Compounds for treatment of fluoroquinolone-resistant bacteria
Compounds that specifically kill fluoroquinolone (FQ) resistant bacteria have been developed and are described herein. The FQs are the most commonly prescribed antibiotics to adults in the U.S. and thus are extremely important drugs. However, bacterial resistant to these drugs is now ubiquitous in some of the most common and deadly Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Indeed, FQs are no longer indicated for treatment of MRSA and VRE infections because of such resistance. The compounds have specific and potent activity versus MRSA and VRE.
1. A compound of Formula I:
wherein
R 1 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
R 2 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
R 3 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched; and
R 4 is H, (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
provided that when R 4 is H, R 1 , R 2 , and R 3 are not each methyl.
2. The compound of claim 1 wherein R 1 is methyl, ethyl, or propyl.
3. The compound of claim 1 wherein R 2 is methyl, ethyl, or propyl.
4. The compound of claim 1 wherein R 3 is methyl, ethyl, propyl, butyl, iso-butyl, pentyl, neo-pentyl, or hexyl.
5. The compound of claim 1 wherein R 4 is H or methyl.
6. The compound of claim 1 wherein R 1 is methyl or ethyl; R 2 is methyl, ethyl, or propyl; R 3 is methyl, ethyl, propyl, or butyl; and R 4 is H or methyl.
7. The compound of claim 1 that is active against fluoroquinolone resistant bacteria with an MIC of less than 4 μg mL −1 .
8. The compound of claim 1 that is active against fluoroquinolone resistant bacteria with an MIC of less than 0.3 μg mL −1 .
9. The compound of claim 1 selected from compounds 2-15:
10. A pharmaceutical composition comprising a compound claim 1 in combination with a pharmaceutically acceptable diluent, excipient, or carrier.
11. A method of killing or inhibiting the growth of a bacteria comprising contacting a bacteria with an effective antibacterial amount of a compound of claim 1 .
12. The method of claim 11 wherein the bacteria is methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE).
13. A method of treating a bacterial infection in a subject comprising administering to a subject having a bacterial infection an effective amount of a compound of claim 1 .
14. A method of treating an infection caused by fluoroquinolone-resistant bacteria comprising administering to a mammal in need of such treatment an effective antibacterial amount of a compound of Formula II:
wherein
R 1 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
R 2 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
R 3 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched; and
R 4 is H, (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched; provided that when R 4 is H, R 1 , R 2 , and R 3 are not each methyl;
in combination with the administration of an effective antibacterial amount of a fluoroquinolone antibiotic, thereby killing or inhibiting the growth of the fluoroquinolone-resistant bacteria and treating the infection.
15. The method of claim 14 wherein the fluoroquinolone-resistant bacteria are gram positive bacteria.
16. The method of claim 14 wherein the infection is caused methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE).
17. A method of making a compound of Formula I:
wherein
R 1 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
R 2 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
R 3 is (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched; and
R 4 is H, (C 1 -C 12 )alkyl, (C 1 -C 12 )alkyl(C 3 -C 12 )cycloalkyl, or (C 3 -C 12 )cycloalkyl, where alkyl can be straight or branched;
comprising contacting a compound of Formula III:
wherein R 1 , R 2 , and R 3 are as defined for Formula I;
with a dihaloalkane in the presence of a base and a suitable solvent to provide the compound of Formula I.
18. The method of claim 17 wherein the dihaloalkane is dibromomethane or 1,1-dibromoethane.