Prochelators as broad-spectrum antimicrobial agents and methods of use
The present disclosure provides methods of treating (including ameliorating and/or preventing) pathogenic infections by administering a therapeutically effective amount of a prochelator. The present disclosure further provides pharmaceutical compositions and a kit comprising the prochelator therein.
1. A method of treating pathogenic infections in a subject comprising administering to the subject a therapeutically effective amount of a prochelator such that the infection is treated, wherein said prochelator is a compound of Formula I:
wherein:
Y is a covalent bond or —O—R 7 —R 8 —, where R 7 is —CH 2 — or —CO 2 CH 2 — and R 8 is phenylene;
n and m are each an integer from 1 to 3;
each R 1 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy;
R 5 and R 6 are independently selected H, alkyl, or haloalkyl, or together form an alkylene bridge, which alkylene bridge may be unsubstituted or substituted from 1 to 4 times with alkyl, halo, cycloalkyl, aryl, a fused cycloalkyl or a fused aryl ring;
each X is independently selected from the group consisting of N, O, and CH; and
dashed lines represent optional double bonds;
or a pharmaceutically acceptable salt or prodrug thereof, wherein the pathogenic infection comprises a pathogen, wherein the pathogen is fungal or bacterial.
2. The method of claim 1 , wherein said compound is of Formula I and is selected from the group consisting of:
wherein:
Y is a covalent bond or —O—R 7 —R 8 —, where R 7 is —CH 2 — or —CO 2 CH 2 — and R 8 is phenylene, which phenylene is unsubstituted or substituted from 1 to 4 times with independently selected halo or alkyl;
n and m are each an integer from 1 to 3;
each R 1 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy; and
R 5 and R 6 are independently selected H, alkyl, or haloalkyl, or together form an alkylene bridge, which alkylene bridge may be unsubstituted or substituted from 1 to 4 times with alkyl, halo, cycloalkyl, aryl, a fused cycloalkyl or a fused aryl ring;
or a pharmaceutically acceptable salt or prodrug thereof.
3. The method of claim 1 , wherein Y is a covalent bond or —O—R 7 —R 8 —, where R 7 is —CH 2 — or —CO 2 CH 2 — and said R 8 phenylene is unsubstituted or substituted from 1 to 4 times with independently selected halo or alkyl.
4. The method of claim 1 , wherein R 5 and R 6 are independently selected H, alkyl, or haloalkyl.
5. The method of claim 1 , wherein R 5 and R 6 together form an alkylene bridge, which alkylene bridge may be unsubstituted or substituted from 1 to 4 times with alkyl, halo, cycloalkyl, aryl, a fused cycloalkyl or a fused aryl ring.
6. The method of claim 1 , wherein R 5 and R 6 together form a C2 alkylene bridge having a bicyclic cycloalkyl substituted thereon, which C2 alkylene bridge and/or bicyclic cycloalkyl may be unsubstituted or substituted from 1 to 4 times with alkyl or halo.
7. The method of claim 1 , wherein said compound has the formula:
or a pharmaceutically acceptable salt or prodrug thereof.
8. The method of claim 1 , wherein the pathogen comprises fungal pathogen.
9. The method as in claim 8 , wherein the fungal pathogen comprises a yeast.
10. The method as in claim 9 , wherein the yeast comprises C. neoformans.
11. The method as in claim 1 , wherein the pathogen comprises bacterial pathogen.
12. The method as in claim 11 , wherein the bacterial pathogen comprises a gram-negative bacteria.
13. The method as in claim 12 , wherein the gram-negative bacteria comprises E. coli.
14. The method as in claim 11 , wherein the bacterial pathogen comprises a gram-positive bacteria.
15. The method as in claim 14 , wherein the gram-positive bacteria is selected from the group consisting of S. aureus and Mycobacterium.
16. The method according to claim 14 , wherein the gram-positive bacteria comprises S. aureus.
17. The method as in claim 15 , wherein the Mycobacterium comprises M. tuberculosis, M. marinum , or M. leprae.
18. The method of claim 1 , wherein the prochelator is administered either at the onset of disease, prior to disease symptoms or after the onset of disease symptoms.
19. The method of claim 1 , wherein a subject is a mammal.
20. The method as in claim 17 , wherein the subject is human.
21. The method of claim 1 , wherein said compound has the structure of Formula I:
and said pathogen comprises a fungal pathogen.
22. The method of claim 1 , wherein said compound has the structure of Formula IA:
and said pathogen comprises a yeast pathogen.
23. The method of claim 1 , wherein said compound has the formula:
and said pathogen comprises C. neoformans .