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WO2011060976A1 - Composés dérivés de la tryptamine utilisés en tant qu'agents antibactériens - Google Patents

Composés dérivés de la tryptamine utilisés en tant qu'agents antibactériens Download PDF

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Publication number
WO2011060976A1
WO2011060976A1 PCT/EP2010/063405 EP2010063405W WO2011060976A1 WO 2011060976 A1 WO2011060976 A1 WO 2011060976A1 EP 2010063405 W EP2010063405 W EP 2010063405W WO 2011060976 A1 WO2011060976 A1 WO 2011060976A1
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Prior art keywords
group
compound
pharmaceutically acceptable
prodrug
acceptable salt
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Inventor
Mohammed Terrak
Evert Johan Breukink
Stanislas Gobec
Ian Chopra
Thierry Vernet
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Universite de Liege
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
University of Leeds
Universiteit Utrecht Holding BV
Univerza Ljubljana v Fakulteta za Farmazijo
Original Assignee
Universite de Liege
Commissariat a lEnergie Atomique CEA
University of Leeds
Universiteit Utrecht Holding BV
Univerza Ljubljana v Fakulteta za Farmazijo
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Publication of WO2011060976A1 publication Critical patent/WO2011060976A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • the present invention relates to compounds that have a demonstrated antibacterial activity, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments, and to their use in the manufacture of medicaments for use in the treatment of bacterial infections, more specifically of gram positive sensitive and resistant bacteria.
  • Peptidoglycan is an essential component of the bacterial cell wall and its biosynthesis is required for bacterial survival and thus, constitute an important antibacterial target.
  • TP transpeptidation
  • ⁇ -lactams penicillins, cephalosporins, carbapenems
  • resistance to ⁇ -lactams is growing, resulting in multidrug-resistant bacterial strains such as methicillin-resistant
  • glycopeptide antibiotics such as vancomycin have been used clinically with success against otherwise resistant bacteria. Vancomycin blocks the polymerization of peptidoglycan by binding to the terminal D-Ala-D-Ala dipeptide of a so-called lipid II precursor and nascent peptidoglycan.
  • MRSA strains resistant to even these glycopeptide antibiotics have been reported. The threat of bacterial resistance spread is exacerbated by a decrease in new drugs discovery in the last decades, and the low number of antibiotics under development, which could result in a major world-wide public health problem.
  • WO2008/1 10690 discloses a family of tryptamine- derived antibiotics, some of which were found of limited activity against sensitive and ciprofloxacine resistant S. aureus. These active derivatives however were not demonstrated to inhibit other bacteria that may cause infections, specifically in mammalian subjects.
  • the present invention relates to a compound according to formula
  • R 1 represents an optionally substituted benzyl group, which is optionally substituted at the aromatic ring by one ore more alkyl, alkoxy , hydroxyl, thioalkyl, halogen, nitro, cyano or amino groups,
  • R 2 represents a lower alkyl group comprising from 1 to 4 carbon atoms, a lower alkyl group substituted by halogen, a cycloalkyl group, an aryl group , a lower alkoxy group , a lower thioalkyl group, a cycloalkyloxy group, an aralkyloxy group or an alkanoyl group;
  • R 3 , R 4 , R 5 , R 7 and R 8 may independently be the same or different, and represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a formyl group, an amino group which may be protected or substituted, a lower alkyl, cycloalkyl, aryl, lower alkoxy, cycloalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclic heterocyclic group;
  • X represents an oxygen atom or a sulphur atom
  • R 6 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group , an aryl group, a lower alkoxy, cycloalkyloxy, aralkyloxy, alkanoyl, alkanesulfonyl or monocyclic heterocyclic group, all of which may optionally be substituted; for use in treating pathologies associated with bacterial infections in a subject in need of treatment.
  • the present invention further refers to use of the compounds as antibacterial agents, and to a method for the treatment of pathologies associated with bacterial infections in a subject in need of treatment, more specifically compounds acting as peptidoglycan GT inhibitors, and to methods for the treatment of pathologies associated with bacterial infections comprising the administration, to a patient, whether an animal or a human, in need thereof, of at least one compound of formula (I) in a form and amount suitable for achieving the therapeutic effect.
  • the present invention also relates to antibacterial agents and pharmaceutical compositions comprising a compounds, a pharmaceutically acceptable salt, hydrate, solvate, N-oxide and/or prodrug thereof, and to the use of the compound, a
  • Fig. 1 depicts a GT catalyzed glycan chain elongation step in peptidoglycan polymerization.
  • Fig. 2A depicts structures of preferred compounds Example 1 (2-[l-[(2- chlorophenyl)methyl]-2-methyl-5-methylsulfanylindol-3-yl]) and 2 ((2-(l-(3,4- dichlorobenzyl)-2-methyl-5-(methylthio)-lH-indol-3-yl)ethanamine ) according to the invention, as well as comparative Example 1 (NSC 17384)
  • Fig. 2B shows the predicted binding model of a preferred compound according to the invention, 2-[l-[(2-chlorophenyl)methyl]-2-methyl-5- methylsulfanylindol-3-yl] to S. aureus PBP2 active site.
  • Fig.3 depicts the effect of compound Example 2 on bacterial viability.
  • Fig.4 shows the Interaction of a preferred compound according to the invention with lipid vesicles and lipid II.
  • Fig. 5 depicts the dose response curve of the inhibition of E. coli PBPlb by preferred compound Ex.1 according to the invention.
  • Fig.6 shows the effect of preferred compounds Ex.1 and Ex.2 according to the invention and control agents on lipid II cycle.
  • Fig.7 Shows the synthesis of a library of N-benzyltryptamines analogues according to the invention and comparative examples.
  • the present invention relates to a family of compounds which have been discovered to act as a new class of antibiotics. More particularly, it relates to GT inhibitors, as illustrated by the compounds of examples 1 and 2, which have been discovered and shown to be highly active against several purified GT enzymes in the micromolar range. More importantly, the compounds according to the invention were also shown to possess antibacterial activity not only against sensitive, but also against resistant Gram-positive bacteria.
  • the compounds according to the invention have a unique scaffold according to formula (I) as defined herein above, which is completely different from known GT inhibitors, and thus are exemplary for a new class of antibiotics.
  • the only well-characterized inhibitor targeting the GTs is the natural product moenomycin, a potent antibacterial phosphoglyco lipid antibiotic active at nanomolar concentrations.
  • moenomycin a potent antibacterial phosphoglyco lipid antibiotic active at nanomolar concentrations.
  • a delipidated moenomycin derivative is inactive and only the sugar moiety can be reduced to three saccharide units while retaining good antibacterial activity.
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
  • lower alkyl denotes a saturated straight- or branched-chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2- butyl, t-butyl and the like.
  • Preferred lower alkyl groups are groups with 1-4 carbon atoms.
  • lower alkoxy denotes an alkyl group as defined above, which is attached via an oxygen atom.
  • lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 and the like.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl denotes a saturated carbocyclic ring, containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl as used herein is a carbocyclic ring system, containing from 6 to 10 carbon atoms forming one or more rings, and wherein at least one ring is aromatic in nature, for example phenyl, naphthyl or 5,6,7,8-tetrahydronaphthalen-l-yl.
  • the most preferred aryl group is phenyl.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight- chain or branched hydrocarbon groups having from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to 6 carbon atoms, for example the ethenyl, allyl, acetylenyl, propargyl, iso-prenyl and hex-2-enyl groups.
  • alkenyl groups have one or two double bonds
  • alkynyl groups have one or two, triple bonds.
  • heterocyclic embraces both “heteroaryl” and “heterocycloalkyl” groups.
  • heteroaryl as used herein is an aromatic ring system, containing from 5 to 10 ring atoms forming one or more rings, wherein at least one ring atom is a heteroatom selected from the group consisting of O, N and S, and wherein at least one ring is aromatic in nature, for example oxazolyl, pyridyl, thiophenyl, quinolinyl, pyrrolyl, furyl, benzoimidazolyl, imidazolyl and the like.
  • the most preferred group is pyridyl. .
  • heterocycloalkyl denotes a fully saturated ring system, wherein one or two ring atoms are N, O or S, for example piperazinyl, pyrrolidinyl, morpholinyl or piperidinyl.
  • heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more, preferably 1, 2 or 3 carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom (preferably oxygen, sulphur or nitrogen).
  • heteroalkyl refers also to a carboxylic acid or a group derived from a carboxylic acid, such as, for example, acyl, acyl-alkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxy-alkylamide or alkoxycarbonyloxy.
  • heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butoxy, methoxymethyl, ethoxymethyl, methoxyethyl,
  • heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.
  • “Pharmaceutically acceptable” such as pharmaceutically acceptable salt, carrier, excipient, etc., means pharmacologically acceptable and substantially non- toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable salt embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • prodrug refers to a precursor form of the compound that is metabolized to form the active ingredient (see for example R. B. Silverman,
  • the present invention also relates, preferably consist of at least one compound of the formula (I) and at least one pharmacologically acceptable protecting group that is removed under physiological conditions, for example a hydroxy, alkoxy, aralkyloxy, acyl or acyloxy group, such as, for example, a methoxy, ethoxy, benzyloxy, acetyl or acetyloxy group.
  • pharmacologically acceptable protecting group for example a hydroxy, alkoxy, aralkyloxy, acyl or acyloxy group, such as, for example, a methoxy, ethoxy, benzyloxy, acetyl or acetyloxy group.
  • N-oxide refers to N-oxides of tertiary nitrogen atoms in a molecule, which may be more potent than their corresponding tertiary amine, or less. N-oxides may or may not be reduced to their corresponding tertiary amines after indigestion. When N-oxides are converted to their corresponding tertiary amines, the conversion may be in mere trace amounts or nearly quantitative. Further, once formed, N-oxides may be more active than their corresponding tertiary amines, less active or even completely inactive.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • subject herein refers to a living organism, including a human being, pet and farm animal, such as mammal, bird, amphibian, fish, molluse or arthropod.
  • the term "in need of treatment” refers to the inhibition, effective treatment or prevention of infection by a bacterium.
  • the subject in need of treatment is a mammal, more preferably a human being, or a pet or farm animal.
  • In need of treatment more preferably refers to indications in accordance with the present invention are those, which include bacterial infections by Gram-positive bacteria, both sensitive and resistant to ⁇ -lactam and/or glycopeptide antibiotics.
  • the treatment preferably includes inhibition, effective treatment or prevention of infection of bacterial infections wherein preferably the bacteria use
  • GT transglycosylation
  • Peptidoglycan is an essential polymer and the main constituent of the bacterial cell wall. Its biosynthesis pathway requires several steps and offers still many unexplored antibacterial targets for the development of new antibacterial drugs. The last two steps in peptidoglycan biosynthesis typically involve the assembly of the cell wall polymer from the monomeric intermediate. This takes normally place outside the plasma membrane and relies on the activity of the glycosyltransferases (GTs) which use the Lipid II precursor to synthesize glycan chains (Fig. 1) and the transpeptidases which catalyze the cross-linking of two glycan chains via the peptide side chains. Inhibition of either of these two reactions leads to bacterial cell death.
  • GTs glycosyltransferases
  • the 3D structures of GTs and their complexes with moenomycin A have been determined (Heaslet et al, 2009; Lovering et al, 2007; Sung et al, 2009; Yuan et al, 2008), the structures confirmed the catalytic mechanism of glycan chains elongation and the mode of action of moenomycin.
  • the GT domain contains an extended enzymatic cleft which can accommodate six sugar units. It is divided into two sub-sites, a donor site for the elongating chain and acceptor site for the Lipid II substrate.
  • X preferably represents an oxygen atom or a sulphur atom, since compounds with this substitution have strong antibacterial activity.
  • R 1 preferably represents a mono-, di- or tri-substituted benzyl group, more preferably a 2-chlorobenzyl or a 3,4-dichlorobenzyl group.
  • R 2 preferably is an alkyl group comprising from 1 to 4 carbon atoms, preferably methyl.
  • R 3 and R 4 represent a hydrogen atom.
  • X represents sulphur atom, since compounds with sulphur atoms at this position have shown a surprisingly stronger effect in bacterial growth inhibition than those with oxygen atoms,
  • R 1 represents a mono-, di- or tri-substituted benzyl group. More preferred are 2-chlorobenzyl or a 3,4-dichlorobenzyl group, the latter being the most preferred.
  • R 5 , R 7 and R 8 represent a hydrogen atom.
  • Particularly active compounds are 2-[l-[(2-chlorophenyl)methyl]-2-methyl- 5-methylsulfanylindol-3-yl], (2-(l -(3, 4-dichlorobenzyl)-2-methyl-5 -(methylthio)- 1H- indol-3-yl)ethanamine, or combinations thereof.
  • These compounds according to the invention are preferably used in cases wherein the pathologies associated with the bacterial infection are caused by sensitive, or single and/or multiple resistant Gram - positive bacteria.
  • the present invention further relates to (2-(l-(3,4-dichlorobenzyl)-2-methyl-5-
  • (methylthio)-lH-indol-3-yl)ethanamine a pharmaceutically acceptable salt, hydrate, solvate, N-oxide and/or prodrug thereof, and its use as a medicament, preferably its use as an antibacterial agent for treating pathologies associated with bacterial infections in a subject in need of treatment.
  • the compounds according to the invention are preferably employed such that the compounds inhibit the cell wall synthesis in the metabolic pathway of the bacteria. This advantageously inhibits the Glycosyltransferase 51 in the metabolism of the bacteria.
  • the present invention further relates to an antibacterial agent and/or a pharmaceutical composition comprising one or more compounds of the formula (I), a pharmaceutically acceptable salt, N-oxide and/or prodrug thereof.
  • the present invention further relates to a process for preparing an antibacterial composition and/or pharmaceutical composition, the process comprising formulating one or more compounds of the formula (I), a pharmaceutically acceptable salt, N- oxide and/or prodrug thereof, and optionally a utilizable carrier or otherwise suitable additive.
  • the present invention thus also provides pharmaceutical antibacterial compositions containing compounds of the invention, for example compounds of formula (I) and their pharmaceutically acceptable acid addition salts, and a
  • Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • the antibacterial compositions also can be in the form of suppositories or injectable solutions.
  • the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the present invention also relates to a method for the treatment of pathologies associated with bacterial infections or preventing a bacterial infection in a subject, comprising the administration, to a subject in need thereof, of one or more compounds of the formula (I)as defined herein above, a pharmaceutically acceptable salt, N-oxide and/or prodrug thereof.
  • the method for treatment according to the invention is advantageously applied where the subject is a higher animal, preferably a mammalian subject. This may advantageously be a human being, but also applies to wild, farm or pet animals.
  • the method for treatment of pathologies is advantageously associated with bacterial infections by bacteria employing Glycosyltranferase 51 in their metabolic pathway; wherein comprising one or more compounds of the formula (I), a pharmaceutically acceptable salt, N-oxide and/or prodrug thereof, when administered in an appropriate way and amount, inhibit the pathway such that the cell membranes of the bacteria are at least in part damaged,
  • the bacteria may be sensitive, but also single- or multiple resistant bacteria may be treated.
  • pharmaceutically acceptable salt, N-oxide and/or prodrug thereof may advantageously also be used in combination with other antibiotic or otherwise useful compounds.
  • the subject compounds of the formula (I), a pharmaceutically acceptable salt, N-oxide and/or prodrug thereof are used to treat pathologies for gram positive bacteria.
  • the subject invention also relates to the use of one or more compounds of the formula (I), a pharmaceutically acceptable salt, N-oxide and/or prodrug thereof according to the invention for the manufacture of a medicament for the treatment or prevention of a bacterial infection in a subject in need of such treatment, preferably as defined herein above.
  • One or more compounds of the formula (I) according to the invention can advantageously be prepared by methods known in the art, which processes comprise, if desired, converting the compounds obtained into pharmaceutically acceptable salts.
  • the starting materials are either commercially available, are otherwise known in the chemical literature, or can be prepared in accordance with methods well known in the art.
  • the present invention relates also to the therapeutic use of the compounds of the formula (I), their pharmacologically acceptable salts and solvates and hydrates and N-oxides as well as formulations and pharmaceutical compositions.
  • the present invention relates also to the use of those active ingredients in the production of medicaments for preventing and/or treating diseases, especially those diseases that are the result of a bacterial infection.
  • the pharmaceutical compounds of the invention in addition to one or more compounds of the invention, may preferably contain a pharmaceutically acceptable carrier.
  • Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic and organic carriers
  • One or more compounds of the formula (I) according to the invention are preferably generally administered using the known and acceptable methods, either on their own or in combination with any desired other therapeutic agent.
  • Administration can preferably be effected, for example, by one of the following methods: orally, for example in the form of dragees, coated tablets, pills, semi-solid preparations, soft or hard capsules, solutions, emulsions or suspensions; parenterally, for example in the form of an injectable solution; rectally in the form of suppositories; by inhalation, for example in the form of a powder formulation or spray; transdermally or intranasally.
  • the therapeutically acceptable product may preferably be mixed with pharmacologically inert, inorganic or organic
  • pharmaceutical carrier substances for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talcum, stearic acid or salts thereof, skimmed milk powder and the like.
  • pharmaceutical carriers such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used.
  • pharmaceutical carriers such as, for example, water, alcohols, aqueous saline solution, aqueous dextrose, polyols, glycerol, vegetable oils, petroleum and animal or synthetic oils can be used.
  • pharmaceutical carriers such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols can be used.
  • compressed gases suitable for that purpose can be used, such as, for example, oxygen, nitrogen and carbon dioxide
  • the pharmaceutical compositions may further preferably contain preservatives, solubilisers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the present invention also provides a method for preparing compositions of the invention which comprises bringing one or more compounds of formula (I) and/or pharmaceutically acceptable salts, prodrugs and/or N-oxides thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • Figure 2 shows structures of the GT inhibitors compounds Examples 1, 2 and 3 and the predicted binding model of compound 1 to S. aureus PBP2 active site.
  • Figure 2 A shows the structures of the GT inhibitors Example 1 (2-[l-[(2- chlorophenyl)methyl]-2-methyl-5-methylsulfanylindol-3-yl]) and 2, (2-(l-(3,4- dichlorobenzyl)-2-methyl-5-(methylthio)-lH-indol-3-yl)ethanamine, and Example 3 l-Benzyl-2-methyl-5-methoxytryptamine.
  • Figure 2 B depicts a superimposition of the computer model of compound Example 1 on the X-ray structure of moenomycin (moenomycin rings are labeled from A to F) bound to PBP2 (pdb code: 20LV). Amino acids that form interactions with inhibitor Ex.1 are presented as sticks. Hydrophobic residues are shown as semi-transparent yellow surface. (Hydrogen bonds between compound Example 1 free amino group and Asp 156 side chain are presented as dotted lines).
  • Figure 3 depicts the effect of compound Ex.2 on bacterial viability.
  • Figure 3A cell viability curves after exposure of S. aureus to variable concentration of compound Example 2.
  • Figure 3 B shows the cell density of the same cell cultures.
  • Figure 4 depicts the Interaction of compound Example 2 with lipid vesicles and lipid II:
  • Example 2 A.Interaction of Example 2 with DOPC vesicles in the presence and absence of lipid II.
  • Example 2 Effect of Example 2 on membrane potential. Effect of nisin in Micrococcus flavus is shown for comparison. Dye release was monitored at excitation and emission wavelengths of 622 and 670 nm, respectively.
  • E Competition of undecaprenylpyrophosphate (11-PP),
  • Triton X-100 micelles in the presence or absence of 1 mM of compound EX.2.
  • Figure 5 shows the dose response curve of the inhibition of E. coli PBPlb by compound Ex.1. An IC50 value of 58.9 ⁇ ( ⁇ 3.3) was calculated from this curve.
  • Figure 6 shows the effect of compounds Ex.1 and Ex.2 and control agents on lipid II cycle.
  • DOPC dioleoyl-sn-glycero-3-phosphocholine
  • DOPG l,2-dioleoyl-sn-glycero-3- [phospho-rac-(l -glycerol)]
  • DOPG l,2-dioleoyl-sn-glycero-3-[phospho-rac-(3- lysyl(l -glycerol))]
  • lysyl-DOPG l,2-dioleoyl-3-trimethylammonium-propane
  • DOTAP l,2-dioleoyl-3-trimethylammonium-propane
  • Moenomycin A is a gift from Aventis (Romainville, France).
  • the fluorescent dye 3,3'- diethylthiodicarbocyanme iodide (DiSC2(5)) is from Molecular Probes Inc. Lipid I, Lipid II and Dansyl-Lipid II were synthesized and purified as described elsewhere (Breukink et al, 2003). Undecaprenylphosphate and undecaprenylpyrophosphate were obtained by phosphorylation of undecaprenol (Danilov et al, 1989) that was isolated from Laurus nobilis as described (Swiezewska et al, 1994). Radiolabeled [14C]meso-diaminopimelic acid (A2pm)-labelled Lipid II was prepared essentially as previously described (Terrak et al, 1999).
  • E. coli PBPlb was produced and purified as described in Terrak et al., 1999.
  • S. aureus MtgA and PBP2 were produced and purified as described in Terrak et al., 2006 and Lovering et al, 2007, respectively.
  • the gene encoding (A68- Q723) PBP2 of Enterococcus hirae was cloned into pET28a (+) expression plasmid (Novagen) and the His Tag PBP2 was expressed in E. coli BL21 (DE3).
  • the cells were grown at 37°C to an optical density of 0.8 at 600 nm, protein expression was induced with 0.5 mM isopropyl ⁇ -D-l-thiogalactopyranoside and incubation was continued overnight at 18°C.
  • the cells were resuspended in 25 mM HEPES pH 7.5, 500 mM NaCl and the PBP2 was purified in one step on HisTrap column (GE, Heathcare).
  • T. maritima PBPla was produced and purified as described in Offant et al, Febs J. (in press)
  • Lipid II preparation and GT activity assay optimization Lipid II is the natural substrate of the GT.
  • a dansylated form of lipid II (DNS- LII) was synthesized and purified as described elsewhere (Breukink et al, 2003). in vitro using the MraY/MurG coupled assay (Bertsche et al, 2005 with modifications). This analogue is used by GTs to polymerize uncross-linked peptidoglycan, a process that can be directly monitored by following the decrease of fluorescence during the reaction (Schwartz et al., 2001).
  • Activity assays used 50 ⁇ of optimal reaction mixture for each of the four GTs tested : E.
  • coli PBPlb was used at 100 nM in the presence of 10 ⁇ DNS-LII, 20% DMSO, 10 mM CaCl 2 , 50 mM Hepes pH 7.5, 200 mM NaCl, 0.024%> decylPEG, 1 unit of muramidase.
  • S. aureus MtgA was used at 2 ⁇ in the presence of 20 ⁇ DNS-LII, 10% DMSO, 10 mM MnCl 2 , 50 mM Hepes pH 7.5, 200 mM NaCl, 1 unit of muramidase.
  • hirea PBP2 was used at 300 nM in the presence of 10 ⁇ DNS-LII, 20% DMSO, 10 mM CaCl 2 , 50 mM Hepes pH 7.5, 0.024% decylPEG, 1 unit of muramidase.
  • T. maritima PBPla was used at 150 nM in the presence of 10 ⁇ DNS-LII, 20% DMSO, 10 mM CaCl 2 , 50 mM Hepes pH 7.5, 200 mM NaCl, 0.024% decylPEG, 1 unit of muramidase.
  • Radiolabeled [ 14 C]meso-diaminopimelic acid (A 2 pm)-labelled Lipid II was prepared essentially as previously described (Terrak et al, 1999).
  • the reaction for the radioactive assay was performed in the same condition as for the fluorescence assay using [ 14 C]lipid II instead of the fluorescent substrate and by omitting the muramidase.
  • the reaction products were separated by TLC isopropanol- ammonium hydro xide-H 2 0 (5:3: 1; V/V) and analyzed using Typhoon Trio+ Imager and QuantityOne sofware (GE Healthcare).
  • the aim of structure-based virtual screening is to reduce a large number of compounds to a smaller subset, which is more likely to contain biologically active compounds. This is particularly helpful because of the difficulty of having high amount of lipid II substrate.
  • the thirty highest ranked compounds were selected based on the information of their structures, score etc. Only 21 of them were solubilised and tested for E. coli PBPlb GT activity inhibition at 0.2 and 1 mM final concentrations. Compounds which inhibit E. coli PBPlb or interfere with the fluorescent test were tested with radioactive lipid II (Terrak et al, 1999). One compound, Ex.2 according to the invention inhibited the GT activity of E. coli PBPlb.
  • Example 2 was also able to inhibit the activity of four other GTs, S. aureus MtgA and PBP2, T. maritima PBPla and E. hirae PBP2 (Table 1).
  • IC50 values of the active compounds Ex.1 and 2 were determined with dansyl- lipid II fluorescent assay. The initial velocity of the reaction was determined in the presence of variable concentrations of inhibitor (50-1500 ⁇ ) and plotted versus the inhibitor concentration. The IC50 value was determined as the concentration of inhibitor that decreases the initial velocity by a factor of 2 (Fig.2, Table 1), and were all in the micromolar range.
  • MIC Minimum inhibitory concentration determinations were carried out using the Clinical and Laboratory Standard Institute (CLSI, 2009) broth microdilution method. Compounds were solubilised in 100% DMSO at a concentration of 10 mg/ml, and twenty-fold diluted in Mueller-Hinton broth (MHB), just before utilization. Inoculums of each strain (approximately 5.10 5 CFU/ml) were prepared in MHB. The two compounds (Ex.1 and Ex.2) inhibited growth of all Gram positive bacteria and some resistant strains (Table 2), while they showed limited activity against Gram-negative bacteria. The MIC values of compounds Ex.1 and Ex.2 against E. coli 141 1 were 64 and 16 ⁇ g/ml respectively which fell further with polymyxin nonapeptide (PMBN) treatment, or in an acrAB efflux mutant to the values observed in Gram-positive (Table 2).
  • PMBN polymyxin nonapeptide
  • the subject novel compounds for use as antibacterial agents were determined through the use of structure-based virtual screening of small molecules from the National Cancer Institute library.
  • E. coli PBPlb S. aureus MtgA and PBP2 were produced and purified as previously described (Lovering et al, 2007; Terrak et al, 1999; Terrak and Nguyen-Disteche, 2006).
  • the PBPla Glu34-Gly643 from Thermotoga maritima MSB8 was expressed in BL21RIL E. coli cells to limit the effect of rare codons.
  • the cells were grown in LB at 37°C to an optical density of 0.8 at 600 nm, protein expression was induced with 0.5 mM isopropyl ⁇ -D-l-thiogalactopyranoside and incubation was continued overnight at 15°C.
  • the cells were resuspended in the 25 mM HEPES pH 7.5, 500 mM NaCl, 0.74% CYMAL-4 and a pill of CompleteTM EDTA-free protease inhibitors (Roche) and lysed by sonication.
  • the protein was purified on Ni-NTA Superflow column (Qiagen) using buffer A (25 mM HEPES pH 7.5, 500 mM NaCl, 0.37% CYMAL-4) and eluted with two steps of 60 mM and 250 mM imidazole in buffer A.
  • the protein was further purified by a gel filtration and a second Ni-affinity step following TEV cleavage of the poly His tag.
  • the residual contaminants are removed by an ion exchange chromatography which delivered a pure protein as analyzed by SDS-PAGE stained with Coomassie (Offant et al, FEBS J., in press).
  • the gene encoding (A68-Q723) PBP2 of Enterococcus hirae was cloned into pET28a (+) expression plasmid (Novagen) and the His Tag PBP2 was expressed in E. coli BL21 (DE3).
  • the cells were grown at 37°C to an optical density of 0.8 at 600 nm, protein expression was induced with 0.5 mM isopropyl ⁇ -D- 1-thiogalactopyranoside and incubation was continued overnight at 18°C.
  • the cells were resuspended in 25 mM HEPES pH 7.5, 500 mM NaCl and the PBP2 was purified in one step on HisTrap column (GE, Heathcare),
  • the virtual screening was carried out on a suitably equipped workstation,, using the programme eHiTS 6.0 from SimBioSys Inc. (Zsoldos et al, 2006; Zsoldos et al, 2007) for the active site detection and docking. Open Babel
  • the 3D structures of the compounds from the NCI Diversity Set were obtained from the NCI webpage (http://dtp.nci.nih.gov/dw/testmasters/chem3d.html).
  • the 1990 highly diverse compounds of the NCI Diversity Set represented a broad chemical spectrum of whole NCI database.
  • no special preparation of the 3D structures was applied since eHiTS automatically evaluates all of the possible protonation states for ligands and enzymes.
  • the crystal structure of S. aureus PBP2 as a complex with moenomycin (PDB entry 20LV) (Lovering et al, 2007) was used for virtual screening.
  • PBP2 crystal structure was initially prepared with eHiTS. The active site detection was carried out using the 'complex' parameter with high accuracy.
  • the program automatically detected the ligand in the complex and selected the part of the enzyme within a 7A margin around the ligand as the active site.
  • the NCI Diversity Set was then docked to the active site.
  • the scoring was according to the eHiTS Score that is included in the eHiTS software package.
  • reaction conditions were adapted for optimal activity as follows, with only variable conditions given: S. aureus MtgA was used at 2 ⁇ in the presence of 20 ⁇ dansyl-Lipid II, 10% DMSO and 10 mM MnC12. S. aureus PBP2 was used at 2.5 ⁇ in the presence of 20 ⁇ dansyl-Lipid II and 50 mM sodium acetate pH 5. E. hirae PBP2 and T. maritima PBPla were used at 300 nM and 150 nM respectively. Radioactive assay.
  • the reaction, containing a final volume of 30 ⁇ , for the radioactive assay was performed in the same condition as for the fluorescence assay using 4 ⁇ [14C]Lipid II (0.126 ⁇ nmol-1) instead of the fluorescent substrate and by omitting the muramidase.
  • the reaction was stopped with moenomycin (10 ⁇ ) and the products were separated by TLC in isopropanol-ammonium hydroxide-H20 (5:3: 1; V/V) and analyzed using Typhoon Trio+ Imager and ImageQuant TL software (GE Healthcare).
  • IC50 values of compounds Ex.1 and Ex.2 were determined using a fluorescence based assay. The initial velocity of the reaction was determined in the presence of variable concentrations of inhibitor (20-1500 ⁇ ) and plotted versus the inhibitor concentration using Sigma plot program (Systas Software). The IC50 value was determined as the concentration of inhibitor that decreases the initial velocity by a factor of 2 using three independents experiments.
  • Table 1 shows the . IC50 values of compounds Example 1 and 2 for different GTs:
  • EhiPBP2 E. hirae PBP2; TmaPBPIa, T. maritima PBPla.
  • IC50 value of moenomycin for S. aureus PBP2 is 1.3 ⁇ ( ⁇ 0.3) nd, not determined
  • MIC Minimum inhibitory concentration determinations were carried out using the Clinical and Laboratory Standard Institute (CLSI, 2009) broth microdilution method. Compounds were solubilised in 100% DMSO at a concentration of 10 mg/ml, and twenty-fold diluted in Mueller-Hinton broth (MHB), just before utilization. Inoculums of each strain (approximately 5.10 5 CFU/ml) were prepared in MHB. M. hominis
  • Table 2 shows the results of the antibacterial effects of compounds according to the invention.
  • M. hominis > 64 > 64 >64 aureus means Staphylococcus aureus; L. innocua, Listeria innocua ; M. luteus,
  • Micrococcus luteus S. epidermis, Streptococcus epidermis; S. pneumoniae, Streptococcus pneumoniae ; E. coli, Escherichia coli ; P. aeruginosa, Pseudomonas aeruginosa. Mycoplasma hominis; nd, not determined.
  • Bacillus subtilis reporter system which differentiates inhibitors of cell envelope, DNA, RNA, protein and fatty acid biosynthesis by quantifying the upregulation of a specific luciferase reporter construct in each case as described (Fischer et al, 2004; Urban et al, 2007). Table 4 shows the outcome of assays:
  • the assay based on LiaRS two-component system in Bacillus subtilis sensing stress on cell wall caused by compounds interfering with Lipid II cycle was used according to Burkard and Stein, 2008; Mascher et al, 2004.
  • BFS2470 carries a ⁇ -galactosidase reporter gene under the control of lial promoter.
  • DOPC with or without 1 mol% Lipid II vesicles were prepared as described above in 10 mM MES-KOH, 15 mM K2S04 at pH 7. Vesicles (1 mM lipid Pi) were incubated with 5 ⁇ and 20 ⁇ Ex.2, respectively, for 15 min at room temperature. The mixture was centrifuged in a TLA 120.2 rotor using a Beckman Ultracentrifuge (TL-100) for 1.5 h at 100 krpm and 20 °C. The amount of Ex.2 before centrifugation and in the supernatant and pellet was determined by fluorescence on a Cary Eclipse fluorescence spectrophotometer (Varian Inc.). The percentage of Ex.2 in the supernatant and pellet was determined by comparing the maximal value (350 nm) of fluorescence emission intensity.
  • Carboxyfluorescein (CF)-loaded LUVs were prepared in 50 mM MES-KOH,
  • nisin-induced CF leakage from the vesicles was monitored with excitation and emission wavelengths set at 430 nm and 513 nm, respectively.
  • Triton X-100 was added 1 min after the addition of nisin, to a final concentration of 0,2% (w/v) to fully disrupt the lipid vesicles and the
  • the cytoplasmic membrane depolarization activity of Ex.2 was determined with the membrane potential-sensitive dye DiSC2(5) using Staphylococcus simulans and Micrococcus flavus grown in LB broth at 37°C and 30°C, respectively. Bacterial cells in the mid-logarithmic phase were centrifuged, washed in 5 mM HEPES (pH 7.8), and resuspended in the same buffer to an optical density at 600 nm of 0.05 in a 1 cm cuvette. A stock solution of DiSC2(5) was added to a final concentration of 0.4 ⁇ and quenching was allowed to occur at room temperature for approximately 1 min.
  • CTAB Cetyltrimethylammonium bromide

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Abstract

La présente invention concerne un composé de formule I, un sel pharmaceutiquement acceptable de celui-ci et/ou un N-oxyde de celui-ci, ledit composé, sel ou N-oxyde étant destiné à être utilisé comme agent antibactérien.
PCT/EP2010/063405 2009-11-20 2010-09-13 Composés dérivés de la tryptamine utilisés en tant qu'agents antibactériens Ceased WO2011060976A1 (fr)

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WO2013164337A1 (fr) * 2012-04-30 2013-11-07 Janssen R&D Ireland Nouveaux composés et nouvelle utilisation
WO2016191658A1 (fr) * 2015-05-28 2016-12-01 President And Fellows Of Harvard College Inhibiteurs de glycosyl transférases bactériennes
WO2017117581A1 (fr) * 2015-12-31 2017-07-06 The Research Foundation For The State University Of New York Inhibiteurs de ship à base de tryptamine pour le traitement du cancer
WO2019088910A1 (fr) * 2017-11-03 2019-05-09 Bioimics Ab Composés hétérocycliques anti-infectieux et leurs utilisations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013164337A1 (fr) * 2012-04-30 2013-11-07 Janssen R&D Ireland Nouveaux composés et nouvelle utilisation
CN104487425A (zh) * 2012-04-30 2015-04-01 爱尔兰詹森研发公司 治疗细菌性疾病的嘧啶衍生物
CN104487425B (zh) * 2012-04-30 2016-09-14 爱尔兰詹森科学公司 治疗细菌性疾病的嘧啶衍生物
US9725432B2 (en) 2012-04-30 2017-08-08 Janssen Sciences Ireland Us Pyrimidine derivatives for the treatment of bacterial diseases
TWI598099B (zh) * 2012-04-30 2017-09-11 健生科學愛爾蘭無限公司 新化合物及其新用途
EA030899B1 (ru) * 2012-04-30 2018-10-31 Янссен Сайенсиз Айрлэнд Юси Производные 5-фенилпиримидина с антибактериальными свойствами
US10221157B2 (en) 2012-04-30 2019-03-05 Janssen Pharmaceutica Nv Pyrimidine derivatives for the treatment of bacterial diseases
WO2016191658A1 (fr) * 2015-05-28 2016-12-01 President And Fellows Of Harvard College Inhibiteurs de glycosyl transférases bactériennes
WO2017117581A1 (fr) * 2015-12-31 2017-07-06 The Research Foundation For The State University Of New York Inhibiteurs de ship à base de tryptamine pour le traitement du cancer
US10736877B2 (en) 2015-12-31 2020-08-11 Syracuse University Tryptamine-based ship inhibitors for the treatment of cancer
WO2019088910A1 (fr) * 2017-11-03 2019-05-09 Bioimics Ab Composés hétérocycliques anti-infectieux et leurs utilisations
CN111566085A (zh) * 2017-11-03 2020-08-21 百欧伊米克思有限公司 抗感染杂环化合物及其用途

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