US 2013/0281503 A1Published application

Modulation of response regulators by imidazole derivatives

AssigneeNorth Carolina State University

InventorsChristian Melander, John Cavanagh, Richele Thompson

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Abstract

The present disclosure provides methods and compositions useful for screening agents for activity in modulating response regulator signaling activity, which is, in turn, useful for determining whether these agents modulate biofilm formation or lowers the minimum inhibitory concentration (MIC) of an antibiotic, useful in determining or selecting optimum agents and/or agent dosages in modulating a biofilm of interest or lowering the minimum inhibitory concentration (MIC) of an antibiotic, and useful as a research tool for studying response regulators.

Claims34

Dependent claims

A method of screening:

a compound of Formula (X)(I)(a):
wherein:
R5 is an alkyl, alkenyl or alkynyl having an amide group substituted thereon;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20, saturated or unsaturated;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I)(a)(1):
wherein:
R1a, R1b, R2, R3, and R5 are each independently selected from H and alkyl;
R6 is selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from H and alkyl;
and
n=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (II):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru and Rv is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
and
m=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (IV):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (V):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Ry, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20
or a pharmaceutically acceptable salt or prodrug thereof,
or
a compound of Formula (VI):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof, for inhibition of biofilm formation, modulation of microorganism growth, or lowering the minimum inhibitory concentration (MIC) of an antibiotic, said method comprising:
(a) contacting said compound to a response regulator protein or a portion thereof, and then
(b) detecting the presence or absence of binding of said compound to said response regulator protein or portion thereof, said binding indicating said compound has activity in inhibition of biofilm formation, modulation of microorganism growth or lowering the minimum inhibitory concentration (MIC) of an antibiotic.

76 more elements

A method of selecting a compound of Formula (X)(I)(a):

wherein:
R5 is an alkyl, alkenyl or alkynyl having an amide group substituted thereon;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20, saturated or unsaturated;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I)(a)(1):
wherein:
R1a, R1b, R2, R3, and R5 are each independently selected from H and alkyl;
R6 is selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from H and alkyl;
and
n=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (II):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru and Rv is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
and
m=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (IV):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (V):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20
or a pharmaceutically acceptable salt or prodrug thereof,
or
a compound of Formula (VI):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
for activity in treating, reducing or removing a biofilm of interest, modulation of microorganism growth or lowering the minimum inhibitory concentration (MIC) of an antibiotic, comprising:
(a) providing a sample of said biofilm of interest, said sample comprising a response regulator protein or portion thereof,
(b) assaying for binding of said compound to said response regulator protein or portion thereof, said binding indicating said compound has activity in treating, reducing or removing said biofilm of interest, modulating microorganism growth or lowering the minimum inhibitory concentration (MIC) of an antibiotic.

76 more elements

A composition comprising:

(a) an isolated response regulator protein or a portion thereof;
and
(b) a compound of Formula (X)(I)(a):
wherein:
R5 is an alkyl, alkenyl or alkynyl having an amide group substituted thereon;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20, saturated or unsaturated;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I)(a)(1):
wherein:
R1a, R1b, R2, R3, and R5 are each independently selected from H and alkyl;
R6 is selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from H and alkyl;
and
n=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (II):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru and Rv is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
and
m=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (IV):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (V):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20
or a pharmaceutically acceptable salt or prodrug thereof,
or
a compound of Formula (VI):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof.

76 more elements

A compound of Formula (X)(I)(a):

wherein:
R5 is an alkyl, alkenyl or alkynyl having an amide group substituted thereon;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20, saturated or unsaturated;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I)(a)(1):
wherein:
R1a, R1b, R2, R3, and R5 are each independently selected from H and alkyl;
R6 is selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from H and alkyl;
and
n=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (II):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru and Rv is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
and
m=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (IV):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (V):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20
or a pharmaceutically acceptable salt or prodrug thereof,
or
a compound of Formula (VI):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
wherein said compound is coupled to a detectable group.

74 more elements

A method of inhibiting biofilm formation of a cellular species capable of such formation, said method comprising binding of a response regulator of said cellular species with an exogenous agent, said response regulator selected from among a OmpR protein and a BfmR protein, and said agent provided in an amount effective to modulate biofilm-mediating communication of said cellular species, to thereby inhibit biofilm formation of said cellular species.

Dependencies are inferred from the claim text.

Facts

Application: 13/871,259Filed 26 Apr 2013
Priority: 29 Oct 2010
Published: 24 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

G01N 33/566
Immunoassay; Biospecific binding assay; Materials therefor: using specific carrier or receptor proteins as ligand binding reagents where possible…
A01N 43/90
Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds: having two or more relevant hetero rings,…
A61K 31/4168
1,3-Diazoles: having a nitrogen attached in position 2, e.g. clonidine
A61K 31/4192
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,3-Triazoles

Family

Application61/408,378Us provisional application · filed 29 Oct 2010
Application13/871,259Continuation
US 2013/0281503 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method of screening:

a compound of Formula (X)(I)(a):
wherein:
R5 is an alkyl, alkenyl or alkynyl having an amide group substituted thereon;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20, saturated or unsaturated;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (I)(a)(1):
wherein:
R1a, R1b, R2, R3, and R5 are each independently selected from H and alkyl;
R6 is selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
and
each occurrence of Rx and Ry is present or absent (depending upon chain saturation), and is independently selected from H and alkyl;
and
n=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (II):
wherein:
each occurrence of R1, R2, R3, R4, R5, R6, R7 and R8 (depending upon valence requirement) is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru and Rv is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
and
m=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (IV):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof,
a compound of Formula (V):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Ry, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20
or a pharmaceutically acceptable salt or prodrug thereof,
or
a compound of Formula (VI):
wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
each occurrence of Rx, Ry, Ru, Rv, Rz and Rw is present or absent (depending upon chain saturation), and is independently selected from the group consisting of:
H, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfone, sulfoxide, oxo, oxy, nitro, carbonyl, carboxy, amino acid sidechain, amino acid and peptide;
A, B, D, E, F, G and H are each independently selected from carbon, N, S and O, wherein at least one of D, E, F, G and H is carbon;
and
n=0 to 20;
m=0 to 20;
and
p=0 to 20;
or a pharmaceutically acceptable salt or prodrug thereof, for inhibition of biofilm formation, modulation of microorganism growth, or lowering the minimum inhibitory concentration (MIC) of an antibiotic, said method comprising:
(a) contacting said compound to a response regulator protein or a portion thereof, and then
(b) detecting the presence or absence of binding of said compound to said response regulator protein or portion thereof, said binding indicating said compound has activity in inhibition of biofilm formation, modulation of microorganism growth or lowering the minimum inhibitory concentration (MIC) of an antibiotic.

76 more elements

Facts

Application

13/871,259Filed 26 Apr 2013

Priority

29 Oct 2010

Published

24 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

G01N 33/566
Immunoassay; Biospecific binding assay; Materials therefor: using specific carrier or receptor proteins as ligand binding reagents where possible…
A01N 43/90
Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds: having two or more relevant hetero rings,…
A61K 31/4168
1,3-Diazoles: having a nitrogen attached in position 2, e.g. clonidine
A61K 31/4192
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,3-Triazoles