibiting the growth of the microorganism may be a non-therapeutic method whereby the polymer may be formulated as a disinfectant, a sterilizing agent or a surface cleaning agent.
  • the polymer may be used to create an antiseptic environment. Exemplary, non-limiting embodiments of a polymer or a pharmaceutical composition as defined herein will now be disclosed.
  • the polymer as defined herein or the pharmaceutical composition as defined herein may be for killing or inhibiting the growth of a microorganism.
  • the polymer as defined herein or the pharmaceutical composition as defined herein may be used for killing or inhibiting the growth of a microorganism.
  • polymer as defined herein or the pharmaceutical composition as defined herein may be in the manufacture of a medicament for killing or inhibiting the growth of a microorganism.
  • the microorganism may be a bacterium, archaea, fungus, protist, animal, plant, or any mixture thereof.
  • the microorganism may be a disease causing microorganism.
  • the disease may be a microbial infection or microbial disease.
  • the disease causing microorganism may be selected from the group consisting of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Fusarium solani and Candida albicans.
  • the method for treating a microbial infection may comprise the step of administering to a subject the polymer as defined above or the pharmaceutical composition as defined above.
  • the polymer or pharmaceutical composition may treat the microbial infection or disease caused by a microorganism.
  • the polymer as defined above or a pharmaceutical composition as defined above may be for use as an antibiotic.
  • the antibiotic may be for treating a microbial infection or disease.
  • the antibiotic may be used for treating a microbial infection or disease.
  • polymer as defined above or the pharmaceutical composition as defined above may be in the manufacture of a medicament for treating a microbial infection.
  • the microbial infection or disease may be caused by a bacterium, archaea, fungus, protist, animal, plant, or any mixture thereof.
  • the microbial infection or disease may also be caused by a microbe or microorganism.
  • the microbe or microorganism may be selected from the group consisting of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Fusarium solani and Candida albicans.
  • the method for inhibiting or method for treating may be an in vitro method.
  • the method of inhibiting or method of treating may also be an in vivo method.
  • the method for preparing a polymer as defined herein may comprise the steps of:
  • R 1 , R 2 , R 3 and R 4 are independently selected from an optionally substited alkyl, or any two of R 1 , R 2 , R 3 and R 4 is taken together to form at least one bridging group; and x is an integer of at least 1 ;
  • di-imidazole having the following structure: wherein L is selected from the group consisting of ortho phenylene group, para-phenylene group, meta-phenylene group and ethenylene;
  • L is selected from the group consisting of orfAo-phenylene group, group, meia-phenylene group and ethenylene; and X is a halide; under reaction conditions.
  • the diamine having the may be selected from the group diamine may not be limited to these examples.
  • the di-imidazole having the following
  • imidazole may not be limited to these examples.
  • the X of the dihalide may be a halide or halogen from Group VII of the periodic table.
  • X may be a halide or halogen selected from fluoride, chloride, bromide and iodide.
  • the reaction conditions of the above method may comprise the temperature at which the reaction is stirred at, the solvent that the reaction is stirred in or the time period or duration that is required for the reaction to be completed.
  • the temperature of the reaction may be an elevated temperature.
  • the elevated temperature may be in the range of about 60 °C to about 100 °C, about 65 °C to about 100 °C, about 70 °C to about 100 °C, about 75 °C to about 100 °C, about 80 °C to about 100 °C, about 85 °C to about 100 °C, about 90 °C to about 100 °C, about 95 °C to about 100 °C, about 60 °C to about 95 °C, about 60 °C to about 90 °C, about 60 °C to about 85 °C, about 60 °C to about 80 °C, about 60 °C to about 75 °C, about 60 °C to about 70 °C or about 60 °C to about 65 °C.
  • the temperature may preferably be in the range of about 70 to 90 °C.
  • the time period or duration of the reaction may be in the range of about 18 hours to 60 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, about 28 hours, about 30 hours, about 32 hours, about 34 hours, about 36 hours, about 38 hours, about 40 hours, about 42 hours, about 44 hours, about 46 hours, about 48 hours, about 50 hours, about 52 hours, about 54 hours, about 56 hours, about 58 hours, about 60 hours, preferably about 18 hours, or more preferably about 24 hours.
  • the solvent of the reaction may be an organic solvent.
  • the solvent may be a polar solvent or non-polar solvent.
  • the solvent may preferably be a polar organic solvent.
  • the polar organic solvent may be selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), acetonitrile, dicholormethane and ethyl acetate (EtOAc).
  • the polar organic solvent may preferably be tetrahydrofuran (THF) dimethylformamide (DMF) or any mixture thereof.
  • the yields of the various copolymers from the above method or reaction may be in the range of about 45% to about 95%, about 49% to about 95%, about 55% to about 95%, about 60% to about 95%, about 65% to about 95%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, about 90% to about 95%, about 45% to about 90%, about 45% to about 85%, about 45% to about 80%, about 45% to about 75%, about 45% to about 70%, about 45% to about 65%, about 45% to about 60%, about 45% to about 55% or about 45% to about 49%.
  • the diamine and di -imidazole may be contacted at a molar ratio in the range of about 1:5 to about 5: 1, in the range of 1 :4 and 5:1, in the range of 1 :3 and 5: 1, in the range of 1:2 and 5: 1, in the range of 1 : 1 and 5:1, in the range of 2:1 and 5: 1, in the range of 3:1 and 5: 1, in the range of 4: 1 and 5:1, in the range of 1:5 and 4:1, in the range of 1:5 and 3: 1, in the range of 1:5 and 2: 1 or in the range of 1:5 and 1 :1, in the range of 1:5 and 1 :2, in the range of 1 :5 and 1:3 or in the range of 1:5 and 1 :4.
  • the molar ratio may be 1 :3, 1 : 1 or 3: 1.
  • the di-imidazole and dihalide may be contacted at a molar ratio in the range of about 1:6 to about 5:6, in the range of 1 :5 and 5:6, in the range of 1 :4 and 5:6, in the range of 1:3 and 5:6, in the range of 1 :2 and 5:6, in the range of 1 :1 and 5:6, in the range of 2:1 and 5:6, in the range of 3: 1 and 5:6, in the range of 4: 1 and 5:6, in the range of 5: 1 and 5:6, in the range of 5:2 and 5:6, in the range of 5:3 and 5:6, in the range of 5:4 and 5:6, in the range of 5(1):5(1) and 5:6, in the range of 1 :5 and 4:6, in the range of 1 :5 and 3:6, in the range of 1:5 and 2:6 or in the range of 1:5 and 1 :6, in the range of 1 :5 and 5(1):5(1), in the range of 1:5 and 5
  • the di-imidazole, diamine and dihalide may be contacted in any combinations thereof other than mentioned above, at a molar ratio as defined above.
  • FIG. 1 shows the antifungal activity of IBN-132-3 against C. albicans.
  • Fig. IB shows the colony forming unit of C. albicans after 24 hours or 48 hours of treatment with IBN-132-3 (T), Amphotericin B (A) and Fluconazole (F) at different concentrations C. albicans grown in Yeast Mold broth were used as control. Circles indicate no colony observed. The data are expressed as mean ⁇ S.D. of triplicates. *p ⁇ 0.05; **p ⁇ 0.01.
  • FIG. 2 shows the resistance acquisition in the presence of sub-MIC levels of copolymers and antibiotics against 5. aureus (Fig. 2A) and C. albicans (Fig. 2B).
  • FIG. 3 is a series of Scanning Electron Microscopy (SEM) images of C. albicans treated with copolymers (125 ⁇ g/mL) at room temperature for 24 hours.
  • Fig. 3 A is the control
  • Fig. 3B is IBN-131-2
  • Fig. 3C is IBN-132-3
  • Fig. 3D is IBN-212.
  • the cell wall was disrupted after exposure.
  • C. albicans treated with YMB were used as controls. Scale bars represent 5 ⁇ .
  • FIG. 4 shows a series of antimicrobial activities of the copolymers against biofilms.
  • Cell viability remained in C. albicans (Fig. 4A), E.coli (Fig. 4B), S. aureus (Fig. 4C) and P. aeruginosa (Fig. 4D) biofilms treated with different copolymers for 24 hours.
  • the data are expressed as mean ⁇ S.D. of quadruplicates. *statistical significance versus control, *p ⁇ 0.05; **p ⁇ 0.01.
  • PBS Phosphate buffered saline
  • Analytical thin layer chromatography was performed using Merck 60 F-254 silica gel plates with visualization by ultraviolet light (254 nm) and/or heating the plate after staining with a solution of 20% KMn04 w/v in H 2 0. Flash column chromatography was carried out on Kieselgel 60 (0.040-0.063 mm) supplied by Merck (Burlington, Massachusetts, U.S.A.) under positive pressure.
  • the copolymers were synthesized by introducing bis-quaternary ammonium components into poly-imidazolium chain to enhance the structural versatility and achieve optimal antibacterial/antifungal activity.
  • three a, co-tertiary diamines including 1 ,4-diazabicyclo- [2.2.2] -octane (DABCO), tetramethylethane-l,2-diamine (TMED) and 1,4-dimethylpiperazine (DMP) were chosen to form bis-quaternary ammonium.
  • the diamines and di-imidazoles were randomly connected by benzylic or allylic dihalide compounds (either butene or xylylene linkers, Scheme 1). With this structural design, various ammonium-imidazolium random copolymers were synthesized.
  • ammonium-imidazolium copolymers were carried out by mixing di-imidazole, ⁇ , ⁇ -diamine and dihalide linker in polar organic solvents, such as THF and DMF, at 70 to 90 °C for at least 24 hours. Modest to good yields ranging from 49% to 95% were obtained for various copolymers.
  • polar organic solvents such as THF and DMF
  • DABCO polar organic solvents
  • six copolymer samples (IBN-111, IBN-112, IBN-121, IBN-122, IBN-131 and IBN-132) with different linkers were synthesized (Scheme 3).
  • the amount of DABCO to di-imidazole ratios in selected copolymers was adjusted to pursue higher antimicrobial activity.
  • l,4-diazabicyclo-[2.2.2]-octane (DABCO) solo polymers (IBN-110, IBN-120 and IBN-130) were also synthesized using a method similar to the above.
  • the individual polymers (IBN-110, IBN-120 and IBN-130) were used as comparative polymers for testing against the ammonium- imidazolium copolymers.
  • the remaining polymers (IBN-110, IBN-120 and IBN-130) and copolymers (IBN-111, IBN- 112, IBN-121, IBN-122, IBN-131 and IBN-132) may be synthesized accordingly to the respective diamine, di-imidazole and aryl/alkyl linkers as indicated in the final compounds as well as the molar ratios as described in the scheme below (Scheme 3).
  • TMED tetramethylethane-l ,2-diamine
  • copolymers IBN-211 and IBN-212 with para-xylylene linker were obtained using the same general procedure as described above, and based on the molar ratios and the respective diamine, di-imidazoles and aryl linkers as shown in the scheme below (Scheme 4).
  • ortho- xylylene or frares-butene linker was used, two small molecules (IBN-220 and IBN-230) were formed instead.
  • L1 p-phenylene
  • the molecular weights of the polymers and copolymers were measured with gel permeation chromatography (GPC). Similar to many step-growth polymers, these compounds are characterized by relatively low degree of polymerization (M w ⁇ 10,000) and high dispersity values (1.3 ⁇ D ⁇ 3.1) (Table 1). The distribution of molecular weights was affected by the polymers' solubility in solvents. Generally, the polymers have higher solubility in DMF than in THF due to the higher polarity of DMF. So most of the polymers synthesized in DMF have higher molecular weights.
  • Staphylococcus aureus (ATCC 6538, Gram-positive), Escherichia coli (ATCC 8739, Gram- negative), Pseudomonas aeruginosa (ATCC 9027, Gram-negative), and Candida albicans (ATCC 10231, fungus) were used as representative microorganisms to challenge the antimicrobial functions of the imidazolium salts. All bacteria and fungus were stored frozen at - 80 °C, and were grown overnight at 37 °C in Mueller Hinton Broth (MHB, BD Singapore) prior to experiments. Fungus was grown overnight at 22 °C in Yeast Mold broth (YMB, BD Singapore).
  • the polymers were dissolved in MHB or YMB at a concentration of 4 mg mL 1 and the minimal inhibitory concentrations (MICs) were determined by microdilution assay.
  • Bacterial solutions 100 ⁇ L, 3 ⁇ 10 8 CFU mL 1
  • 100 ⁇ ⁇ of polymer solutions normally ranging from 4 mg mL 1 to 2 ⁇ g mL 1 in serial two-fold dilutions
  • the plates were incubated at 37 °C for 24 hours with constant shaking speed at 300 rpm.
  • the MIC measurement against Candida albicans is similar to bacteria except that the fungus solution is ⁇ 10 6 CFU mL 1 in YMB and the plates were incubated at room temperature.
  • the minimum inhibitory concentrations were taken as the concentration of the antimicrobial oligomer/polymer at which less than 50% microbial growth was observed with the microplate reader (TEC AN).
  • Medium solution containing microbial cells alone were used as control (100% microbial growth).
  • the assay was performed in four replicates and the experiments were repeated at least two times.
  • IBN-132-3 THF was dissolved in YMB (2 ⁇ g/mL to 62 ⁇ g/mL in serial two-fold dilution). A hundred microliters of each solution were placed into a 96-well microplate. A hundred microliters of C. albicans suspension (10 6 CFU/ml) was then added into each well. Fungus growing in YMB was used as control. For MFC, antibiotics, Amphotericin B and Fluconazole, were also tested as positive control. The 96-well plate was kept in an incubator at room temperature under constant shaking.
  • Drug resistance was induced by treating S. aureus or C. albicans repeatedly with copolymers and control antibiotics.
  • First MICs of the tested copolymers were determined against S. aureus or C. albicans using the broth microdilution method.
  • serial passaging was initiated by transferring microbial suspension grown at the sub-MIC of the copolymers (1/2 of MIC at that passage for S. aureus and 1/8 of MIC at that passage for C. albicans) for another MIC assay. After 24 hours of incubation, cells grown at the sub-MIC of the test compounds/antibiotics were once again transferred and assayed for MIC.
  • the MIC against S. aureus or C. albicans was tested for 15 passages.
  • Drug-resistant behavior was evaluated by recording the changes in the MIC normalized to that of the first passage.
  • Conventional antibiotic Amphotericin B was used as the control against C. albicans and Norfloxacin was used as the control against S. aureus.
  • Fungus C. albicans cells were cultured in YMB at room temperature. Bacteria cells were cultured in MHB at 37 °C. All the microorganisms were grown overnight to reach mid logarithmic growth phase. The concentrations of the microbe were adjusted to give an O.D. value of 0.07 at 600 nm. The bacterial solutions were then diluted 10 3 fold to achieve an initial loading of 3 x 10 5 CFU/mL while C. albicans cells were used without further dilution. 100 ⁇ ⁇ of the microbial solution was added to each well of 96-flat bottom well plate and incubated at room temperature for the fungus and at 37 °C for the bacteria, under constant shaking.
  • a (2-methoxy-4-nitro-5-sulfo-phenol)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay was used to quantify the live microbe on the surface of each well by measuring the mitochondrial enzyme activity in live cells.
  • mitochondrial dehydrogenases of the viable microbial cells reduced XTT to an orange colored formazan derivative, and the change in O.D. reading was recorded to analyze the viability of cells on the surfaces.
  • the polymer/copolymer solutions 100 ⁇ -, different concentrations) were added to the wells containing biofilm. Antibiotic solutions and pure medium were used as controls.
  • Fresh rat red blood cells were diluted with PBS buffer to give an RBC stock suspension (4 vol% blood cells). 100 ⁇ . aliquots of RBC suspension were mixed with 100 copolymer solutions of various concentrations (ranging from 4 mg mL 1 to 2 ⁇ g mL 1 in serial two-fold dilutions in PBS). After 1 hour of incubation at 37 °C, the mixture was centrifuged at 2000 rpm for 5 min. Aliquots (100 ⁇ ) of the supernatant were transferred to a 96-well plate. Haemolytic activity was determined as a function of hemoglobin release by measuring absorbance of the supernatant at 576 nm using a microplate reader.
  • a control solution that contained only PBS was used as a reference for 0% haemolysis. Absorbance of red blood cells lysed with 0.5% Triton-X was taken as 100% haemolysis. The data were expressed as mean and S.D. of four replicates, and the tests were repeated two times.
  • C. albicans cells (10 6 CFU/mL) grown in YMB without or with the copolymers at 125 for 24 hours were collected and centrifuged at 3000 rpm for 5 minutes. The precipitates were washed twice with PBS buffer. Then the samples were fixed with glutaraldehyde (2.5%) for 4 hours followed by washing with deionized (DI) water. Dehydration was performed using a series of ethanol/water solution (35%, 50%c, 75%o, 90%o, 95%o and 100%). The dehydrated samples were mounted on copper tape. After drying for 2 days, the samples were further coated with platinum for imaging with JEOL JSM-7400F (Japan) field emission scanning electron microscope operated at an accelerating voltage of 3 keV.
  • DI deionized
  • DABCO-imidazolium copolymers were evaluated against four different and clinically relevant microbes: S. aureus, E. coli, P. aeruginosa, and C. albicans. Their minimum inhibitory concentrations (MICs) against the four microbes were presented in Table 3. All the DABCO polymers and DABCO-imidazolium copolymers exhibit antimicrobial activities against the tested microbe. Interestingly, the structure of the linkers affects the antimicrobial activity. In general, polymer and copoplymers containing rrares-butenyl linkers are the most active material.
  • polymer and copoplymers with o-xylenyl linkers are more active than those with />-xylenyl linkers. Therefore, the antimicrobial activity sequence of polymers is of fraras-butene linker > orf/zo-xylylene linker > ara-xylylene linker.
  • the DABCO-imidazolium copolymers with iraras-butene linker show superior antifungal activity (Table 3). MICs against C. albicans are all less than 10 ⁇ g/mL. They are more effective than DABCO polymer IBN-130 or imidazolium polymer PIM-45, implying synergistic effect when DABCO and imidazolium are combined together. Copolymers synthesized in THF, which generally have lower molecular weight than polymer synthesized in DMF, demonstrate higher antifungal activity and lower toxicity (Table 3, entries 15 to 20).
  • IBN-132-3 synthesized in THF with DABCO to di-imidazolium ratio is 3, is the most active antifungal compound with MIC of 2 ⁇ g/mL. No significant hemolysis was observed at the highest concentration, 2000 ⁇ g/mL of IBN-132-3.
  • IBN-132-3 The killing efficacy of IBN-132-3 (THF) at different concentrations against C. albicans after 48 hours of treatment was shown in Fig. 1A.
  • IBN-132-3 can inhibit the growth of C. albicans at low concentration, even below MIC. At half MIC (1 ⁇ g/mL), the growth of C. albicans is slower than control. The inhibition increases when the concentration increases and 3 log reduction was observed at 8 ⁇ g/mL concentration.
  • the antifungal activity of IBN-132-3 was compared with two conventional antibiotics which are currently used in clinical treatment, Amphotericin B (AmB) and Fluconazole (Fig. IB and Table 4). The growth of C.
  • IBN-132-3 The MIC of IBN-132-3 is 2 ⁇ g/mL, lower than that of AmB (4 ⁇ g mL for 24 hours treatment). Although the minimum fungicidal concentration (MFC) of AmB for 24 hours treatment (16 ⁇ g/mL) is lower than that of IBN-132-3 (62 ⁇ g/mL), after 48 hours, the concentration of C. albicans increased due to amphotericin B's poor stability.
  • the MICs of copolymers with TMED or DMP units were also tested and the results were shown in Table 5 and 6.
  • the polymers and copolymers obtained all show good antimicrobial activity.
  • the two small molecules, IBN-220 and IBN-230 are inactive.
  • E. C. E. coli
  • S. A. S. aureus
  • P. A. P. aeruginosa
  • C. A. C. albicans
  • F. S. F. solani
  • the antifungal mechanism was studied by visualizing a typical cell structure with or without treatment via scanning electron microscopy (SEM).
  • SEM scanning electron microscopy
  • the morphological changes of C. albicans after being treated with copolymers are shown in Fig. 3.
  • Fig. 3A Compared with the intact cell wall of the control (Fig. 3A), the cell wall of copolymer -treated C. albicans was disrupted and subsequently dissolved after 24 hours of exposure (Fig. 3B to Fig. 3D).
  • the copolymers work via an associative mechanism, which required appropriately balanced hydrophobic and hydrophilic regions to kill fungi.
  • the copolymers became integrated within the cellular exterior causing membrane destabilization and lysis. This membrane -lytic mechanism might be the reason for reduced potency of developing drug resistance.
  • biofilms Individual organisms in biofilms are embedded within a matrix of slimy, extracellular polymers and typically display a phenotype that is very different from that of planktonic cells. In particular, bacteria/fungi in biofilms are much more tolerant to antimicrobials than their planktonic counterparts. As a result, drug treatments for biofilms are sometimes futile. It was reported that Candida biofilms are resistant to several clinically important antifungal agents, including Amphotericin B and Fluconazole. Herein, the activities of the copolymers against biofilms were also tested.
  • ammonium-imidazolium copolymers possess excellent antimicrobial activity against a broad range of microbe or microorganism and related biofilms, and may possess essential degradation and non-resistance properties.
  • Ammonium- imidazolium copolymers comprising iraras-butenyl linkers may be the most active material.
  • the activity of the ammonium-imidazolium copolymers can be adjusted by using different ratio of monomers and linkers with different hydrophobicity and flexibility properties.
  • the polymers as defined above may be used as a composition in association with a carrier or a pharmaceutical composition in association with a pharmaceutically acceptable carrier.
  • the polymer or the composition as defined above may be used as a non-therapeutic agent for killing or inhibiting the growth of a microorganism.
  • the polymers as defined above may be used in a number of applications due to their ability to inhibit the growth of a microorganism.
  • the polymers or the pharmaceutical composition as defined above may be used in a number of applications in due to their ability to inhibit the growth of a microorganism or be used in treating a microbial infection or disease whereby the polymer or the pharmaceutical composition is administered to a subject.
  • the polymers or the pharmaceutical composition as defined above may be used for killing or inhibiting the growth of a microorganism.
  • the polymers or the pharmaceutical composition as defined above may be used in the manufacture of a medicament for killing or inhibiting the growth of a microorganism.
  • the polymers or the pharmaceutical composition as defined above may be used for treating a microbial infection or disease.
  • the polymers or the pharmaceutical composition as defined above may also be used as an antibiotic.
  • the polymers or the pharmaceutical composition as defined above may be used in the manufacture of a medicament for treating a microbial infection or disease.
  • the microbial infection or disease may be caused by a microorganism that is selected from the group consisting of bacterium, archaea, fungus, protist, animal, plant, or any mixture thereof.
  • the polymers as defined above may exhibit antimicrobial activities against the tested microbe (bacterium) e.g. Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, and.
  • the polymers as defined above may exhibit antifungal activities against the fungal species e.g. Candida albicans and Fusarium solani.
  • the new ammonium-imidazolium copolymers as defined above may have tuneable degradation profiles under different conditions, which would have wide ranging applications in agricultural and environmental disinfection.
  • Bacteria and fungi may have showed lower propensity to develop resistance toward the copolymers compared to conventional antibiotics.
  • DABCO-imidazolium copolymers exhibited excellent antifungal activity and biocompatibility.
  • these copolymers are easy to synthesize and relatively low cost, with wide ranging applications in medical, agricultural and environmental disinfection.
  • the copolymers may also be used in topical wound treatment, as preservatives or disinfectants for consumer care and personal care products.

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Abstract

La présente invention concerne des copolymères d'ammonium quaternaire-imidazolium représentés par la formule (I) suivante : dans laquelle les divers groupes sont tels que définis dans la description. La présente invention concerne également le polymère représenté par la formule (II) suivante : dans laquelle les divers groupes sont tels que définis dans la description. La présente invention concerne également leurs procédés de préparation, une composition antimicrobienne, un gel antimicrobien contenant ces polymères de formule (I) et (II), et des utilisations de ces polymères dans le traitement d'une infection ou d'une maladie microbienne.
PCT/SG2018/050495 2017-11-01 2018-09-28 Copolymères d'ammonium quaternaire-imidazolium utilisés en tant que nouveaux matériaux antibactériens et antifongiques WO2019088917A1 (fr)

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SG11202002936YA SG11202002936YA (en) 2017-11-01 2018-09-28 Imidazolium-quaternary ammonium copolymers as novel antibacterial and antifungal materials

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CN116410464B (zh) * 2023-04-14 2024-07-30 湖南大学 可点击化学修饰的主链阳离子聚合物及其制备方法

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