US2016009733A1PendingUtilityA1
Regulation of nitric oxide release and biofilm development
Assignee: NEWSOUTH INNOVATIONS PTY LTDPriority: May 16, 2011Filed: Sep 25, 2015Published: Jan 14, 2016
Est. expiryMay 16, 2031(~4.9 yrs left)· nominal 20-yr term from priority
A61P 9/00A61P 43/00A61P 31/06A61P 31/04A61P 27/16A01N 51/00C07D 501/54C07D 501/34C07D 501/30C07D 501/46A61K 31/545A61P 13/12A61K 31/546C07D 501/56C07D 501/42C07D 503/18A61K 45/06A61K 47/55A61P 11/00A61K 47/481C07D 501/20C07D 503/14C07D 501/24A61K 31/365Y02A50/30
32
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Claims
Abstract
The present invention relates generally to methods and compounds for regulating the release of nitric oxide in the vicinity of biofilm-forming microorganisms to regulate programmed cell death in the microorganisms and thereby promote dispersal of microorganism from biofilms and/or inhibit biofilm formation or development. More particularly, the invention relates to the use of compounds to provide spatial and temporal control over nitric oxide release.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (I), or a salt thereof:
wherein T is a bond or a linker, R 2 and R 3 are organic residues and X is selected from the group consisting of:
wherein R 1 is an organic residue.
2 . A compound according to claim 1 having the structure:
wherein R 1 , R 2 , R 3 and T are as defined above, including salts thereof
3 . A compound according to claim 1 or claim 2 wherein T is a linker which is a bivalent hydrocarbon having between 1 and 6 carbon atoms.
4 . A compound according to claim 3 wherein T is CH 2 .
5 . A compound according to any one of claims 1 to 4 wherein R 1 is a substituent that corresponds to a substituent attached to the 7-NHC(O)— group of a cephalosporin antibiotic.
6 . A compound according to any one of claims 1 to 5 , wherein R 1 is selected from the group consisting of:
7 . A compound according to any one of claims 1 to 4 wherein R 1 is Y-aryl or Y-heteroaryl where Y is a bivalent hydrocarbon having between 1 and 4 carbon atoms.
8 . A compound according to claim 7 wherein aryl is selected from the group consisting of: phenyl, biphenyl, naphthyl, anthracenyl and phenanthrenyl, and wherein heteroaryl is a 5- or 6-membered ring wherein between 1 and 4 carbon atoms are replaced with nitrogen and/or sulfur atoms.
9 . A compound according to claim 7 or claim 8 wherein heteroaryl is selected from the group consisting of: thienyl, tetrazolyl, imidazolyl, triazolyl and pyrrolyl.
10 . A compound according to claim 7 wherein R 1 is selected from the group consisting of: —CH 2 -phenyl, —CH 2 -thienyl and —CH 2 -tetrazolyl.
11 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 are independently =selected from: hydrogen, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, (CH 2 ) p OC(O)PhOC(O)C 1 -C 6 alkyl, (CH 2 ) p OC(O)APhC 1 -C 6 alkyl, branched or straight chain C 1 -C 20 alkyl, branched or straight chain C 2 -C 20 alkenyl, branched or straight chain C 2 -C 20 alkynyl, wherein the alkyl, alkenyl or alkynyl chains may optionally be interrupted by one or more groups/heteroatoms selected from O, S, NH, NH 2 + , and wherein the alkyl, alkenyl or alkynyl groups may optionally be substituted by one or more substituents selected from the group consisting of: halogen, cyano, COOH, (CH 2 ) p C(O)OC 1 -C 6 alkyl, C(O)OC 1 -C 6 alkenyl, SO 3 H, SO 2 halogen, SO 2 NH 2 , NH 2 , NH 3 + , OH, SH, OC 1 -C 6 alkyl, OC 2 -C 6 alkenyl, OC 2 -C 6 alkynyl, aryl and heteroaryl, or alternatively R 2 and R 3 , together with the nitrogen to which they are attached, form a 4-, 5-, 6-, 7-or 8-membered ring which may optionally contain 1, 2, 3, 4, 5 or 6 additional nitrogen atoms and may be saturated, unsaturated or partially unsaturated, and wherein the 4-, 5-, 6-, 7-or 8-membered ring may optionally be substituted by one or more substituents selected from the group consisting of: —C(O)C 1 -C 3 alkylene-naphthyl-OC 1 -C 6 alkyl, —C(O)C 1 -C 3 alkylene-Ph—C(O)—Ph, —C(O)CH 2 O(CH 2 ) p OCH 3 , —C(O)OPhNO 2 , —C(O)OPhNH 2 , —C(O)O(CH 2 ) p Chalogen 3 , —C(O)O(CH 2 O) p CH 3 , C 1 -C 6 -alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)C 1 -C 6 alkyleneCOOC 1 -C 6 alkyl, —C(O)C 1 -C 3 alkylenePhC 1 -C 6 alkyl, —C(O)O-pyrrolidinyl-2,5-dione, —C(O)C 1 -C 3 alkylenePhC 1 -C 6 alkyl, —C(O)(CH 2 ) p OC 1 -C 6 alkyl, —C(O)O(CH 2 ) p halogen, —C(O)O(CH 2 ) p Ph, —(CH 2 ) p SH, -S0 2 naphthyl-NC 1 -C 6 alkyl, —C(O)ONC 1 -C 6 alkyl, —(CH 2 ) p OH, —C(O)PhOAc, —C(O)(CH 2 ) p NHC(O)C 1 -C 6 alkyl, —C(O)NH 2 , —C(O)M, —C(O)NR 4 R 5 , —(CH 2 ) p CH(OH)CHOH, halogen, cyano, —COOH, —C(O)O(CH 2 ) p Ph, —C(O)OC 1 -C 6 alkyl, —C(O)OC 2 -C 6 alkenyl, —C(O)OC 2 -C 6 alkynyl, —C(O)SC 1 -C 6 alkyl, —C(O)SC 2 -C 6 alkenyl, —C(O)SC 2 -C 6 alkynyl, —C(O)C 1 -C 6 alkyl, SO 3 H, SO 2 halogen, SO 2 phenyl, SO 2 NH 2 , SO 2 NR 4 R 5 , SO 2 PhNHCOC 1 -C 6 alkyl, NH 2 , OH, SH, OC 1 -C 6 alkyl, OC 2 -C 6 alkenyl, OC 2 -C 6 alkynyl, aryl and heteroaryl, and wherein A is a bivalent hydrocarbon radical having between 1 and 4 carbon atoms, p is a number between 0 and 4, R 4 and R 5 independently represent C 1 -C 6 alkyl and M is pyridyl, pyrimidinyl, pyrazinyl, phenyl or triazinyl.
12 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 are independently selected from: hydrogen, C 5 -C 7 cycloalkyl, (CH 2 ) p OC(O)PhOC(O)C 1 -C 6 alkyl, (CH 2 ) p OC(O)APhC 1 -C 6 alkyl, branched or straight chain C 1 -C 10 alkyl, branched or straight chain C 2 -C 10 alkenyl and branched or straight chain C 2 -C 10 alkynyl, wherein the alkyl, alkenyl or alkynyl chains may optionally be interrupted by between one and three groups/heteroatoms selected from O, S, NH and NH 2 + , and wherein the alkyl, alkenyl or alkynyl chains may optionally be substituted by between one and six substituents selected from the group consisting of: halogen, phenyl, ethoxy, methoxy, propoxy, COOH, (CH 2 ) p COOC 1 -C 4 alkyl, NH 2 , NH 3 + , OH and SH, and wherein A is a bivalent hydrocarbon radical having between 1 or 2 carbon atoms and p is 0, 1 or 2.
13 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 are independently selected from: hydrogen, C 5 -C 7 cycloalkyl, branched or straight chain C 1 -C 10 alkyl, branched or straight chain C 2 -C 10 alkenyl, branched or straight chain C 2 -C 10 alkynyl, wherein the alkyl, alkenyl or alkynyl chains may optionally be interrupted by between one and three groups selected from O, NH and NH 2 + , and wherein the alkyl, alkenyl or alkynyl chains may optionally be substituted by between one and four substituents selected from the group consisting of: halogen, phenyl, methoxy, COOH, CH 2 COOC 1 -C 4 alkyl, NH 2 and NH 3 + .
14 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 are independently selected from: hydrogen, cyclohexyl, branched or straight chain C 1 -C 10 alkyl or branched or straight chain C 2 -C 10 alkenyl, wherein the alkyl or alkenyl chains may optionally be interrupted by one or two groups selected from NH and NH 2 + , and wherein the alkyl, alkenyl or alkynyl chains may optionally be substituted by between one and three substituents selected from the group consisting of: phenyl, methoxy, COOH, NH 2 and NH 3 + .
15 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 , together with the nitrogen to which they are attached, form a 4-, 5-, 6- or 7-membered ring which may optionally contain 1, 2, 3, 4 or 5 additional nitrogen atoms and may be saturated, unsaturated or partially unsaturated, and wherein the 4-, 5-, 6- or 7-membered ring may optionally be substituted by one or more substituents selected from the group consisting of: SO 2 NMe 2 , SO 3 H, SO 2 halogen, SO 2 NH 2 , —C(O)O(CH 2 ) p Ph, —C(O)Me, —C(O)pyridyl, —(CH 2 ) p OH, —C(O)NH 2 , —COOH, —C(O)NMe 2 , —C(O)NEt 2 , phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolidinyl, imidazolyl, C 1 -C 6 -alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OC 1 -C 6 alkyl, —C(O)OC 2 -C 6 alkenyl, —C(O)OC 2 -C 6 alkynyl, —C(O)O(CH 2 ) p Ph, —(CH 2 ) p SH, halogen, SO 2 PhNHCOC 1 -C 6 alkyl, NH 2 , SH, OC 1 -C 6 alkyl, and wherein p is a number between 0 and 2.
16 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 , together with the nitrogen to which they are attached, form a 5-, 6-, or 7-membered ring which may optionally contain 1, 2 or 3 additional nitrogen atoms and may be saturated, unsaturated or partially unsaturated, and wherein the 5-, 6-, or 7-membered ring may optionally be substituted by between one and four substituents selected from the group consisting of: SO 2 NMe 2 , SO 2 NH 2 , —COO(CH 2 ) p Ph —C(O)Me, —C(O)pyridyl, —(CH 2 ) p OH, —C(O)NH 2 , —COOH, —C(O)NMe 2 , —C(O)NEt 2 , phenyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolidinyl, imidazolyl, C 1 -C 6 -alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C(O)OC 1 -C 6 alkyl, —C(O)OC 2 -C 6 alkenyl, —C(O)OC 2 -C 6 alkynyl, —C(O)O(CH 2 ) p Ph, —(CH 2 ) p SH, halogen, NH 2 , SH, OC 1 -C 6 alkyl, p is a number between 0 and 2.
17 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 , together with the nitrogen to which they are attached, form a saturated 5-, 6-, or 7-membered ring which may optionally contain 1, 2 or 3 additional nitrogen atoms, and wherein the 5-, 6-, or 7-membered ring may optionally be substituted by between one and three substituents selected from the group consisting of: SO 2 NMe 2 , SO 2 NH 2 , —C(O)Me, —C(O)pyridyl, —(CH 2 ) p 0H, —C(O)NH 2 , —COOH, —C(O)NMe 2 , —C(O)NEt 2 , phenyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolidinyl, imidazolyl, C 1 -C 6 -alkyl, C 2 -C 6 alkenyl, —C(O)OC 1 -C 6 alkyl, —C(O)OC 2 -C 6 alkenyl, halogen, NH 2 , SH, OC 1 -C 6 alkyl, p is a number between 0 and 2.
18 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 , together with the nitrogen to which they are attached form a structure selected from the group consisting of:
19 . A compound according to any one of claims 1 to 10 wherein R 2 and R 3 are independently selected from C 1 -C 10 alkyl, or alternatively R 2 and R 3 , together with the nitrogen to which they are attached, form a 5- or 6-membered ring which may optionally contain between 1 and 3 additional nitrogen atoms, and which may optionally be substituted with an aryl or heteroaryl group.
20 . A compound according to claim 19 wherein R 2 and R 3 are independently selected from C 1 -C 6 alkyl, or alternatively R 2 and R 3 , together with the nitrogen to which they are attached, form a saturated 5- or 6-membered ring which may optionally contain 1 additional nitrogen atom, and which may optionally be substituted with a substituent selected from the group consisting of: pyrimidinyl and phenyl.
21 . A compound according to claim 20 wherein R 2 and R 3 are independently selected from C 1 -C 6 alkyl, or alternatively R 2 and R 3 , together with the nitrogen to which they are attached, form a structure selected from the group consisting of:
22 . A compound according to claim 1 or 2 having a structure selected from the group consisting of:
including salts thereof.
23 . A compound according to any one of claims 1 to 22 further comprising an antibiotic compound attached via the R 2 and/or R 3 substituent.
24 . A compound according to claim 23 wherein the antibiotic is ciprofloxacin or N-desmethyl levofloxacin.
25 . A composition for promoting the dispersal of microorganisms from a biofilm or inhibiting the formation and/or development of biofilms, the composition comprising a compound according to any one of claims 1 to 24 .
26 . A composition according to claim 25 further comprising one or more additional antibiotics or antimicrobial agents.
27 . A composition according to claim 25 or 26 wherein the composition induces differentiation events in microorganisms within biofilms which lead to dispersal.
28 . A composition according to claim 26 or 27 wherein the composition prevents induction of differentiation events in microorganisms which lead to biofilm formation.
29 . A composition according to any one of claims 25 to 28 wherein the composition increases the sensitivity of biofilm-forming microorganisms to an antimicrobial agent or antibiotic.
30 . A method for promoting dispersal of microorganisms from a biofilm, the method comprising exposing the biofilm to an effective amount of a compound according to any one of claims 1 to 24 or a composition according to any one of claims 25 to 29 .
31 . A method for inhibiting biofilm formation and/or development, the method comprising exposing biofilm-forming microorganisms to an effective amount of a compound according to any one of claims 1 to 24 or a composition according to any one of claims 25 to 29 .
32 . A method according to claim 31 wherein the compound or composition is coated, impregnated or otherwise contacted with a surface or interface susceptible to biofilm formation.
33 . A method according to claim 32 wherein the surface is a surface of an implantable medical device, prosthesis or medical or surgical equipment.
34 . A method according to any one of claims 30 to 33 wherein the biofilm-forming microorganisms express a β-lactamase or a transpeptidase.
35 . A method according to claim 34 wherein the biofilm-forming microorganisms express a β-lactamase.
36 . A method according to claim 35 wherein the β-lactamase is a penicillinase.
37 . A method according to claim 35 or 36 wherein the biofilm or biofilm-forming microorganisms are exposed to a β-lactam antibiotic prior to or concomitant with exposure to the compound or composition.
38 . A method according to claim 37 wherein the β-lactam antibiotic induces production of extracellular β-lactamase in said biofilm-forming microorganisms.
39 . A method according to claim 37 or claim 38 wherein the β-lactam antibiotic is imipenem.
40 . A method according to any one of claims 30 to 39 wherein the biofilm forms on a bodily surface of a subject, internal or external to the subject, and exposure of the biofilm or biofilm-forming microorganisms to the compound or composition is via administration of the compound or composition to the subject.
41 . A method according to any one of claims 30 to 40 wherein promoting dispersal of microorganisms from a biofilm or preventing formation of biofilms comprises inducing differentiation events in microorganisms within biofilms which lead to dispersal or comprises preventing induction of differentiation events in microorganisms which lead to biofilm formation.
42 . A method according to any one of claims 30 to 40 wherein promoting dispersal of microorganisms from a biofilm or preventing formation of biofilms comprises increasing the sensitivity of a microorganism to antimicrobial agents.
43 . A method according to any one of claims 30 to 42 wherein the biofilm or biofilm-forming microorganisms are exposed to an effective amount of the compound or composition such that the concentration of the nitric oxide donor or nitric oxide released and thus exposed to the biofilm or microorganisms is non-toxic to the environment or to the subject in which the biofilm or microrgansims are found.
44 . A method according to claim 43 wherein the concentration of nitric oxide is in the nanomolar, micromolar or millimolar range.
45 . A method according to claim 44 wherein the nitric oxide concentration is from about 1 nM to about 500 μM.
46 . A method according to any one of claims 30 to 45 wherein the biofilm is a single species biofilm.
47 . A method according to any one of claims 30 to 45 wherein the biofilm is a multiple species biofilm.
48 . A method according to any one of claims 30 to 47 wherein the microorganisms within the biofilm or capable of forming a biofilm comprise one or more species selected from Pseudomonas spp., Pseudoalieromonas spp., Staphylococcus spp,., Streptococcus spp., Shigella spp., Mycobacterium spp., Enterococcus spp., Escherichia spp., Salmonella spp., Legionella spp., Haemophilus spp., Bacillus spp., Desulfovibrio spp., Shewanella spp., Geobacter spp., Klebsiella spp., Proteus spp., Aeromonas spp., Arthrobacter spp., Micrococcus spp., Burkholderia spp., Serratia spp., Porphyromonas spp., Fusobacterium spp. and Vibrio spp.
49 . A method according to claim 48 wherein the microorganisms are selected from Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus, Mycobacterium tuberculosis, Escherichia coli, Bacillus licheniformis, Burkholderia cenocepacia, Serratia marcescens, Fusobacterium nucleatum, and Vibrio cholerae.
50 . A method according to any one of claims 30 to 49 wherein the biofilm is on or within the body of a subject and is associated with a disease or disorder suffered by the subject.
51 . A method according to claim 50 wherein the disease or disorder is selected from cystic fibrosis, bacterial endocarditis, otitis media, Legionnaire's disease, tuberculosis and kidney stones.
52 . A method for treating or preventing a biofilm-associated infection, disease or disorder in a subject wherein the infection is caused by a microorganism capable of forming a biofilm, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 24 or a composition according to any one of claims 25 to 29 .
53 . Use of a compound according to any one of claims 1 to 24 for the manufacture of a composition for use in promoting dispersal of microorganisms from a biofilm or for inhibiting the formation or development of a biofilm.
54 . Use of a compound according to any one of claims 1 to 24 for the manufacture of a medicament for treating or preventing a biofilm-associated infection, disease or disorder in a subject wherein the infection is caused by a microorganism capable of forming a biofilm.Cited by (0)
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