Reduction-triggered antibacterial sideromycins

Patent metadata

Field	Value
Publication number	US-11014891-B2
Application number	US-201415031736-A
Country	US
Kind code	B2
Filing date	Oct 23, 2014
Priority date	Oct 23, 2013
Publication date	May 25, 2021
Grant date	May 25, 2021

Abstract

A compound is provided, comprising: an Fe(III)-binding or an Fe(III)-bound siderophore; one or more optional linker covalently bound to the siderophore; a drug; and an Fe(III) to Fe(II) reduction triggered linker bound to the drug and the linker or, if no linker is present, then bound to the drug and the siderophore. Compositions and methods including the compound are also provided.

First claim

The invention claimed is:

1. A compound, comprising:
an Fe(III)-binding siderophore, or an Fe(III)-bound siderophore;
one or more optional linkers covalently bound to the siderophore;
a drug; and
an Fe(III) to Fe(II) reduction triggered linker having the following formula Q bound to the drug and the linker or, if no linker is present, then bound to the drug and the siderophore:

wherein J is a covalent bond or group having the formula —(CO)NR′— or —NR′—, J being bound to the linker or, if no linker is present, then to the siderophore;
wherein K is a covalent bond, —O—, or —NR′—, K being bound to the drug; and
R′ is independently H or alkyl;
or pharmaceutically acceptable salt or solvate thereof;

wherein the drug is an antibiotic selected from the group consisting of amikacin, aminoglycoside, amoxicillin, amphotericin, ampicillin, ansamycin, azithromycin, aztreonam, bacillomycin, BAL30072, beta-lactam, biapenem, carbacephalosporins, carbapenem, carbomycin, carbomycin A, carumonam, cefaclor, cefalotin, cephalosporin, cethromycin, chloramphenicol, chlortetracycline, clarithromycin, clindamycin, daptomycin, demeclocycline, dirithromycin, doripenem, doxorubicin, doxycycline, ertapeneme, erythromycin, ethambutol, fluoroquinolone, gentamicin, imipenem, isoniazid, josamycin, kanamycin, kitasamycin, lincomycin, linezolid, loracarbef, macrolide, meropenem, methacycline, midecamycin, monobactam, mupirocin, neomycin, nystatin, oleandomycin, oleandomycin, oxazolidinones, oxytetracycline, panipenem, penem, penicillin, peptide antibiotic, polymixin, pyrrolnitrin, quinolone, rifampin, rifamycins, rolitetracycline, roxithromycin, solithromycin, spiramycin, cstreptomycin, sulfabenzamide, sulfacetamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, sulfisoxazole, telithromycin, tetracycline, tigimonam, troleandomycin, tylosin, tylocine, vancomycin, zyvox, or combination thereof.

2. The compound of claim 1 , wherein the siderophore comprises a natural siderophore, semi-synthetic siderophore, synthetic siderophore, or combination thereof.

3. The compound of claim 1 , wherein the siderophore comprises one or more iron(III)-binding ligands.

4. The compound of claim 1 , the siderophore comprises one or more iron(III)-binding catechols, hydroxamic acids, beta-hydroxy acids, heteroaromatic ligands, or combination thereof.

5. The compound of claim 1 , having one of the following formulas:

wherein
A is drug;
each L is independently a linker;
each R 1 is independently H, —C(═O)alkyl, —C(═O)aryl, or —C(═O)O-alkyl;
each R 2 is independently H, alkyl, alkoxy, hydroxy, carboxy, halo, nitro, amino, or cyano;
each n is independently 1, 2, or 3;
each p is independently 0-11;
each j is independently 0-11;
each k is independently 1-11;
each l is independently 1-11;
each o is independently 0-11; and
each m is independently 0-11;
Fe(III)-bound form thereof, pharmaceutically acceptable salt thereof, solvate thereof, or combination thereof.

6. The compound of claim 1 , wherein the compound has one of the following formulas:

wherein
A is a drug;
each L is independently a linker; and
each p is independently 0-11;
Fe(III)-bound form thereof, pharmaceutically acceptable salt thereof, solvate thereof, or combination thereof.

7. The compound of claim 1 , wherein one or more than one linker is present.

8. The compound of claim 1 , wherein more than one linker is present.

9. The compound of claim 1 , wherein no linker is present.

10. A pharmaceutical composition, comprising the compound of claim 1 , or mixture thereof, and a pharmaceutically acceptable diluent or carrier.

11. The pharmaceutical composition of claim 10 , wherein the diluent or carrier comprises a pharmaceutically acceptable hydrogel.

12. A method for treating a bacterial infection in a subject suffering from said bacterial infection, comprising administering the compound of claim 1 to the subject.

13. A method for treating a bacterial infection in a subject suffering from said bacterial infection, comprising administering the composition of claim 10 to the subject.

14. The method of claim 12 , wherein the bacterial infection is caused by an antibiotic-resistant bacterium, Gram-positive bacterium, or Gram-negative bacterium.

15. The method of claim 13 , wherein the bacterial infection is caused by an antibiotic-resistant bacterium, Gram-positive bacterium, or Gram-negative bacterium.

16. A method for killing or inhibiting the growth of a bacterium, comprising contacting the bacterium with the compound of claim 1 .

17. A method for killing or inhibiting the growth of a bacterium, comprising contacting the bacterium with the composition of claim 10 .

Assignees

• Univ Notre Dame Du Lac

Inventors

• Miller Marvin J
• Ji Cheng

Classifications

• C07D501/00

  Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-C07D-0993.gif] , e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring · CPC title

• C07D261/14

  Nitrogen atoms · CPC title

• C07D265/26

  Two oxygen atoms, e.g. isatoic anhydride · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D207/40

  2,5-Pyrrolidine-diones · CPC title