Small molecule inhibitors of the BfrB:Bfd interaction

12251,370

17/299267

December 03, 2019

The present technology provides compounds of Formula I and related methods for treating a bacterial infection as well as methods for inhibiting interaction of a bacterioferritin and a bacterioferritin-associated ferredoxin.

BOARD OF SUPERVISORS OF LOUISIANA STATE UNIVERSITY AND AGRICULTURAL AND MECHANICAL COLLEGE (Baton Rouge, LA, US); UNIVERSITY OF KANSAS (Lawrence, KS, US); THE BOARD OF REGENTS FOR OKLAHOMA STATE UNIVERSITY (Stillwater, OK, US)

Board of Supervisors of Louisiana State University and Agricultural and Mechanical College (Baton Rouge, LA, US), University of Kansas (Lawrence, KS, US), The Board of Regents for Oklahoma State University (Stillwater, OK, US)

1. A compound according to Formula I [chemical expression included] or a pharmaceutically acceptable salt and/or a solvate thereof, wherein R 2 and R 3 are each independently C 1 -C 6 alkoxy, H, or OH, and R 1 is C 1 -C 6 alkoxy, H, OH, or halo, and at least one of R 1 , R 2 , and R 3 is OH or C 1 -C 6 alkoxy; R 4 and R 5 are each independently H or halo; X 1 is CH 2 or O; and m is 0, 2, 3, 4, or 5; provided that when X 1 is O, m is not 0; and provided that when R 2 is OH, R 1 , R 3 , R 4 , and R 5 are each H, X 1 is CH 2 , and m is not 0.

2. The compound of claim 1 , wherein R 1 , R 2 , and R 3 are each independently H or OH, and at least one of R 1 , R 2 , and R 3 is OH; R 4 and R 5 are each independently H or halo; X 1 is CH 2 or O; and m is 0, 2, 3, 4, or 5; provided that when X 1 is O, m is not 0; and provided that when R 2 is OH, R 1 , R 3 , R 4 , and R 5 are each H, X 1 is CH 2 , and m is not 0.

3. The compound of claim 1 , wherein the compound is of Formula IA [chemical expression included] or a pharmaceutically acceptable salt and/or a solvate thereof, wherein n is 1, or 3; provided that R 2 is not OH when n is 1 and R 1 , R 3 , R 4 , and R 5 are each H.

4. The compound of claim 1 , wherein one of R 1 and R 3 is OH, one of R 1 and R 3 is H, and R 2 is H.

5. The compound of claim 1 , wherein R 4 and R 5 are each independently H, chlorine, or fluorine.

6. The compound of claim 1 , wherein R 4 and R 5 are each independently H or chlorine.

7. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising: an amount of a compound of claim 1 ; and a pharmaceutically acceptable carrier, wherein the amount of the compound is effective for treating a bacterial infection in a subject.

9. The pharmaceutical composition of claim 8 , wherein the bacterial infection comprises a Gram-negative bacterial infection.

10. The pharmaceutical composition of claim 8 , wherein the bacterial infection comprises a Pseudomonas aeruginosa infection, a Acinetobacter baumannii infection, a Klebsiella pneumonia infection, a Yersinia pestis infection, a Shigella dysenteriae infection, a Enterobacter sp. infection, a Acinetobacter sp. infection, a Salmonella typhimurium infection, a Serratia sp. infection, or a combination of any two or more thereof.

11. A method of treating a bacterial infection in a subject, the method comprising administering an effective amount of a compound of claim 1 to the subject.

12. The method of claim 11 , the method further comprising administering an effective amount of fluoroquinolone antibiotic to the subject.

13. The method of claim 11 , wherein the bacterial infection comprises a Gram-negative bacterial infection.

14. The method of claim 11 , wherein the bacterial infection comprises a Pseudomonas aeruginosa infection, a Acinetobacter baumannii infection, a Klebsiella pneumonia infection, a Yersinia pestis infection, a Shigella dysenteriae infection, a Enterobacter sp. infection, a Acinetobacter sp. infection, a Salmonella typhimurium infection, a Serratia sp. infection, or a combination of any two or more thereof.

15. A method of treating a bacterial infection in a subject, the method comprising administering a pharmaceutical composition of claim 8 the subject.

16. The method of claim 15 , wherein the bacterial infection comprises a Gram-negative bacterial infection.

17. The method of claim 15 , wherein the bacterial infection comprises a Pseudomonas aeruginosa infection, a Acinetobacter baumannii infection, a Klebsiella pneumonia infection, a Yersinia pestis infection, a Shigella dysenteriae infection, a Enterobacter sp. infection, a Acinetobacter sp. infection, a Salmonella typhimurium infection, a Serratia sp. infection, or a combination of any two or more thereof.

18. A method of inhibiting interaction of a bacterioferritin and a bacterioferritin-associated ferredoxin, the method comprising contacting a compound of claim 1 the bacterioferritin, the bacterioferritin-associated ferredoxin, or both the bacterioferritin and the bacterioferritin-associated ferredoxin.

19. The method of claim 18 , wherein the bacterioferritin is a Pseudomonas aeruginosa , a Acinetobacter baumannii , a Klebsiella pneumonia , a Yersinia pestis , a Shigella dysenteriae , a Enterobacter sp., a Acinetobacter sp., a Salmonella typhimurium , a Serratia sp., or a combination of any two or more thereof.

20. The method of claim 18 , wherein the bacterioferritin-associated ferredoxin is a Pseudomonas aeruginosa bacterioferritin-associated ferredoxin, a Acinetobacter baumannii bacterioferritin-associated ferredoxin, a Klebsiella pneumonia bacterioferritin-associated ferredoxin, a Yersinia pestis bacterioferritin-associated ferredoxin, a Shigella dysenteriae bacterioferritin-associated ferredoxin, a Enterobacter sp. bacterioferritin-associated ferredoxin, a Acinetobacter sp. bacterioferritin-associated ferredoxin, a Salmonella typhimurium bacterioferritin-associated ferredoxin, a Serratia sp. bacterioferritin-associated ferredoxin, or a combination of any two or more thereof.

2014/0296310 October 2014 Alex et al.
2022/0031661 February 2022 Rivera et al.
WO-2017/049409 March 2017

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