Short conjugated oligoelectrolytes and uses thereof

Patent metadata

Field	Value
Publication number	US-11713318-B2
Application number	US-201917040320-A
Country	US
Kind code	B2
Filing date	Mar 21, 2019
Priority date	Mar 23, 2018
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

Compositions and methods of making and using thereof are provided with a specific antimicrobial activity and efficacy toward Gram-positive and Gram-negative bacteria and low levels of toxicity toward mammalian cells. The compositions include water-soluble molecules characterized by a hydrophobic interior fragment and side groups containing cationic groups. A class of these molecules is provided with variations in the length of the internal conjugated segment and in other molecular features, which impact the efficacy and toxicity. The substituents on the cationic functional group, the structural variations on the solubilizing group, and the length of the conjugated segment are important features affecting the antimicrobial property and the non-toxicity to mammalian cells of the composition.

First claim

We claim:

1. A conjugated oligoelectrolyte (COE) having a structural Formula 5:

or a pharmaceutically acceptable salt thereof, wherein R 12 is —O—R 14 —N(R 15 ) 3 or —O—R 14 -R 17 ; R 13 is H; R 14 is —(CH 2 ) 2 —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 — or —(CH 2 ) 10 —; a R 15 is methyl; a R 15 a is methyl or C 2 -C 10 alkyl; and a R 15 is C 2 -C 10 alkyl, hydroxyalkyl, aminoalkyl,

or —((CH 2 ) 2 —O) 1-4 —CH 3 ; or two R 15 are taken together with the nitrogen to which they are attached to form a monocyclic N-linked heterocyclyl; and the remaining R 15 is C 1 -C 10 alkyl; R 17 is NH—(═NH)NH 2 ; w is 0, 1 or 2; and the counter ions include I − , Br − , Cl − , F − , organic anion, BIm 4 − or B(ArF) 4 − .

2. The COE of claim 1 , wherein the monocyclic N-linked heterocyclyl is 5-membered or a 6-membered monocyclic N-linked heterocyclyl.

3. A COE having a structure selected from the group consisting of:

4. The COE of claim 3 , having a minimum inhibition concentration (MIC) of no greater than 1 μg/mL, between 1-5 μg/mL, or between 5-15 μg/mL against one or more bacteria selected from the group consisting of ST ATCC 14028, EC ATCC 25922, PA ATCC 10145, KPN ATCC13883, MRSA USA300, MSSA Newman, MRSA MT3302, MRSA MT3315, and MSSA MT3305 as determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines by broth dilution.

5. A pharmaceutical composition comprising an effective amount of the COE of claim 1 ; and a pharmaceutically acceptable excipient.

6. A method of treating, reducing the severity of and/or slowing the progression of a bacterial infection in a mammalian subject comprising administering an effective amount of a conjugated oligoelectrolyte (COE) of claim 1 .

7. The method of claim 6 , wherein the bacterial infection is due to a bacteria selected from the group consisting of Salmonella enterica Typhimurium, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae , methicillin-resistant S. aureus , methicillin-sensitive S. aureus, E. faecium, A. baumannil, E. cloacae, S. epidermidis, K. aerogenes, S. flexneri , E pseudotuberculosis, N. gonorrhoeae , and S. pneumoniae.

Assignees

• Univ California

Inventors

• Bazan Guillermo
• Zhang Zichao
• Moreland Alex
• Mahan Michael J
• Heithoff Douglas M
• Limwongyut Jakkarin
• Nie Chenyao

Classifications

• C07D471/08 Primary

  Bridged systems · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07C217/62

  linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07C279/08

  being further substituted by singly-bound oxygen atoms · CPC title

• C07C309/24

  of a carbon skeleton containing six-membered aromatic rings · CPC title