Methods for use of small molecule activators of hem-y / protoporphyrinogen oxidase (ppo)

Patent metadata

Field	Value
Publication number	US-2016213780-A1
Application number	US-201615004141-A
Country	US
Kind code	A1
Filing date	Jan 22, 2016
Priority date	Jan 22, 2015
Publication date	Jul 28, 2016
Grant date	—

Abstract

A method for treating a microbial infection involves administering an effective amount of a compound of the formula:

wherein R 1 is H, alkyl, aryl, heteroaryl, R 2 is H, halogen, alkyl, aryl, heteroaryl, R 3 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide, R 4 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide, R 5 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide, R 6 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide, R 7 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide, R 8 is —CR 3 , O, S, wherein R 5 and R 6 , R 7 and R 6 , R 5 and R 4 , R 4 and R 3 can cyclize forming a 3-10 member ring comprising C, O, S, and/or N optionally substituted with one or more R 3 ; and administering light therapy, such as a photodynamic therapy (PDT) light source.

First claim

What is claimed is:

1 . A method for treating a microbial infection, comprising:
administering an effective amount of a compound of the formula:

wherein,
R 1 is H, alkyl, aryl, heteroaryl;
R 2 is H, halogen, alkyl, aryl, heteroaryl;
R 3 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 4 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 5 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 6 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 7 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 8 is —CR 3 , O, S;

wherein R 5 and R 6 , R 7 and R 6 , R 5 and R 4 , R 4 and R 3 can cyclize forming a 3-10 member ring comprising C, O, S, and/or N optionally substituted with one or more R 3 ; and
administering light therapy.

2 . The method of claim 1 , wherein:
R 1 is H, alkyl, aryl; R 2 is H, halogen, alkyl, aryl, heteroaryl; R 3 is H, alkyl, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide, aryl, heteroaryl; R 4 is H, alkyl, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide; R 5 is H, alkyl, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide; R 6 is H, alkyl, aryl.

3 . The method of claim 1 , wherein
R 1 is H, CH 3 , or

R 2 is H, CH 3 , CH 2 CH 3 ,

R 3 is H, OH,

R 4 is H, OH,

or R 4 and R 5 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms;
R 5 is H, OH,

or R 4 and R 5 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms, or R 5 and R 6 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms;
R 6 is H, or R 5 and R 6 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms;
R 7 is H or OH; and
R 8 is O or S.

4 . The method of claim 1 , wherein the fermentation inhibitor is selected from the compounds set forth in Table 1.

5 . The method of claim 1 , wherein the compound is:

6 . The method of claim 1 , wherein the compound is provided in a pharmaceutical composition.

7 . The method of claim 1 , and further comprising administration of another compound or composition having microbial activity.

8 . The method of claim 1 , wherein the compound is administered topically.

9 . The method of claim 1 , wherein the light therapy is a photodynamic therapy.

10 . A method of activating HemY or PPO in a cell, including:
selecting the cell in which activation of HemY or PPO is desired; and contacting the cell with a compound of the formula:

wherein,
R 1 is H, alkyl, aryl, heteroaryl;
R 2 is H, halogen, alkyl, aryl, heteroaryl;
R 3 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 4 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 5 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 6 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 7 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 8 is —CR 3 , O, S;

wherein R 5 and R 6 , R 7 and R 6 , R 5 and R 4 , R 4 and R 3 can cyclize forming a 3-10 member ring comprising C, O, S, and/or N optionally substituted with one or more R 3 , thereby activating HemY or PPO in the cell.

11 . The method of claim 10 , wherein:
R 1 is H, alkyl, aryl; R 2 is H, halogen, alkyl, aryl, heteroaryl; R 3 is H, alkyl, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide, aryl, heteroaryl; R 4 is H, alkyl, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide; R 5 is H, alkyl, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide; R 6 is H, alkyl, aryl.

12 . The method of claim 10 , wherein
R 1 is H, CH 3 , or

R 2 is H, CH 3 , CH 2 CH 3 ,

R 3 is H, OH,

R 4 is H, OH,

or R 4 and R 5 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms;
R 5 is H, OH,

or R 4 and R 5 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms, or R 5 and R 6 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms;
R 6 is H, or R 5 and R 6 , taken together with the carbon atoms to which they are bonded, can form an aromatic ring containing 6 carbon atoms;
R 7 is H or OH; and
R 8 is O or S.

13 . A method for producing hemoproteins, comprising:
culturing a cell capable of generating hemoproteins; and contacting the cell with a compound of the formula:

wherein,
R 1 is H, alkyl, aryl, heteroaryl;
R 2 is H, halogen, alkyl, aryl, heteroaryl;
R 3 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 4 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 5 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 6 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 7 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R 8 is —CR 3 , O, S;

wherein R 5 and R 6 , R 7 and R 6 , R 5 and R 4 , R 4 and R 3 can cyclize forming a 3-10 member ring comprising C, O, S, and/or N optionally substituted with one or more R 3 .

14 . The method of claim 1 , wherein the fermentation inhibitor is selected from the compounds set forth in Table 1.

15 . The method of claim 13 , and further comprising separating a supernatant from the cultured cell; and isolating the hemoproteins from the supernatant.

16 . A S. aureus cell, comprising a construct including Phrt upstream of a nucleotide encoding the E. coli toxin RelE.

17 . A method of identifying a compound th

Assignees

• Univ Vanderbilt

Inventors

• Skaar Eric P
• Surdel Matthew
• Sulikowski Gary A
• Dutter Brendan
• Reid Paul
• Waterson Alex

Classifications

• A61N5/0624

  for eliminating microbes, germs, bacteria on or in the body · CPC title

• A61N5/062

  Photodynamic therapy, i.e. excitation of an agent · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C12Q2600/136

  Screening for pharmacological compounds · CPC title