Antibiotic conjugates
Provided are antibiotic conjugate compounds of formula (I) and pharmaceutical compositions thereof. Also provided are methods of treating treat bacterial infection, including infections caused by Gram-negative bacteria, by administering compounds of formula (I).
1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Sid is a siderophore moiety selected from the group consisting of
L is a bond, —C(O)—, —C(O)NHCH(R 1 )—C(O)—, —C(O)OCH(R 2 )—C(O)—, or
R 1 and R 2 are each hydrogen, C 1-6 alkyl, cyano, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein the C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, OH, oxo, and cyano;
R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or Rand R 4 together with the C atom to which they are attached form a 3- to 8-membered ring;
Cyc 1 is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein the 6- to 12-membered aryl or 5- to 12-membered heteroaryl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, OH, oxo, and cyano;
Y is O or NH;
G is -G 1 or —X—(CH 2 ) p C(O)-G 1 ;
X is O or S;
p is 0, 1, 2, 3, 4, or 5; and
G 1 is a drug moiety attached through an oxygen or nitrogen atom,
a wherein G 1 is an oxazolidinone antibiotic.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is bond, —C(O)—, or —C(O)NHCH(R 1 )—C(O)—.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —C(O)NHCH(R 1 )—C(O)—.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently hydrogen or C 1-6 alkyl.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the C atom to which they are attached form a 3- to 8-membered ring.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the C atom to which they are attached form
wherein t is 0, 1, 2, 3, 4, or 5.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cyc 1 is
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is NH.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is G 1 .
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is —OC(O)-G 1 .
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L is bond, —C(O)—, or —C(O)NHCH(R 1 )—C(O)—,
R 1 is phenyl; and
G is G 1 or —OC(O)-G 1 .
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
15 . A compound of formula (A):
wherein
Siderophore is selected from the group consisting of
Drug is an oxazolidinone antibiotic;
n is 0 or 1; and
m is 0 or 1,
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 , having a structure of
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Sid is a siderophore moiety
18 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19 . A method of treating bacterial infection, wherein the infection is caused by Acinetobacter, Pseudomonas , Enterobacteria, or combinations thereof, comprising administering to a subject infected by a bacterium an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20 . The method of claim 19 , wherein the bacterium is a Gram-negative bacterium.
21 . The method of claim 19 , wherein the bacterium is an antibiotic-resistant bacterium.
22 . The method of claim 19 , wherein the bacterium produces a β-lactamase.
23 . The method of claim 19 , wherein the infection is caused by Acinetobacter baumannii.
24 . A method of killing or inhibiting the growth of a bacterium, wherein the bacterium is Acinetobacter, Pseudomonas , Enterobacteria, or combinations thereof, comprising contacting the bacterium with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
25 . The method of claim 24 , wherein the bacterium is a Gram-negative bacterium.
26 . The method of claim 24 , wherein the bacterium is an antibiotic-resistant bacterium.
27 . The method of claim 24 , wherein the bacterium produces a β-lactamase.
28 . The method of claim 24 , wherein the bacterium is by Acinetobacter baumannii.