Inhibition of mycobacterial type VII secretion
The invention relates to compounds and pharmaceutically acceptable salts thereof, and to their medical use. Exemplary medical uses are the prevention and treatment of a bacterial infection, for example, a mycobacterial infection, such as a Mycobacterium tuberculosis infection, e.g., in a respiratory system and/or extrapulmonic. The invention further relates to a use of such compounds, pharmaceutically acceptable salts thereof or prodrugs of the compounds as chemotherapeutic agents. Also, the invention relates to a use of such compounds, pharmaceutically acceptable salts thereof or prodrugs of the compounds for inhibiting mycobacterial type VII secretion. The compounds have the following formula wherein Q and X are, respectively, CH and C, CR 2 and C, CH and N, CR 2 and N, or N and C; R 1 is hydrogen, halide or optionally substituted linear or branched alkoxy having 1 or 2 carbon atoms; R 2 is independently selected from hydrogen, halide or optionally substituted linear or branched alkoxy having 1 or 2 carbon atoms, and R 3 is optionally substituted linear or branched alkoxy having 1-6 carbon atoms, haloalkyl having 1-6 carbon atoms, n-propyl, 2-propenyl, 2-propynyl, or n-pentyl, or a pharmaceutically acceptable salt of the compound, for use in the prevention or treatment of a bacterial infection.
1 . A method of treating or inhibiting a bacterial infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (Ia), wherein the formula is
wherein
Q and X are, respectively, CH and C, CR 2 and C, CH and N, CR 2 and N, or N and C;
R 1 is hydrogen, halide or optionally substituted linear or branched alkoxy having 1 or 2 carbon atoms;
R 2 is independently selected from hydrogen, halide or optionally substituted linear or branched alkoxy having 1 or 2 carbon atoms, and
R 3 is optionally substituted linear or branched alkoxy having 1-6 carbon atoms, haloalkyl having 1-6 carbon atoms, n-propyl, 2-propenyl, 2-propynyl, or n-pentyl,
or a pharmaceutically acceptable salt of the compound.
2 . The method according to claim 1 ,
wherein
R 1 is hydrogen, chloride or methoxy; and/or
R 2 is independently hydrogen, chloride or methoxy, and/or
R 3 is n-propyl, n-pentyl, 2-methoxyethyl, or 3,3,3-trifluoropropyl.
3 . The method according to claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt of any of the compounds.
4 . The method according to claim 1 , wherein the bacterial infection is a mycobacterial infection.
5 . The method according to claim 4 , wherein the bacterial infection is a Mycobacterium tuberculosis infection.
6 . The method according to claim 1 , wherein the bacterial infection is a bacterial infection in a respiratory system.
7 . The method according to claim 6 , wherein the bacterial infection is extrapulmonic.
8 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt is administered to substantially inhibit type VII secretion of a bacterium.
9 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt is administered to substantially inhibit type VII secretion of a mycobacterium.
10 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt is administered to substantially inhibit ESX-1 dependent secretion.
11 . The method according to claim 1 , wherein the compound or the pharmaceutically acceptable salt is administered to substantially inhibit ESX-5 dependent secretion.
12 . The method according to claim 1 , wherein the bacterial infection is pulmonary tuberculosis.
13 . The method according to claim 1 , wherein the administration is parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, ocular, intravaginal, or by inhalation.