SMALL MOLECULE INHIBITORS OF BACTERIAL TOXINS
Described herein are compounds and compositions for use in treatment or prevention of an inflammatory bowel disease, gastrointestinal cancer, or a systemic bacterial infection in a subject in need thereof. The subject may be colonized by one or more pathogenic bacterial strains such as B. fragilis, E. faecalis , or C. perfringens . In certain aspects, the disclosure provides a method of diminishing the pathogenic effects of these bacterial strains by administering a compound that binds to and/or inhibits one or more toxins produced thereby.
1 . A compound of Formula IB:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
X is —NH—;
Y is —OH;
R 1 is alkyl, haloalkyl, -alkylene-OH, alkylene-Oalkyl, -alkylene-NH 2 , -alkylene-C(═O)NH 2 , heteroaralkyl, aryl, aralkyl, -alkylene-S-alkyl, -alkylene-S-haloalkyl, -alkylene-S-aralkyl, or -alkylene-S-heteroaralkyl;
R 2 is H, —(CH 2 ) n -aryl, —CH 2 -alkyl, —CH(Me)-alkyl, —CH 2 -heterocyclyl, —(CH 2 ) n -heteroaryl, or —CH 2 -haloalkyl;
R 3 is —OH, —O-alkyl, or —O-haloalkyl;
R 3a is H or halogen; and
n is an integer from 1-3,
provided that the compound is not
2 . The compound of claim 1 , wherein the compound of Formula IB has the structure of Formula IB-1:
or a stereoisomer or a pharmaceutically acceptable salt there.
3 . The compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl, —C 1 -C 6 alkylene-OH, haloalkyl, —C 1 -C 6 alkylene-O—(C 1 -C 3 alkyl), —(C 1 -C 3 alkylene)-S—(C 1 -C 3 alkyl), —(C 1 -C 3 alkylene)-S—(C 1 -C 3 haloalkyl), —(C 1 -C 3 alkylene)-SCH 2 -heteroaryl, phenyl, —CH 2 -phenyl, —CH 2 -heteroaryl, or —CH 2 C(═O)NH 2 .
4 . The compound of claim 1 , wherein R 1 is —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH(OH)CH 3 , —CH 2 CH 2 SCH 3 ,
—CH 2 -phenyl, —CH 2 -(4-methoxyphenyl), —CH 2 -(4-thiomethylphenyl), —CH 2 -(4-nitrophenyl), —CH 2 -(3-trifluoromethylphenyl), —CH 2 -(4-trifluoromethylphenyl), —CH 2 -(3-fluorophenyl), —CH 2 -(4-fluorophenyl), —CH 2 -(3-indolyl), —CH 2 -(4-imidazolyl),
—CH 2 C(═O)NH 2 ,
—CH(CH 3 )SCH 2 CH 3 , —CH(CH 3 )SCH 2 -(3-pyridyl), —CH(CH 3 )SCH 2 -(4-pyridyl), or —CH(CH 3 )SCH 2 CF 3 .
5 . The compound of claim 1 , wherein R 1 is ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, isopentyl, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CF 2 CF 3 , (C 1-3 alkylene)-OH, (C 1-3 alkylene)-O—CH 3 , (C 1-3 alkylene)-S—CH 3 , CH 2 -pyridyl, CH 2 -thiophenyl, CH 2 -oxazolyl, CH 2 -thiazolyl, CH 2 -phenyl, or phenyl.
6 . (canceled)
7 . (canceled)
8 . The compound of claim 1 , wherein R 1 is C 2-6 alkyl or phenyl.
9 . (canceled)
10 . The compound of claim 8 , wherein R 1 is a C 2-6 alkyl.
11 . The compound of claim 10 , wherein the C 2-6 alkyl is ethyl or isobutyl.
12 . The compound of claim 11 , wherein the C 2-6 alkyl is ethyl.
13 . (canceled)
14 . The compound of claim 8 , wherein R 1 is phenyl.
15 . The compound of claim 14 , wherein the phenyl is substituted with one or more halogen, —OH, —OMe, —CHF 2 , —CH 2 F, or —CF 3 .
16 . The compound of claim 13 , wherein the phenyl is 4-fluorophenyl.
17 . (canceled)
18 . The compound of claim 3 , wherein the C 1-3 alkylene is a methylene.
19 . The compound of claim 3 , wherein R 2 is —CH 2 —C 1-6 alkyl), —(CH 2 ) n —C 6-12 aryl), or —(CH 2 ) n -(5- to 14-membered heteroaryl).
20 . The compound of claim 19 , wherein R 2 is —(CH 2 ) n -(5- to 14-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S).
21 . (canceled)
22 . The compound of claim 20 , wherein the 5- to 14-membered heteroaryl is pyridyl, thiophenyl, thiazolyl, oxazolyl, or indolyl.
23 . (canceled)
24 . The compound of claim 22 , wherein the 5- to 14-membered heteroaryl is 3-pyridyl or 5-indolyl.
25 . The compound of claim 19 , wherein n is 1 or 2.
26 . A compound of Formula V:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
X is —NH—;
Y is —OH—;
R 2 is —(CH 2 ) n -aryl, —CH 2 -alkyl, —CH(Me)-alkyl, —(CH 2 ) n -heteroaryl, or —CH 2 -haloalkyl; and
R 3 is H, alkyl, -alkylene-NR 5 R 6 , haloalkyl, aryl, aralkyl, or heteroaryl, each of which is optionally substituted;
R 5 is H, alkyl, aralkyl, heteroaralkyl, —C(O)alkyl, —C(O)aryl, —C(O)heteroaryl, or —C(O)aralkyl;
R 6 is H, alkyl, or aryl; and
n is an integer from 1-3.
27 .- 62 . (canceled)
63 . The compound of claim 1 , wherein the compound of Formula I has the structure:
64 . The compound of claim 1 , wherein the compound of Formula I has the structure:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
65 . The compound of claim 26 , wherein the compound has structure:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
66 . (canceled)
67 . (canceled)
68 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
69 . A method of treating inflammatory bowel disease in a subject in need thereof, the method comprising, administering to the subject a therapeutically effective amount of a compound of claim 1 .
70 . (canceled)
71 . A method of treating gastrointestinal (GI) cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
72 . (canceled)
73 . A method of treating a systemic bacterial infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
74 .- 101 . (canceled)
102 . The compound of claim 1 , wherein R 3 is —OH.
103 . The compound of claim 1 , wherein the compound of Formula (I) has the structure:
or a pharmaceutically acceptable salt thereof.