Dicationic 2,5-diarylfuran aza-analogs as anti-protozoan agents

A compound of Formula (I):

• wherein A and B are different and N or CH;
• Y and Z are CH;
• X is O or S;
• R2, R4, R5, and R7 are each H;
• R3 and R6 are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R1 and R8 can be present or absent and when present are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R13 and R14 can be present or absent and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• and C1, C2, and D2 are each C or N.

A compound of Formula (I):

• wherein A and B are CH;
• X is O;
• Y is O;
• Z is not present;
• R2, R4, R5, and R7 are each H;
• R3 and R6 are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R1 and R8 can be present or absent and when present are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R13 and R14 can be present or absent and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, aryloxyl, aralkoxy and hydroxyl;
• and C1, C2, D1, and D2 are each C or N.

A method of treating a microbial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):

• wherein:
• X is selected from the group consisting of O, S, and NR17, where R17 is hydrogen or lower alkyl;
• A and Y are CH, N, NR17, O, or S;
• C1 and C2 are each C or N, wherein C1 and C2 are the same or different;
• D1 and D2 are each C or N, wherein D1 and D2 are the same or different;
• B and Z are CH, N or NR17, provided that B, Z, or both B and Z are not present when A, Y, or both A and Y are O, S, or NR17;
• R13, R14, R1 and R8 can be present or absent, and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxyl, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, alkoxyl, aryloxyl, aralkoxy and hydroxyl;
• R3 and R6 are each independently selected from the group consisting of H, hydroxy, lower alkyl, cycloalkyl, aryl, aralkyl, alkoxyl, hydroxycycloalkyl, alkoxycycloalkyl, hydroxyalkyl, aminoalkyl, acyloxy, acetoxy, and alkylaminoalkyl;
• and R2, R4, R5 and R7 are each independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl, or R2 and R4 together or R5 and R7 together represent a C2 to C10 alkyl, hydroxyalkyl, or alkylene, or R3 and R4 together or R6 and R7 together are:
• wherein n is a number from 1 to 3, and R9 is H or —CONHR10NR11R12, wherein R10 is lower alkyl and R11 and R12 are each independently selected from the group consisting of H and lower alkyl;
• and
• wherein at least one A, B, Y, and Z are selected from group consisting of N, NR17, O, and S.

A method of treating a microbial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):

• wherein A and B are different and N or CH;
• Y and Z are CH;
• X is O or S;
• R2, R4, R5, R7 are each H;
• R3 and R6, are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R1 and R8 can be present or absent and when present are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R13 and R14 can be present or absent and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• and C1, C2, and D2 are each C or N.

A method of treating a microbial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I):

• wherein A and B are CH;
• X is O;
• Y is O;
• Z is not present;
• R2, R4, R5, and R7 are each H;
• R3 and R6 are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R1 and R8 can be present or absent and when present are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R13 and R14 can be present or absent and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, aryloxyl, aralkoxy and hydroxyl;
• and C1, C2, D1, and D2 are each C or N.

A pharmaceutical formulation comprising:

• (a) a compound of Formula (I):
• wherein:
• X is selected from the group consisting of O, S, and NR17, where R17 is hydrogen or lower alkyl;
• A and Y are CH, N, NR17, O, or S;
• C1 and C2 are each C or N, wherein C1 and C2 are the same or different;
• D1 and D2 are each C or N, wherein D1and D2 are the same or different;
• B and Z are CH, N or NR17, provided that B, Z, or both B and Z are not present when A, Y, or both A and Y are O, S, or NR17;
• R13, R14, R1 and R8 can be present or absent, and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxyl, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, alkoxyl, aryloxyl, aralkoxy and hydroxyl;
• R3 and R6 are each independently selected from the group consisting of H, hydroxy, lower alkyl, cycloalkyl, aryl, aralkyl, alkoxyl, hydroxycycloalkyl, alkoxycycloalkyl, hydroxyalkyl, aminoalkyl, acyloxy, acetoxy, and alkylaminoalkyl;
• and R2, R4, R5 and R7 are each independently selected from the group consisting of H, lower alkyl, alkoxyalkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl, or R2 and R4 together or R5 and R7 together represent a C2 to C10 alkyl, hydroxyalkyl, or alkylene, or R3 and R4together or R6 and R7 together are:
• wherein n is a number from 1 to 3, and R9 is H or —CONHR10NR11R12, wherein R10 is lower alkyl and R11 and R12 are each independently selected from the group consisting of H and lower alkyl;
• and
• wherein at least one A, B, Y, and Z are selected from group consisting of N, NR17, O, and S;
• and
• (b) a pharmaceutically acceptable carrier.

A pharmaceutical formulation comprising:

• (a) a compound of Formula (I):
• wherein A and B are different and N or CH;
• Y and Z are CH;
• X is O or S;
• R2, R4, R5, R7 are each H;
• R3 and R6 are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R1 and R8 can be present or absent and when present are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R13 and R14 can be present or absent and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aralkoxy and hydroxyl;
• and C1, C2, D1, and D2 are each C or N;
• and
• (b) a pharmaceutically acceptable carrier.

A pharmaceutical formulation comprising:

• (a) a compound of Formula (I):
• wherein A and B are CH;
• X is O;
• Y is O;
• Z is not present;
• R2, R4, R5, and R7 are each H;
• R3 and R6 are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R1 and R6 can be present or absent and when present are selected from the group consisting of H, OH, methyl, methoxy, and acetoxy;
• R13 and R14 can be present or absent and when present are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• R15 and R16 are selected from the group consisting of H, lower alkyl, halogen, alkoxy, aryloxyl, aralkoxy and hydroxyl;
• and C1, C2, D1, and D2 are each C or N;
• and
• (b) a pharmaceutically acceptable carrier.