Anti-infective agents against intracellular pathogens
A new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of Formula I: wherein X wherein X is —CF 3 , Ar is selected from and R is selected from where R′ is L-Lys, D-Lys, β-Ala, L-Lue, L-Ile, Phe, SO 2 CH 2 CH 2 NH 2 , SO 2 NH 2 , Asn, Glu or Gyl, and R″ is methyl, ethyl, allyl, CH 2 CH 2 OH, CH 2 CN, CH 2 CH 2 CN, CH 2 CONH 2 ,
1. A compound of Formula I
wherein X is —CF 3 , Ar is
and R is selected from
R′ is SO 2 CH 2 CH 2 NH 2 or SO 2 NH 2 or an amino acid attached through the α-carboxyl group selected from the group consisting of L-Lys, D-Lys, β-Ala, L-Leu, L-Ile, Phe, Asn, Glu and Gly, and
R″ is methyl, ethyl, allyl, CH 2 CH 2 OH, CH 2 CN, CH 2 CH 2 CN, CH 2 CONH 2 , —COCH 2 CH 2 N NH, —COCH 2 CH 2 N O, —COCH 2 CH 2 N NCH 3 , —COCH 2 CH 2 CONH—
or pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein the compound has the following formula XII
or pharmaceutically acceptable salts thereof.
3. A method of inducing apoptosis in rapidly proliferating cancer cells selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer, the method comprising the step of contacting a therapeutically effective amount of a compound of formula I
wherein X is —CF 3 , Ar is
and R is selected from
R′ is SO 2 CH 2 CH 2 NH 2 or SO 2 NH 2 or an amino acid attached through the α-carboxyl group selected from the group consisting of L-Lys, D-Lys, β-Ala, L-Leu, L-Ile, Phe, Asn, Glu and Gly, and
R″ is methyl, ethyl, allyl, CH 2 CH 2 OH, CH 2 CN, CH 2 CH 2 CN, CH 2 CONH 2 , —COCH 2 CH 2 N NH, —COCH 2 CH 2 N O, —COCH 2 CH 2 N NCH 3 , —COCH 2 CH 2 CONH—
or pharmaceutically acceptable salts thereof, with the rapidly proliferating cells.
4. A method for treating, inhibiting, or delaying the onset of cancer, wherein the cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer, in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of Formula I:
wherein X is —CF 3 , Ar is
and R is selected from
R′ is SO 2 CH 2 CH 2 NH 2 or SO 2 NH 2 or an amino acid attached through the α-carboxyl group selected from the group consisting of L-Lys, D-Lys, β-Ala, L-Leu, L-Ile, Phe, Asn, Glu and Gly, and
R″ is methyl, ethyl, allyl, CH 2 CH 2 OH, CH 2 CN, CH 2 CH 2 CN, CH 2 CONH 2 , —COCH 2 CH 2 N NH, —COCH 2 CH 2 N O, —COCH 2 CH 2 N NCH 3 , —COCH 2 CH 2 CONH—
or pharmaceutically acceptable salts thereof, to the subject in need of such treatment.
5. The method of claim 4 wherein the subject is a human.
6. A method of inducing autophagy in cells infected by an intracellular bacteria comprising administering to a subject diagnosed with a disease caused by the bacteria an effective amount of at least one compound according to claim 1 .
7. The method according to claim 6 , wherein the subject is an animal.
8. The method according to claim 7 , wherein the subject is a human.
9. The method according to claim 6 , wherein the bacteria is chosen from Mycobacterium tuberculosis, Francisella tularensis, Francisella novicida, Streptococcous pyogenes, Rickettsiae spp., and Salmonella typhimurium.
10. A method for reducing the release of bacterial endotoxins in a subject having an infection by intracellular bacteria and that has undergone antibiotic treatment comprising administering to the subject a therapeutically effective amount of at least one compound according to claim 1 .
11. The method according to claim 10 , wherein the subject is an animal.
12. The method according to claim 11 , wherein the subject is a human.
13. The method according to claim 9 , wherein the cells infected by an intracellular bacteria are beclin-1 expressing cells.
14. The method according to claim 9 , wherein the cells infected by an intracellular bacteria are macrophage cells.
15. The method according to claim 10 , wherein the intracellular bacteria is chosen from Mycobacterium tuberculosis, Francisella tularensis, Francisella novicida, Streptococcous pyogenes, Rickettsiae spp., and Salmonella typhimurium.
16. The method according to claim 15 , wherein the intracellular bacteria have infected macrophage cells.