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. They 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 stmins by administering a compound that binds to and/or inhibits one or more toxins produced thereby.
1 .- 100 . (canceled)
101 . A compound of Formula VB:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
X is —C(O)— or —S(O) 2 —;
Y is —SC(O)R 1 or —SH;
R a is H, alkyl, haloalkyl, aryl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl;
R 1 is alkyl, haloalkyl, or —NR 4 R 5 ;
R 2 is H, alkyl, or cycloalkyl;
R 3 is —OH, alkoxy, —O-alkylene-NR 7 R 8 , —C(O)R, or —C(O)N(H)-alkylene-C(O)NR 7 R 8 , wherein the alkylene is optionally substituted;
R 3a is H, alkyl, halogen, alkoxy, haloalkyl or haloalkoxy;
R 4 , R, R 7 , and R 8 are each independently H, alkyl, cycloalkyl, —CH 2 cycloalkyl, aryl, or —CH 2 aryl;
R 6 is alkyl, haloalkyl, alkoxy, or —N(H)alkyl;
m is 0, 1, 2, or 3; and
n is 1 or 2,
wherein when n is 1, R is not H.
102 . The compound of claim 101 , wherein X is —C(O)—.
103 . The compound of claim 101 , wherein the compound of Formula (VB) has a structure according to:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
104 . The compound of claim 101 , wherein Y is —SC(O)R 1 , wherein R 1 is C 1-5 alkyl or —NR 4 R 5 .
105 . The compound of claim 101 , wherein R 4 and R 5 are each independently H, alkyl, or optionally substituted phenyl.
106 . The compound of claim 101 , wherein R 2 is H.
107 . The compound of claim 101 , wherein R 3 is alkoxy, —O-alkylene-NR 7 R 8 , —C(O)R 6 , or —C(O)N(H)-alkylene-C(O)NR 7 R 8 .
108 . The compound of claim 107 , wherein:
(i) the alkylene is a CI-3alkylene optionally substituted with oxo, alkyl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, alkylene-aryl, or alkylene-heteroaryl; or
(ii) the —O-alkylene-NR 7 R 8 is
wherein R b is H, alkyl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, alkylene-aryl, or alkylene-heteroaryl, optionally wherein R b is H, —C 1-5 alkyl, or —CH 2 aryl; and/or
(iii) the —C(O)N(H)-alkylene-C(O)NR 7 R 8 is
wherein R c is H, alkyl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, alkylene-aryl, or alkylene-heteroaryl, optionally wherein R c is —C 1-5 alkyl, or —CH 2 aryl; and/or
(iv) the alkoxy is —OMe.
109 . The compound of claim 101 , wherein R 6 is alkyl, haloalkyl, or alkoxy.
110 . The compound of claim 109 , wherein R 6 is Me, Et, CH 2 CF 3 , —OMe, —CH 2 O(C 1-5 alkyl), —CH 2 S(C 1-5 alkyl), or —CH 2 N(H)(C 1-5 alkyl).
111 . The compound of claim 101 , wherein R 7 and R 8 are each independently H, Me, or —CH 2 Ph.
112 . The compound of claim 101 , wherein R a is H, alkyl, haloalkyl, or alkylene-cycloalkyl.
113 . The compound of claim 112 , wherein R a is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isoamyl, or neopentyl.
114 . The compound of claim 101 , wherein m is 0 or 1.
115 . The compound of claim 101 , wherein n is 1.
116 . The compound of claim 101 , wherein R 3a is H, F, Me, i-Pr, CF 3 , CF 2 H, —CH 2 F, or —OMe.
117 . The compound of claim 101 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
118 . A pharmaceutical composition comprising a compound of claim 101 and a pharmaceutically acceptable carrier or excipient.
119 . A method of treating inflammatory bowel disease in a subject in need thereof comprising, administering to the subject a therapeutically effective amount of the compound of claim 101 .
120 . A method of treating gastrointestinal (GI) cancer in a subject in need thereof, comprising, administering to the subject a therapeutically effective amount of the compound of claim 101 .
121 . A method of treating a systemic bacterial infection in a subject in need thereof comprising, administering to the subject a therapeutically effective amount of the compound of claim 101 .
122 . The method of claim 119 , wherein the subject is colonized by one or more pathogenic bacterial strain, wherein the pathogenic bacterial strain is a strain of B. fragilis expressing the BFT toxin, a strain of E. faecalis expressing the gelatinase GelE, or a strain of C. perfringens expressing the collagenase ColA.