Antibacterial aminoglycoside analogs
Compounds having antibacterial activity are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q 1 , Q 2 , Q 3 , R 8 and R 9 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
1. A compound having the following structure (I):
or a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein:
Q 1 is hydrogen;
Q 2 is hydrogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 4 R 5 , —(CR 10 R 11 ) p R 12 ,
Q 3 is hydrogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 4 R 5 , —(CR 10 R 11 ) p R 12 ,
each R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 10 is, independently, hydrogen or C 1 -C 6 alkyl, or R 1 and R 2 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R 2 and R 3 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R 1 and R 3 together with the atoms to which they are attached can form a carbocyclic ring having from 4 to 6 ring atoms, or R 4 and R 5 together with the atom to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms;
each R 6 and R 7 is, independently, hydrogen, hydroxyl, amino or C 1 -C 6 alkyl, or R 6 and R 7 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms;
each R 9 is, independently, hydrogen or methyl;
each R 11 is, independently, hydrogen, hydroxyl, amino or C 1 -C 6 alkyl;
each R 12 is, independently, hydroxyl or amino;
each n is, independently, an integer from 0 to 4;
each m is, independently, an integer from 0 to 4; and
each p is, independently, an integer from 1 to 5, and
wherein at least one of Q 2 and Q 3 is —C(═NH)NR 4 R 5 .
2. A compound of claim 1 , wherein R 8 is hydrogen.
3. A compound of claim 1 , wherein each R 9 is methyl.
4. A compound of claim 1 , wherein Q 3 is hydrogen.
5. A compound of claim 1 , wherein Q 2 is —(CR 10 R 11 ) p R 12 .
6. A compound of claim 5 wherein each R 10 is hydrogen.
7. A compound of claim 6 wherein each R 11 is hydrogen.
8. A compound of claim 1 , wherein Q 2 is optionally substituted cycloalkylalkyl.
9. A compound of claim 8 wherein Q 2 is unsubstituted.
10. A compound of claim 8 wherein Q 2 is substituted with hydroxyl or amino.
11. A compound of claim 1 , wherein Q 2 is optionally substituted heterocyclylalkyl.
12. A compound of claim 11 wherein Q 2 is unsubstituted.
13. A compound of claim 11 wherein Q 2 is substituted with hydroxyl or amino.
14. A compound of claim 1 , wherein Q 3 is —(CR 10 R 11 ) p R 12 .
15. A compound of claim 14 wherein each R 10 is hydrogen.
16. A compound of claim 15 wherein each R 11 is hydrogen.
17. A compound of claim 1 , wherein Q 3 is optionally substituted cycloalkylalkyl.
18. A compound of claim 17 wherein Q 3 is unsubstituted.
19. A compound of claim 17 wherein Q 3 is substituted with hydroxyl or amino.
20. A compound of claim 1 , wherein Q 3 is optionally substituted heterocyclylalkyl.
21. A compound of claim 20 wherein Q 3 is unsubstituted.
22. A compound of claim 20 wherein Q 3 is substituted with hydroxyl or amino.
23. A compound of claim 1 , wherein Q 3 is optionally substituted heterocyclyl.
24. A compound of claim 23 wherein Q 3 is unsubstituted.
25. A compound of claim 23 wherein Q 3 is substituted with hydroxyl or amino.
26. A compound of claim 1 , wherein Q 2 is —C(═NH)NH 2 .
27. A compound of claim 1 , wherein Q 3 is —C(═NH)NH 2 .
28. A compound of claim 1 , wherein the compound is:
6′,2′-bis-Guanidinium-sisomicin;
6′-(2-Hydroxy-ethyl)-2′-guanidinium-sisomicin;
6′-(Methyl-trans-3-amino-cyclobutyl)-2′-guanidinium-sisomicin; or
6′-Methyl-2′-guanidinium-sisomicin.
29. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
30. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.