Histone deacetylase inhibitors for enhancing activity of antifungal agents

1. A composition comprising a selective and synergistic amount of

(i) a histone deacetylase inhibitor, or a hydrate, solvate, pharmaceutically acceptable salt thereof, wherein the histone deacetylase inhibitor is a compound of formula (A)

or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein

R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, preferably cycloalkyl, aryl, heteroaryl or heterocyclyl, any of which maybe optionally substituted;

x is an integer from 0 to 5, wherein the chain of length x is optionally substituted and wherein one carbon atom of the chain of length x is optionally replaced with a heteroatom;

n is an integer from 0 to 2; and

Y is H;

with the provisos that when x is 4, n is not 2, and when x is 3, n is not 3;

(ii) an antifungal effective amount of an antifungal agent, wherein the antifungal agent is an azole; and

(iii) a pharmaceutically acceptable carrier,

wherein the selective and synergistic amount of a histone deacetylase inhibitor is not toxic to mammalian cells.

2. The composition of claim 1 , wherein the histone deacetylase inhibitor is selected from the group consisting of

and hydrates, solvates, pharmaceutically acceptable salts thereof.

3. The composition of claim 1 , wherein the histone deacetylase inhibitor is selected from the group consisting of

or a hydrate, solvate, pharmaceutically acceptable salt thereof.

4. The composition of claim 1 , wherein the histone deacetylase inhibitor is

or a hydrate, solvate, pharmaceutically acceptable salt thereof.

5. The composition of claim 1 , wherein the antifungal agent is selected from the group consisting of ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole and ravuconazole.

6. A method of selectively sensitizing a fungal cell to an antifungal agent comprising contacting the cell with a selective sensitizing effective amount of a histone deacetylase inhibitor, or a hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein the selective sensitizing effective amount of the histone deacetylase inhibitor or hydrate, solvate, or pharmaceutically acceptable salt thereof, is synergistic with an antifungal effective amount of an antifungal agent, and wherein

(i) the histone deacetylase inhibitor is a compound of formula (A)

wherein

R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, preferably cycloalkyl, aryl, heteroaryl or heterocyclyl, any of which maybe optionally substituted;

x is an integer from 0 to 5, wherein the chain of length x is optionally substituted and wherein one carbon atom of the chain of length x is optionally replaced with a heteroatom;

n is an integer from 0 to 2; and

Y is H;

with the provisos that when x is 4, n is not 2, and when x is 3, n is not 3;

(ii) the antifungal agent is ketoconazole, fluconazole, itraconazole, or voriconazole; and

(iii) the fungal cell is a C. albicans, C. glabrata , or A. fumigatus cell.

7. The method of claim 6 , wherein the histone deacetylase inhibitor is selected from the group consisting of

8. The method of claim 6 , wherein the histone deacetylase inhibitor is selected from the group consisting of

9. A method of selectively sensitizing a fungal cell to an antifungal agent comprising contacting the cell with a selective sensitizing effective amount of a histone deacetylase inhibitor, or a hydrate, solvate, or pharmaceutically acceptable salt, thereof, wherein the selective sensitizing effective amount of the histone deacetylase inhibitor or hydrate, solvate, or pharmaceutically acceptable salt thereof, is synergistic with an antifungal effective amount of an antifungal agent, and wherein

(i) the histone deacetylase inhibitor is

(ii) the antifungal agent is ketoconazole, fluconazole, itraconazole, voriconazole, fenpropimorph, terbinafine, or nikkomycin; and

(iii) the fungal cell is a C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, A. fumigatus, C. lusitaniae, C. dubliniensis, A. flavus, A. niger, A. terreus, Pseudallescheria boydii, Fusarium sp, Paecilomyces lilacinus, Rhizopus arrhizus, Coccidioides immitis, Trichosporon, Mucor Sp., or Histoplasma cell.