Inhibition of RNA function

A method for inhibition of RNA function comprising contacting cells comprising RNA with a pharmacologically effective inhibitory amount of

• (a) a compound having the formula (I):
• 18
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.

A method for inhibition of microbial infection in a subject comprising administering to said subject a pharmacologically effective inhibitory amount of

• (a) a compound having the formula (I):
• 22
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.

A method for inhibiting a viral infection in a subject comprising administering to said subject a pharmacologically effective inhibitory amount of

• (a) a compound having the formula (I):
• 26
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.

A method for inhibition of viral RNA function comprising administering to a subject a pharmacologically effective inhibitory amount of

• (a) a compound having the formula (I):
• 30
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.

A method for inhibition of microbial RNA function comprising administering to a subject a pharmacologically effective inhibitory amount of

• (a) a compound having the formula (I):
• 34
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.

A method for increasing or decreasing the production of a protein comprising the step of contacting a target messenger RNA molecule that encodes said protein with

• (a) a compound having the formula (I):
• 38
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.

A pharmaceutical composition comprising an amount of

• (a) a compound having the formula (I):
• 39
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide,
• that is pharmacologically effective to inhibit one or more functions of a viral or microbial RNA.

A pharmaceutical composition comprising an amount of

• (a) a compound having the formula (I):
• 43
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide,
• that is pharmacologically effective in inhibiting a viral or microbial infection.

A compound having the formula (III):

• 47
• in which R is (CH2)3R12;
• R10 is halogen or C1-C4 alkoxy;
• R11 is hydrogen if R10 is halogen and is hydrogen or methyl if R10 is alkoxy;
• and R12 is selected from —N(CH2CH2)OH, —N(n-C4H9), —N(CH2C6H5),
• 48
• if R10 is halogen, and is —N(CH3)2 if R10 is alkoxy.

A complex formed between the TAR site of HIV RNA and

• (a) a compound having the formula (I):
• 49
• in which:
• A is O;
• NR1;
• S(O)n where n is 0, 1 or 2;
• CR2R3;
• or —A′—CR4R5 where A′ is O, NR1, S(O)n wherein n is 0, 1 or 2 or CR6R7, wherein R1 through R7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• B is N—R, O, S or CR8R9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R8 and R9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
• or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH3)—C(O)—;
• provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
• D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
• and pharmaceutically acceptable salts thereof;
• (b) yohimbine;
• (c) usnic acid;
• or
• (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.