Compositions and methods for inhibition of mycobacteria

Patent metadata

Field	Value
Publication number	US-10300071-B2
Application number	US-201615248844-A
Country	US
Kind code	B2
Filing date	Aug 26, 2016
Priority date	Feb 28, 2014
Publication date	May 28, 2019
Grant date	May 28, 2019

Abstract

A composition comprising a drug selected from the group consisting of an arylphenoxypropionate derivative, an aryloxyphenoxyacetate derivative, an aryloxyphenylacetate derivative, a substituted quinol, or a salt, hydrate, or prodrugs thereof, or a combination thereof, in an amount and formulation sufficient to inhibit a mycobacterium is disclosed.

First claim

The invention claimed is:

1. A composition comprising:
a drug comprising 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylpropanamide, 1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, or 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methoxypropanamide, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in an amount and formulation sufficient to inhibit a mycobacterium expressing Acetyl-CoA carboxyltransferase β-subunit D6 (AccD6); and
a pharmaceutically acceptable carrier.

2. The composition of claim 1 , further comprising a salt, a buffer, a preservative, or a solubility enhancer.

3. The composition of claim 1 , wherein the mycobacterium is Mycobacterium tuberculosis or Mycobacterium bovis.

4. A method of inhibiting a mycobacterium expressing Acetyl-CoA carboxyltransferase β-subunit D6 (AccD6) comprising:
administering a composition comprising a drug, having the formula:

wherein:
R 1 is selected from —OH, —OCH 3 , —NHOCH 3 , —NHCH 3 , and —NHCH(CH 3 ) 2 groups;
R 2 and R 3 are both H or at least one of R 2 and R 3 is —CH 3 ; and
R 4 is selected from a 1,3-benzothiazole-2-yl, 1,3-benzothiazole-2-yl substituted with a halogen or —OCH 3 group, and quinoxaline-2-yl, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to the mycobacterium in an amount and for a time sufficient to inhibit AccD6 in the mycobacterium.

5. The method of claim 4 , wherein the mycobacterium is pathogenic.

6. The method of claim 4 , wherein the mycobacterium is selected from the group consisting of Mycobacterium tuberculosis or Mycobacterium bovis.

7. The method of claim 4 , wherein the composition is substantially nontoxic to animals.

8. The method of claim 4 , wherein the mycobacterium is drug resistant.

9. The method of claim 4 , wherein the mycobacterium is multi-drug resistant.

10. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 0.1 μM and 50 μM.

11. The method of claim 4 , wherein R 1 is selected from —OH, —OMe, —NHOCH 3 , —NHCH 3 , and —NHCH(CH 3 ) 2 groups;
R 2 and R 3 are both H or one of R 2 and R 3 is —CH 3 ; and
R 4 is 1,3-benzothiazole-2-yl.

12. The method of claim 4 , wherein the drug is 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methylpropanamide, 1-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(propan-2-yl)urea, or 2-{4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenyl}-N-methoxypropanamide.

13. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 0.3 μM and 20 μM.

14. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 1 μM and 10 μM.

15. The method of claim 4 , wherein the drug has a minimum inhibitory concentration for the mycobacterium of between 1 μM and 25 μM.

16. The method of claim 4 , wherein the drug has a unit dosage of between 1 mg/kg body weight and 500 mg/kg body weight.

17. The method of claim 4 , wherein the drug has a unit dosage of between 5 mg/kg body weight to about 350 mg/kg body weight.

18. The method of claim 4 , wherein the drug has a unit dosage of between 0 mg/kg body weight and about 200 mg/kg body weight.

Assignees

• Texas A & M Univ Sys

Inventors

• Reddy Manchi C M
• Sacchettini James C
• Zhou Nian E
• Mccutchen Billy F

Classifications

• A61P31/06

  for tuberculosis · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title