Compounds, compositions and methods for controlling biofilms and bacterial infections

A method for treating, controlling, reducing or inhibiting a bacterial infection in a subject in need thereof by administering to the subject an effective amount of a composition comprising a compound having the following chemical structure:

• wherein:
• R1 is selected from the group consisting of hydrogen, hydroxyl, halide, methoxy, acetoxy, —CH2 OH, —CH2CH2OH, —CN, —C1-2(halo)alkyl, —CH2Cl, —C(O)H, —C(O)NH2, —SH, CF3, CCl3, and —NAA, wherein each A is independently selected from the group consisting of H and C1-C2 alkyl;
• R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, —NYY wherein each Y is independently selected from H and C1-C5 alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C2-5 secondary amides, (C1-5)(C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5 alkenyls, C2-5 substituted alkenyls, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl, and —OC(O)C1-5R5R6 wherein R5 is an alkylene or alkenylene of up to 5 carbons and R6 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• provided that:
• i) R2 is not hydroxyl when R1 is hydrogen or hydroxyl;
• ii) R2 is not —OC(O)CH3 when R1 is hydrogen;
• and
• iii) R2 is not —OC(O)—CH═CH-(m-hydroxy, p-methoxy-phenyl) or —OC(O)—CH═CH-(p-hydroxy-phenyl) when R1 is hydroxyl;
• one of R3 and R4 is hydrogen and the other is methyl;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof;
• and an acceptable carrier, thereby treating, controlling, reducing or inhibiting the bacterial infection.

A compound corresponding to the following chemical structure:

• wherein R1 is selected from the group consisting of fluoro, chloro, —C(O)H, —C(O)NH2, —SH and —NH2, and R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, NYY, wherein each Y is independently selected from H and C1-C5 alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C2-5 secondary amides, (C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5 alkenyls, C2-5 substituted alkenyls, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl, and —OC(O)C1-5R5R6 wherein R5 is an alkylene or alkenylene of up to 5 carbons and R6 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• provided that R2 is not C1-5 substituted alkyl, —C1-5(halo)alkyl, or C1-5 alcohol when R1 is —SH;
• and one of R3 and R4 is hydrogen and the other is methyl;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof.

A composition comprising a compound corresponding to the following structure:

• wherein:
• R1 is selected from the group consisting of hydrogen, hydroxyl, halide, methoxy, acetoxy, —CH2 OH, —CH2CH2OH, —CN, —C1-2(halo)alkyl, —CH, Cl, —C(O)H, —C(O)NH2, —SH, CF3, CCl3, and —NAA, wherein each A is independently selected from the group consisting of H and C1-C2 alkyl;
• R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, —NYY wherein each Y is independently selected from H and C1-C5 alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C2-5 secondary amides, (C1-5)(C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5 alkenyls, C2-5 substituted alkenyls, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl, and —OC(O) C1-5R5R6 wherein R5 is an alkylene or alkenylene of up to 5 carbons and R6 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• provided that:
• i) R2 is not hydroxyl when R1 is hydrogen, hydroxyl, methoxy, chloride or —CN;
• ii) R2 is not chloride or —OC(O)CH3 when R1 is hydrogen;
• iii) R2 is not —OC(O)—CH═CH-(m-hydroxy, p-methoxy-phenyl) or —OC(O)—CH═CH-(p-hydroxy-phenyl) when R1 is hydroxyl;
• and
• iv) R2 is not C1-5 substituted alkyl, —C1-5(halo)alkyl, or C1-5 alcohol when R1 is hydrogen, halide, hydroxyl, methoxy, acetoxy or —SH;
• one of R3 and R4 is hydrogen and the other is methyl;
• and
• R1 is in the β stereochemical configuration and R2 is in the α stereochemical configuration;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof;
• and a pharmaceutically acceptable carrier.

A composition comprising an antimicrobial agent and a compound corresponding to the following chemical structure:

• wherein:
• R1 is selected from the group consisting of hydrogen, hydroxyl halide, methoxy, acetoxy, —CH2 OH, —CH2CH2OH, —CN, —C1-2(halo)alkyl, —CH2Cl, —C(O)H, —C(O)NH22, —SH, CF3, CCl3, and —NAA, wherein each A is independently selected from the group consisting of H and C1-C2 alkyl;
• R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, —NYY wherein each Y is independently selected from H and C1-C5 alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C2-5 secondary amides, (C1-5)(C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5 alkenyls, C2-5 substituted alkenyls, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl, and —OC(O) C1-5R5R6 wherein R5 is an alkylene or alkenylene of up to 5 carbons and R6 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• provided that:
• i) R2 is not hydroxyl when R1 is hydrogen, hydroxyl, methoxy, chloride or —CN;
• ii) R2 is not chloride or —OC(O)CH3 when R1 is hydrogen;
• iii) R2 is not —OC(O)—CH═CH-(m-hydroxy, p-methoxy-phenyl) or —OC(O)—CH═CH-(p-hydroxy-phenyl) when R1 is hydroxyl;
• and
• iv) R2 is not C1-5 substituted alkyl, —C1-5(halo)alkyl, or C1-5 alcohol when R1 is hydrogen, halide, hydroxyl, methoxy, acetoxy or —SH;
• one of R3 and R4 is hydrogen and the other is methyl;
• and salts, hydrates solvates, prodrugs and N-oxides thereof.

A method for inhibiting or reducing a biofilm comprising contacting the biofilm or a cell capable of biofilm formation with an effective amount of a composition comprising a compound corresponding to the following chemical structure:

• wherein:
• R1 is selected from the group consisting of hydrogen, hydroxyl, halide, methoxy, acetoxy, —CH2 OH, —CH2CH2OH, —CN, —C1-2(halo)alkyl, —CH2Cl, —C(O)H, —C(O)NH2, —SH, CF3, CCl3, and —NAA, wherein each A is independently selected from the group consisting of H and C1-C2 alkyl;
• R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, —NYY wherein each Y is independently selected from H and C1-5 alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C2-5 secondary amides, (C1-5)(C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5, alkenyls, C2-5 substituted alkenyls, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl, and —OC(O)C1-5R5R6 wherein R5 is an alkylene or alkenylene of up to 5 carbons and R6 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• provided that:
• i) R2 is not hydroxyl when R1 is hydrogen or hydroxyl;
• ii) R2 is not —OC(O)CH3 when R1 is hydrogen;
• and
• iii) R2 is not —OC(O)—CH═CH-(m-hydroxy, p-methoxy-phenyl) or —OC(O)—CH═CH-(p-hydroxy-phenyl) when R1 is hydroxyl;
• one of R3 and R4 is hydrogen and the other is methyl;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof;
• and an acceptable carrier, thereby preventing, inhibiting or reducing the biofilm or its formation.

A compound corresponding to the following chemical structure:

• wherein:
• R1 is selected from the group consisting of hydrogen, hydroxyl, halide, methoxy, acetoxy, —CH2 OH, —CH2 CH2OH, —CN, —C1-2(halo)alkyl, —CH2 Cl, —C(O)H, —C(O)NH2, —SH, CF3, CCl3, and —NAA, wherein each A is independently selected from the group consisting of H and C1-C2 alkyl;
• R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, —NYY wherein each Y is independently selected from H and C1-C5 alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C2-5 secondary amides, (C1-5)(C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5 alkenyls, C2-5 substituted alkenyls, substituted or unsubstituted C5-7 aromatics, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl, and —OC(O)C1-5R13R14 wherein R13 is an alkylene or alkenylene of up to 5 carbons and R14 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• wherein R1 is in the β stereochemical configuration and R2 is in the α stereochemical configuration and provided that:
• i) R2 is not hydroxyl when R1 is hydrogen, hydroxyl, methoxy, chloride or —CN;
• ii) R2 is not chloride or —OC(O)CH3 when R1 is hydrogen;
• iii) R2 is not —OC(O)—CH═CH-(m-hydroxy, p-methoxy-phenyl) or —OC(O)—CH═CH-(p-hydroxy-phenyl) when R1 is hydroxyl;
• and
• iv) R2 is not C1-5 substituted alkyl, —C1-5(halo)alkyl, or C1—, alcohol when R1 is hydrogen, halide, hydroxyl, methoxy, acetoxy or —SH;
• R3 is selected from the group consisting of hydrogen, methyl, halide, and —NH2;
• R4 is selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)H, —C(O)NH2, —SH, —S(O)NH2, carboxylic acid groups, C1-3 acyl halides, C1-3 acyl residues, C2-3 secondary amides, C1-3 alcohols, (C1-2)(C1-2) ethers, C2-3 alkyls, C1-3 substituted alkyls, C2-3 alkenyls, and C2-3 substituted alkenyls;
• R5, and R12 are independently selected from the group consisting of hydrogen, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)NH2, —OC(O)C1-3, —SH, —S(O)NH2, and —C1-3(halo)alkyl;
• R6 and R7 are independently is selected from the group consisting of hydrogen, hydroxyl, halide, and —NH2;
• one of R8 and R10 is hydrogen and the other is methyl;
• R9 and R11 are independently selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —NH2, and —CN;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof.

A compound corresponding to the following chemical structure:

• wherein:
• R1 is selected from the group consisting of C1 alcohol, —C1 (chloro)alkyl, —C(O)H, —C(O)NH2, and —NH2,
• R2 is hydroxyl;
• R3 is selected from the group consisting of hydrogen, methyl, halide, and —NH2;
• R4 is selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)H, —C(O)NH2, —SH, —S(O)NH2, carboxylic acid groups, C1-3 acyl halides, C1-3 acyl residues, C2-3 secondary amides, C1-3 alcohols, (C1-2)(C1-2) ethers, C2-3 alkyls, C1-3 substituted alkyls, C2-3 alkenyls, and C2-3 substituted alkenyls;
• R5, and R12 are independently selected from the group consisting of hydrogen, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)NH2, —OC(O)C1-3, —SH, —S(O)NH2, and —C1-3(halo)alkyl;
• R6 and R7 are independently is selected from the group consisting of hydrogen, hydroxyl, halide, and —NH2;
• one of R8 and R10 is hydrogen and the other is methyl;
• R9 and R11 are independently selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —NH2, and —CN;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof.

A compound corresponding to the following chemical structure:

• wherein:
• R1 is selected from the group consisting of fluoro, chloro, —C(O)H, —C(O)NH2, —SH and —NH2;
• R2 is selected from the group consisting of hydroxyl, halide, —CN, —C(O)NH2, —SH, —S(O)NH2, CF3, CCl3, —NYY, wherein each Y is independently selected from H and C1-C5alkyl, C1-5 acyl halides, —C1-5(halo)alkyl, C1-5 acyl residues, C1-5 secondary amides, (C1-5)tertiary amides, C1-5 alcohols, C1-5 substituted alkyls, C2-5 alkenyls, C2-5 substituted alkenyls, substituted or unsubstituted C5-7 aromatics, —OC(O)—OC(CH3)3, —OC(O)—CH═CH-phenyl, —OC(O)—R, wherein R is an unbranched or branched C1-C5 alkyl and —OC(O)C1-5R13R14 wherein R13 is an alkylene or alkenylene of up to 5 carbons and R14 is selected from the group consisting of substituted and unsubstituted C5-7 aromatics, substituted and unsubstituted C5-7 cycloalkyls, and substituted and unsubstituted C5-7 heterocycloalkyls;
• provided that R2 is not C1-5 substituted alkyl, —C1-5(halo)alkyl, or C1-5 alcohol when R1 is —SH;
• R3 is selected from the group consisting of hydrogen, methyl, halide, and —NH2;
• R4 is selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)H, —C(O)NH2, —SH, —S(O)NH2, carboxylic acid groups, C1-3 acyl halides, C1-3 acyl residues, C2-3 secondary amides, C1-3 alcohols, (C1-2(C1-2) ethers, C2-3 alkyls, C1-3 substituted alkyls, C2-3 alkenyls, and C2-3 substituted alkenyls;
• R5, and R12 are independently selected from the group consisting of hydrogen, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)NH2, —OC(O)C1-3, —SH, —S(O)NH2, and —C1-3(halo)alkyl;
• R6 and R7 are independently is selected from the group consisting of hydrogen, hydroxyl, halide, and —NH2;
• one of R8 and R10 is hydrogen and the other is methyl;
• R9 and R11 are independently selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —NH2, and —CN;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof.

A compound corresponding to the following chemical structure:

• wherein:
• R1 is hydroxyl;
• R2 is selected from the group consisting of —C(O)H, —C(O)NH2, —NH2 and —SH;
• R3 is selected from the group consisting of hydrogen, methyl, halide, and —NH2;
• R4 is selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)H, —C(O)NH2, —SH, —S(O)NH2, carboxylic acid groups, C1-3 acyl halides, C1-3 acyl residues, C2-3 secondary amides, C1-3 alcohols, (C1-2)(C1-2) ethers, C2-3 alkyls, C1-3 substituted alkyls, C2-3 alkenyls, and C2-3 substituted alkenyls;
• R5, and R12 are independently selected from the group consisting of hydrogen, hydroxyl, halide, C1-3 alkoxy, —CN, —NH2, —C(O)NH2, —OC(O)C1-3, —SH, —S(O)NH2, and —C1-3(halo)alkyl;
• R6 and R7 are independently is selected from the group consisting of hydrogen, hydroxyl, halide, and —NH2;
• one of R8 and R10 is hydrogen and the other is methyl;
• R9 and R11 are independently selected from the group consisting of hydrogen, methyl, hydroxyl, halide, C1-3 alkoxy, —NH2, and —CN;
• and salts, hydrates, solvates, prodrugs and N-oxides thereof.