Substituted tetracycline compounds for the treatment of malaria
View Patent ↗This invention provides a method for treating or preventing malaria in a subject. The method includes administering to the subject an effective amount of a substituted tetracycline compound, such that malaria is treated or prevented. In one aspect, the invention relates to pharmaceutical compositions which include an effective amount of a tetracycline compound to treat malaria in a subject and a pharmaceutically acceptable carrier. The substituted tetracycline compounds of the invention can be used to in combination with one or more anti-malarial compounds or can be used to treat or prevent malaria which is resistant to one or more other anti-malarial compounds.
1. A method for treating or preventing malaria in a subject, comprising administering to said subject an effective amount of a substituted tetracycline compound of formula I or a pharmaceutically acceptable salt thereof:
wherein:
X is CR 6′ R 6 ;
R 2 and R 2′ are each hydrogen;
R 4′ and R 4″ are each alkyl;
R 4 is NR 4′ R 4″ ;
R 3 , R 11 and R 12 are each hydrogen;
R 10 is hydrogen;
R 5 is hydroxyl, hydrogen or thiol;
R 6 and R 6′ are independently hydrogen, hydroxyl, thiol or alkyl;
R 7 is substituted or unsubstituted furanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted thienyl or substituted or unsubstituted benzothienyl;
R 9 is hydrogen; and
R 8 is hydrogen; such that malaria is treated or prevented in said subject.
2. The method of claim 1 , wherein R 5 , R 6 , and R 6′ are each hydrogen.
3. The method of claim 1 , wherein R 7 is substituted furanyl or substituted thienyl.
4. The method of claim 3 , wherein R 7 is substituted with halogen, alkoxy, amino, acyl, alkyl, nitro, formyl, amido, alkenyl, alkynyl, or aryl.
5. The method of claim 4 , wherein R 7 is substituted with alkoxy and further wherein said alkoxy is methoxy, ethoxy, propoxy, methylene dioxy, or ethylene dioxy.
6. The method of claim 4 , wherein R 7 is substituted with alkyl and further wherein said alkyl is substituted or unsubstituted methyl, ethyl, propyl, butyl or pentyl.
7. The method of claim 6 , wherein said substituted methyl, ethyl, propyl, butyl or pentyl is substituted with an amino, carbocyclic or heterocyclic group.
8. The method of claim 4 , wherein R 7 is substituted with acyl and further wherein said acyl is acetyl.
9. The method of claim 1 , wherein R 7 is substituted or unsubstituted benzofuranyl or substituted or unsubstituted benzothienyl.
10. The method of claim 1 , wherein R 7 is unsubstituted thienyl or unsubstituted furanyl.
11. The method of claim 3 , wherein said substituent comprises an ionizable nitrogen atom.
12. The method of claim 1 , wherein R 7 is selected from the group consisting of:
wherein:
R a and R b are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, or heterocyclic;
g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and
X a is substituted carbon.
13. The method of claim 1 , wherein said compound is selected from the group consisting of:
14. The method of claim 1 , wherein said compound is selected from the group consisting of:
15. The method of claim 1 , wherein said subject is a human.
16. The method of claim 1 , wherein said substituted tetracycline compound has anti-gram positive microbial activity.
17. The method of claim 16 , wherein said anti-gram positive microbial activity is greater than about 0.05 μg/ml.
18. The method of claim 17 , wherein said anti-gram positive microbial activity is greater than about 5 μg/ml.
19. The method of claim 1 , wherein said substituted tetracycline compound is non-antibacterial.
20. The method of claim 1 , wherein said substituted tetracycline compound has a cytotoxicity of 25 μg/ml or greater.
21. The method of claim 1 , wherein said substituted tetracycline compound has a MIC of 150 nM or less.
22. The method of claim 21 , wherein said substituted tetracycline compound has a MIC of 50 nM or less.
23. The method of claim 22 , wherein said substituted tetracycline compound has a MIC of 10 nM or less.
24. The method of claim 23 , wherein said substituted tetracycline compound has a MIC of 5 nM or less.
25. The method of claim 1 , wherein said malaria is caused by a plasmodium protozoan selected from the group consisting of: P. falciparum, P. vivax, P. ovale , and P. malariae.
26. The method of claim 1 , wherein said malaria is resistant to one or more anti-malarial compounds selected from the group consisting of proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine and 1,16-hexadecamethylenebis(N-methylpyrrolidinium)dibromide.
27. The method of claim 1 , further comprising administering an anti-malarial compound selected from the group consisting of: proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, 1,16-hexadecamethylenebis(N-methylpyrrolidinium)dibromide and combinations thereof.
28. A method for increasing the antimalarial activity of an antimalarial compound, comprising administering said antimalarial compound in combination with an effective amount of a substituted tetracycline compound, such that the antimalarial activity of said antimalarial compound is increased, wherein said tetracycline compound is of formula I or a pharmaceutically acceptable salt thereof:
wherein:
X is CR 6′ R 6 ;
R 2 and R 2′ are each hydrogen;
R 4′ and R 4″ are each alkyl;
R 4 is NR 4′ R 4″ ;
R 3 , R 11 and R 12 are each hydrogen;
R 10 is hydrogen;
R 5 is hydroxyl, hydrogen or thiol;
R 6 and R 6′ are independently hydrogen, hydroxyl, thiol or alkyl;
R 7 is substituted or unsubstituted furanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted thienyl or substituted or unsubstituted benzothienyl;
R 9 is hydrogen; and
R 8 is hydrogen.
29. The method of claim 28 , wherein said anti-malarial compound is selected from the group consisting of: proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, 1,16-hexadecamethylenebis(N-methylpyrrolidinium)dibromide and combinations thereof.
30. A method for preventing malaria in a mammal, comprising administering to said mammal an effective amount of a substituted tetracycline compound, such that malaria is prevented in said mammal, wherein said tetracycline compound is of formula I or a pharmaceutically acceptable salt thereof:
wherein:
X is CR 6′ R 6 ;
R 2 and R 2′ are each hydrogen;
R 4′ and R 4″ are each alkyl;
R 4 is NR 4′ R 4″ ;
R 3 , R 11 and R 12 are each hydrogen;
R 10 is hydrogen;
R 5 is hydroxyl, hydrogen or thiol;
R 6 and R 6′ are independently hydrogen, hydroxyl, thiol or alkyl;
R 7 is substituted or unsubstituted furanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted thienyl or substituted or unsubstituted benzothienyl;
R 9 is hydrogen; and
R 8 is hydrogen.
31. The method of claim 30 , wherein said substituted tetracycline compound is selected from the group consisting of:
32. The method of claim 30 , wherein said substituted tetracycline compound is selected from the group consisting of:
33. The method of claim 30 , wherein said substituted tetracycline compound is non-antibacterial.
34. The method of claim 30 , wherein said substituted tetracycline compound has anti-gram positive microbial activity.
35. The method of claim 34 , wherein said anti-gram positive microbial activity is greater than about 0.05 μg/ml.
36. The method of claim 35 , wherein said anti-gram positive microbial activity is greater than about 5 μg/ml.
37. The method of claim 36 , wherein said substituted tetracycline compound has a cytotoxicity of 25 μg/ml or greater.
38. The method of claim 30 , wherein said substituted tetracycline compound has a MIC of 150 nM or less.
39. The method of claim 38 , wherein said substituted tetracycline compound has a MIC of 50 nM or less.
40. The method of claim 39 , wherein said substituted tetracycline compound has a MIC of 10 nM or less.
41. The method of claim 40 , wherein said substituted tetracycline compound has a MIC of 5 nM or less.
42. A pharmaceutical composition comprising an effective amount of a substituted tetracycline compound to treat malaria in a mammal and a pharmaceutically acceptable carrier, wherein said tetracycline compound is of formula I or a pharmaceutically acceptable salt thereof:
wherein:
X is CR 6′ R 6 ;
R 2 and R 2′ are each hydrogen;
R 4′ and R 4″ are each alkyl;
R 4 is NR 4′ R 4″ ;
R 3 , R 11 and R 12 are each hydrogen;
R 10 is hydrogen;
R 5 is hydroxyl, hydrogen or thiol;
R 6 and R 6′ are independently hydrogen, hydroxyl, thiol or alkyl;
R 7 is substituted or unsubstituted furanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted thienyl or substituted or unsubstituted benzothienyl;
R 9 is hydrogen; and
R 8 is hydrogen.
43. The pharmaceutical composition of claim 42 , wherein said substituted tetracycline compound is selected from the group consisting of:
44. The pharmaceutical composition of claim 42 , further comprising an anti-malarial compound.
45. The pharmaceutical composition of claim 44 , wherein the anti-malarial compound is selected from the group consisting of proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, 1,16-hexadecamethylenebis(N-methylpyrrolidinium)dibromide and pyronaridine.