Compounds and methods for inhibiting Cif virulence factor

1. A pharmaceutical composition formulated for pulmonary administration comprising an inhibitor of Cystic fibrosis transmembrane conductance regulator Inhibitory Factor (Cif) activity in admixture with a pharmaceutically acceptable carrier, wherein the inhibitor of Cif activity has the structure of Formula I

wherein

X is absent or present and when present is —O—, —NH—, —S—, —CH 2 —, —NHC(O)NH—, or —C(O)NHC(O)NH—;

n is 1 to 5;

m is 2 to 5; and

R 1 and R 2 are substituted anywhere on their respective rings, wherein

each occurrence of R 1 is independently a hydrogen, hydroxyl, amino, cyano, halo, nitro, mercapto, phosphate, —SO 2 NH 2 , —CH(CH 3 ) 2 , —COOH, —C(O)CH 3 , —CO 2 Me, —CONHNH 2 , —CONHCH 3 , —NHC(O)R 11 , —OCH 2 COOH, —OC(O)CH 2 CH 3 , alkyl, alkenyl, alkynyl, aryl, alkoxy, or amido group,

at least one R 2 is a nitro, or —NHC(O)R 11 group; at least one R 2 is halo; and each other occurrence of R 2 is independently a hydrogen, hydroxyl, amino, cyano, halo, nitro, mercapto, phosphate, —SO 2 NH 2 , —CH(CH 3 ) 2 , —COOH, —C(O)CH 3 , —CO 2 Me, —CONHNH 2 , —CONHCH 3 , —NHC(O)R 11 , —OCH 2 COOH, —OC(O)CH 2 CH 3 , alkyl, alkenyl, alkynyl, aryl, alkoxy, or amido group,

wherein R 11 is an alkyl, amino, —CH 2 C (O)OCH 2 CH 3 , —CH 2 CH 2 COOH, —CH 2 CH 2 C(O)OCH 2 CH 3 , —CH(CH 3 ) 2 group.

2. A method for ameliorating or treating a respiratory disease, or a secondary infection thereof, comprising administering to a subject in need of treatment the pharmaceutical composition of claim 1 , thereby ameliorating or treating the subject's respiratory disease, or secondary infection thereof.

3. The method of claim 2 , wherein the respiratory disease is chronic obstructive pulmonary disease, pneumonia, a Pseudomonas aeruginosa infection, an Acinetobacter infection or cystic fibrosis.

4. The method of claim 2 , wherein the secondary infection is a viral infection, an Acinetobacter infection or a Pseudomonas aeruginosa infection.

5. A pharmaceutical composition formulated for pulmonary administration comprising an inhibitor of Cystic fibrosis transmembrane conductance regulator Inhibitory Factor (Cif) activity in admixture with a pharmaceutically acceptable carrier, wherein the inhibitor of Cif activity has the structure of Formula IV,

wherein

R 5 is amino, nitro, or —NHC(O)R 11 group;

R 6 is a hydroxyl group;

R 7 and R 7′ are independently a hydrogen or halo group;

R 8 is an hydroxyl, amino, cyano, halo, nitro, mercapto, phosphate, —SO 2 NH 2 , —COOH, —C(O)CH 3 , —CO 2 Me, —CONHNH 2 , —CONHCH 3 , —NHC (O)R 11 , —OCH 2 COOH, —OC (O)CH 2 CH 3 , alkyl, alkenyl, alkynyl, aryl, alkoxy, or amido group;

R 9 is a hydrogen group; and

R 11 is

(i) alkyl,

(ii) amino,

(iii) —(CH 2 ) x C(O)OCH 2 CH 3 , wherein x is 1 to 5, or

(iv) —(CH 2 ) x COOH, wherein x is 2 to 5.