Acridone compounds
A class of acridone compounds has been discovered that exhibits chemosensitizing and antiparasitic activity. Described herein are pharmaceutical compositions and methods for their use to treat parasitic infections, such as malaria and toxoplasmosis, and to sensitize resistant cells, such as multidrug resistant cells to other therapeutic agents. The pharmaceutical compositions and methods may also be used to treat and/or prevent psychotic diseases such as schizophrenia.
1. A compound according to the formula
or a pharmaceutically acceptable salt thereof;
wherein R is —R 2 NR 3 R 4 or —R 1 G;
X is halogen, haloalkyl, —OR 5 or —YR 1 G;
n is 1-4;
Y is —CH 2 —, —CH 2 O—, —O—, —N(R 6 )— or —S—;
R 5 is lower alkyl, haloalkyl or —R 7 NR 8 R 9 ,
R 1 , R 2 and R 7 independently are optionally substituted alkyl;
G is —NR 10 R 11 , halogen or fluoroalkyl;
R 3 , R 4 , R 6 , R 8 and R 9 independently are H, lower alkyl, or aralkyl;
R 10 and R 11 independently are H, lower alkyl, aralkyl or together form an aliphatic or aromatic ring optionally including one or more additional heteroatoms.
2. The compound of claim 1 according to the formula
wherein each R 1 is independently optionally substituted alkyl, and each G is independently —NR 10 R 11 , halogen or fluoroalkyl.
3. The compound of claim 1 , wherein R 1 is an optionally substituted alkyl chain.
4. The compound of claim 1 according to the formula
wherein m and p independently are from 2 to 10.
5. The compound of claim 4 , wherein m and p independently are from 2 to 5.
6. The compound of claim 1 , wherein G is —NR 10 R 11 .
7. The compound of claim 6 , wherein R 10 and R 11 are lower alkyl.
8. The compound of claim 7 , wherein R 10 and R 11 are ethyl.
9. The compound of claim 1 , wherein R 10 and R 11 , together form a ring.
10. The compound of claim 9 , wherein the ring is aromatic.
11. The compound of claim 9 , wherein the ring is pyrrolidino, pyridine, piperidino, morpholino, piperazino, imidazolyl, pyrazolyl or triazolyl.
12. The compound of claim 1 , wherein X is a halogen or haloalkyl group.
13. The compound of claim 1 , according to the formula
14. The compound of claim 1 , according to the formula
15. The compound of claim 1 , according to the formula
wherein n is from 2 to 5.
16. The compound of claim 1 , according to the formula
17. The compound of claim 1 , according to the formula
18. A pharmaceutical composition, comprising an effective amount of a compound of claim 1 ; and
a pharmaceutically acceptable carrier.
19. The composition of claim 18 , further comprising a second compound.
20. The composition of claim 19 , wherein the second compound is an anticancer agent, antimalarial agent, antiparasitic, antibiotic or antiretroviral agent.
21. The composition of claim 19 , wherein the second compound is an antimalarial agent.
22. The composition of claim 19 , wherein the first and second compounds are synergistic.
23. The composition of claim 18 , further comprising an antimalarial quinoline.
24. The composition of claim 21 , wherein the antimalarial agent is a Cinchona alkaloid.
25. The composition of claim 24 , wherein the Cinchona alkaloid is quinine or quinidine.
26. The composition of claim 18 , wherein the compound is
27. The composition of claim 26 , further comprising an antimalarial quinoline compound.
28. The composition of claim 27 , wherein the antimalarial quinoline compound is quinine.
29. The composition of claim 26 , further comprising a Cinchona alkaloid.
30. The composition of claim 29 , wherein the Cinchona alkaloid is quinine or quinidine.
31. A method for inhibiting the growth of Plasmodium sp., comprising contacting at least one Plasmodium sp. parasite with a growth inhibitory amount of the compound of claim 1 .
32. The method of claim 31 , wherein the Plasmodium sp. is P. falciparum, P. vivax, P. ovale, P. malariae , or a combination thereof.
33. The method of claim 31 , wherein the Plasmodium sp. is P. falciparum.
34. The compound of claim 1 , wherein the compound has the formula
35. The compound of claim 1 , wherein X is halogen, R is —(CH 2 ) m NR 3 R 4 , and —YR 1 G is —O(CH 2 ) n NR 10 R 11 , wherein m is from 2 to 10 and n is from 2 to 5.
36. The compound of claim 35 , wherein X is Cl, R is —(CH 2 ) 2 N(Et) 2 , and —YR 1 G is —O(CH 2 ) n N(H)(—C(CH 3 ) 3 .
37. The compound of claim 36 , wherein —YR 1 G is —O(CH 2 ) 3 N(H)(—C(CH 3 ) 3 .
38. The compound of claim 1 , wherein R is —(CH 2 ) m NR 3 R 4 , and —YR 1 G is —O(CH 2 ) n NR 10 R 11 , wherein m is from 2 to 10 and n is from 2 to 5.
39. The compound of claim 1 , wherein R is —(CH 2 ) m NR 10 R 11 , wherein m is from 2 to 10.
40. The compound of claim 1 , —YR 1 G is —O(CH 2 ) n NR 10 R 11 , wherein n is from 2 to 5.
41. The compound of claim 2 , wherein —YR 1 G is —O(CH 2 ) 3 N(H)(—CH 3 ) 3 .
42. The compound of claim 13 , wherein —YR 1 G is —O(CH 2 ) 3 N(H)(—C(CH 3 ) 3 .
43. The compound of claim 1 , wherein there are two to four X groups.
44. The compound of claim 43 , wherein the X groups are each halogen.
45. The compound of claim 1 , wherein the compound has the formula
46. The compound of claim 1 , wherein the compound has the formula
47. The composition of claim 18 , wherein X is halogen, R is —(CH 2 ) m NR 3 R 4 , and —YR 1 G is —O(CH 2 ) n NR 10 R 11 , wherein m is from 2 to 10 and n is from 2 to 5.