Compounds with copper- or zinc-activated toxicity against microbial infection

Patent metadata

Field	Value
Publication number	US-12534440-B2
Application number	US-201917277631-A
Country	US
Kind code	B2
Filing date	Sep 20, 2019
Priority date	Sep 20, 2018
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

Heterocyclic compounds with a novel pyrazole thioamide-based NNSN structural motif, having highly effective zinc- or copper-activated toxicity against microbial infections at micromolar or nanomolar minimum inhibitory concentrations (MIC), and methods of making and using the same.

First claim

The invention claimed is:

1 . A copper(I)- or zinc(II)-activated compound of formula I or formula II:

or a pharmaceutically-acceptable salt thereof, where:
R 1 is a substituted aryl; and
R 2 is a branched or unbranched alkyl or alkenyl that may be substituted, or R 2 is a substituted or unsubstituted amine, a substituted or unsubstituted amide, an ether, a thioether, an ester, a carboxylic acid, a substituted or unsubstituted aryl, a thiourea group, or a benzyloxy group; and
R 3 is hydrogen, a halogen, a branched or unbranched alkyl or alkenyl, a cycloalkyl, a heterocycle, an ether, a thioether, an ester, an amine, an amide, a hydrazine, a hydrazone, or a nitro group; and
R 4 is hydrogen, a halogen, a branched or unbranched alkyl or alkenyl, a cycloalkyl, a heterocycle, an ether, a thioether, an ester, an amine, an amide, a hydrazine, a hydrazone, or a nitro group; and
R 5 is hydrogen or a branched or unbranched alkyl or alkenyl that may be substituted.

2 . The compound of claim 1 , wherein said compound inhibits activity of mycobacteria, Gram-negative bacteria, and/or Gram-positive bacteria in the presence of copper(I) or zinc(II).

3 . The compound of claim 1 , wherein said compound inhibits activity of an antibiotic-resistant bacteria in the presence of copper(I) or zinc(II).

4 . The compound of claim 1 , wherein said compound has an MIC of less than 10 μM.

5 . The compound of claim 1 , wherein said compound has an MIC of less than 1 μM.

6 . The compound of claim 1 , wherein each of said branched or unbranched alkyls or alkenyls may be halogen-, sulfonic acid-, or nitro-substituted.

7 . The compound of claim 1 , wherein each of said aryls may be substituted by one or more halogens, nitro groups, alkoxies, or alkyls.

8 . The compound of claim 1 , wherein said compound is formula (I), and R 1 is a halogen-substituted aryl, R 2 is primary amine, and each of R 3 , R 4 , and R 5 are hydrogen.

9 . The compound of claim 8 , wherein R 1 is a halogen-substituted phenyl or benzyl group, and R 2 is a primary amine group.

10 . The compound of claim 1 , wherein said compound is formula (II), each R 1 is a halogen-substituted aryl, each of R 3 and R 4 are hydrogen, and each R 5 is hydrogen or an alkyl.

11 . The compound of claim 10 , wherein R 1 is a halogen-substituted phenyl or benzyl group.

12 . The compound of claim 1 , wherein said compound is selected from the group consisting of 3-amino-N-(4-chlorophenyl)-1H-pyrazole-1-carbothioamide, 3-amino-N-(4-nitrophenyl)-1H-pyrazole-1-carbothioamide, 3-amino-N-(4-methoxyphenyl)-1H-pyrazole-1-carbothioamide, 3-amino-N-(p-tolyl)-1H-pyrazole-1-carbothioamide, 3-amino-N-(4-bromophenyl)-1H-pyrazole-1-carbothioamide, 3-amino-N-(4-fluorophenyl)-1H-pyrazole-1-carbothioamide, N-(4-chlorophenyl)-3-(dimethylamino)-1H-pyrazole-1-carbothioamide, N-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-1-methylthioureido)-1H-pyrazole-1-carbothioamide, 3-(benzyloxy)-N-(4-chlorophenyl)-1H-pyrazole-1-carbothioamide, N-(4-chlorophenyl)-3-methyl-4-nitro-1H-pyrazole-1-carbothioamide, 3-amino-N-(2-chlorophenyl)-1H-pyrazole-1-carbothioamide, 3-amino-N-(3-chlorophenyl)-1H-pyrazole-1-carbothioamide, N-(2-chlorophenyl)-3-(3-(2-chlorophenyl)thioureido)-1H-pyrazole-1-carbothioamide, Ethyl 1-((2-chlorophenyl) carbamothioyl)-1H-pyrazole-3-carboxylate, Ethyl 1-((3-chlorophenyl) carbamothioyl)-1H-pyrazole-3-carboxylate, and Ethyl 1-((4-chlorophenyl) carbamothioyl)-1H-pyrazole-3-carboxylate.

13 . The compound of claim 1 , wherein said compound is selected from the group consisting of

and a pharmaceutically-acceptable salt thereof.

14 . A method of inhibiting bacterial infection in a subject, said method comprising administering a therapeutically-effective amount of a copper(I)- or zinc(II)-activated compound according to claim 1 to said subject, wherein said compound reacts with endogenous copper(I) and/or zinc(II) in said subject at a site of bacterial infection to yield a copper and/or zinc analog of an iminium cation active against said bacterial infection.

15 . The method of claim 14 , wherein said compound is administered intramuscularly, subcutaneously, intradermally, intranasally, intravenously, orally, or topically.

16 . The method of claim 14 , wherein said compound is dispersed in a pharmaceutically-acceptable carrier.

17 . The method of claim 16 , comprising a plurality of said compounds dispersed in said carrier.

18 . The method of claim 17 , comprising a plurality of different compounds.

19 . The method of claim 14 , further comprising providing a unit dosage form of said compound dispersed in a pharmaceutically-acceptable carrier prior to said administering.

20 . The method of claim 14 , wherein said subject is a human or a non-human animal.

21 . The method of claim 14 , wherein said bacterial infection is caused by a microorganism selected from the group consisting of Mycobacterium tuberculosis, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus mitis, Streptococcus mutans, Streptococcus bovis , Group B Streptococcus, Listeria monocytogenes, Cutibacterium acnes, Chlamydia trachomatis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Salmonella typhimurium, Bacillus subtilis, Neisseria meningitides, Neisseria gonorrhoeae, Haemophilus influenzae, Acinetobacter baumannii , and Mycoplasma spp.

22 . The method of claim 14 , wherein said bacterial infection is caused by a resistant bacteria selected from the group consisting of Vancomycin-resistant Enterococcus faecium (VRE), Methicillin-resistant Staphylococcus aureus (MRSA), and Fluoroquinolone-resistant Pseudomonas aeruginosa.

23 . The method of claim 14 , wherein said compound is co-administered with a conventional antibiotic.

24 . A composition comprising a copper(I)- or zinc(II)-activated compound according to claim 1 dispersed in a pharmaceutically-acceptable carrier.

25 . The composition of claim 24 , wherein said carrier is selected from the group consisting of sterile isotonic aqueous buffer, normal saline, phosphate buffered saline, DMSO, sterile water, oil-in-water emulsion, water-in-oil emulsion, petrolatum, paraffin, glycerins, mineral oil, propylene glycol, polyethylene glycol, stearic acid, parabens, vegetable oils, seed/nut oils, and mixtures thereof.

26 . A method of inhibiting replication of bacteria in a cell, said method comprising contacting the cell with a copper(I)- or zinc(II)-activated compound according to claim 1 or pharmaceutical composition thereof, wherein the bacteria is selected from mycobacteria, Gram-negative bacteria, and/or Gram-positive bacteria.

Assignees

• Univ Kansas State
• Uab Res Found

Inventors

• Bossmann Stefan H
• Kalubowilage Madumali
• Zhang Man
• Delpe-Acharige Anjana
• Eschliman Kayla
• Wolschendorf Frank
• Kutsch Olaf
• Dalecki Alex
• Narmore Whitney

Classifications

• C07D231/22

  with aryl radicals attached to ring nitrogen atoms · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D231/42 Primary

  Benzene-sulfonamido pyrazoles · CPC title

• A61K31/415

  1,2-Diazoles · CPC title