4-oxazolidinone antimicrobial agents
Provided herein are oxazolidinone derivatives that can exhibit anti-microbial activity and/or activity as biofilm modulating agents (e.g., activity as biofilm inhibitors and/or activity as biofilm dispersal agents). The compounds can exhibit potent activity anti-microbial activity (e.g., potent activity against Gram-positive positive bacteria including methicillin-resistant Staphylococcus aureus ). The compounds can exhibit potent activity against biofilms. In some cases, the compounds can exhibit both anti-microbial activity and biofilm modulation properties.
1. A compound defined by Formula I
or a pharmaceutically acceptable salt or prodrug thereof, wherein
X is O;
R 1 is chosen from alkyl, cycloalkyl, and alkylcycloalkyl each optionally substituted with one or more substituents individually chosen from R 5 ;
R 2 is chosen from alkyl, haloalkyl, aryl, cycloalkyl, alkylaryl, and alkylcycloalkyl, each optionally substituted with one or more substituents individually chosen from R 5 ;
R 3 is hydrogen;
R 4 is hydrogen; and
R 5 is chosen from hydroxy, halogen, —CN, —NO 2 , amino, alkylamino, dialkylamino, alkyl, haloalkyl; alkylthio; haloalkylthio; alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl, alkylcycloheteroalkyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylaminocarbonyl, heteroalkylaminocarbonyl, dialkylaminocarbonyl, and heterodialkylaminocarbonyl.
2. The compound of claim 1 , wherein R 1 is a C 1 -C 4 alkyl group.
3. The compound of claim 2 , wherein R 1 is a branched C 3 -C 4 alkyl group.
4. The compound of claim 3 , wherein R 1 is an isopropyl group.
5. The compound of claim 1 , wherein the compound is defined by Formula II
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is chosen from alkyl, cycloalkyl, and alkylcycloalkyl, each optionally substituted with one or more substituents individually chosen from R 5 ;
R 3 is hydrogen;
R 6 is chosen from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, alkylaryl, alkylcycloalkyl, each optionally substituted with one or more substituents individually chosen from R 5 ; and
R 5 is chosen from hydroxy, halogen, —CN, —NO 2 , amino, alkylamino, dialkylamino, alkyl, haloalkyl; alkylthio; haloalkylthio; alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl, alkylcycloheteroalkyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylaminocarbonyl, heteroalkylaminocarbonyl, dialkylaminocarbonyl, and heterodialkylaminocarbonyl.
6. The compound of claim 5 , wherein R 6 comprises a C 1 -C 8 alkyl group.
7. The compound of claim 1 , wherein the compound is defined by Formula III
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is chosen from alkyl, cycloalkyl, and alkylcycloalkyl;
R 3 is hydrogen;
R 7 is chosen from hydrogen, halogen, hydroxyl, —CN, —NO 2 , amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl, alkylcycloheteroalkyl alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylaminocarbonyl, heteroalkylaminocarbonyl, dialkylaminocarbonyl, and heterodialkylaminocarbonyl, each optionally substituted with one or more substituents individually chosen from R 5 ; and
R 5 is chosen from hydroxy, halogen, —CN, —NO 2 , amino, alkylamino, dialkylamino, alkyl, haloalkyl; alkylthio; haloalkylthio; alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl, alkylcycloheteroalkyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylaminocarbonyl, heteroalkylaminocarbonyl, dialkylaminocarbonyl, and heterodialkylaminocarbonyl.
8. A biofilm preventing, removing, or inhibiting composition comprising a carrier and an effective amount of a compound defined by claim 1 .
9. A method of treating a subject infected with a bacterium comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
10. A method of controlling biofilm formation on a substrate comprising contacting the substrate with a compound defined by claim 1 in an amount effective to inhibit biofilm formation.
11. A medical device comprising:
(a) a medical device substrate; and
(b) an effective amount of a compound of claim 1 , either coating the substrate, or incorporated into the substrate, wherein said effective amount of said compound prevents or inhibits the growth of a biofilm thereon.