Small molecule rnase inhibitors and methods of use

A method of treating or preventing a microbial infection in a subject, comprising administering to the subject an effective amount of an RNase inhibitor of the following structure:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• A1, A2, A3, A4, and A5 are each independently selected from N and CR1;
• R1, R2, and R3 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, or substituted or unsubstituted carboxyl;
• R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted heteroalkyl;
• and
• Y is O, S, or NR5.

A method of inhibiting a bacterial ribonuclease comprising contacting the bacterial ribonuclease with an effective amount of an RNase inhibitor of the following structure:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• Ar is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• L is
• wherein X1 and X2 are each independently O or S, and wherein X3 is CH2 or NH;
• and
• R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, or substituted or unsubstituted carboxyl.

A method of inhibiting a bacterial ribonuclease comprising contacting the bacterial ribonuclease with an effective amount of an RNase inhibitor of the following structure:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• A1, A2, A3, A4, and A5 are each independently selected from N and CR1;
• R1, R2, and R3 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, or substituted or unsubstituted carboxyl;
• R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted heteroalkyl;
• and
• Y is O, S, or NR5.

A compound of the following structure:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• Ar is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
• L is
• wherein X1 and X2 are each independently O or S, and wherein X3 is CH2 or NH;
• and
• R1, R2, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, or substituted or unsubstituted carboxyl,
• wherein if R1 and R2 are methyl, R3, R4, R5, and R6 are hydrogen, and Ar is unsubstituted furan, then L is not

A compound of the following structure:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• A1, A2, A3, A4, and A5 are each independently selected from N and CR1;
• R1, R2, and R3 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, or substituted or unsubstituted carboxyl;
• R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted heteroalkyl;
• and
• Y is O, S, or NR5,
• wherein if A1, A2, A4, and A5 are CH, R2 and R3 are hydrogen, A3 is CCl, and Y is S, then R4 is not —CH2CH2CO2H.