Antimalarial and antiproliferative pharmacophore models, novel tryptanthrin compounds having increased solubility, and methods of making and using thereof

• US 20040033934A1
• Filed: 02/07/2003
• Published: 02/19/2004
• Est. Priority Date: 02/09/2002
• Status: Active Grant

• Current Assignee: United States Army (U.S. Department Of Defense)
• Original Assignee: United States Army (U.S. Department Of Defense)
• Inventors: Bhattacharjee, Apurba K., Hicks, Rickey P., Nichols, Daniel A.
• Granted Patent: US 7,259,167 B2
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: G16C 20/50 Molecular design, e.g. of drugs
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein is a pharmacophore model for antimalarial activity and methods of making and using thereof. The pharmacophore comprises two hydrogen bond acceptor (lipid) functions and two hydrophobic (aromatic) functions. The pharmacophore model was made using a test set of tryptanthrin compounds which exhibit antimalarial activity. Also disclosed are tryptanthrin compounds having greater solubility and bioactivity as compared to prior art tryptanthrin compounds and methods of making and using thereof. Also disclosed are methods of treating malaria in a subject.

Claims

1. A pharmacophore for antiproliferative, antibacterial, antifungal, or antiprotozoal activity of a compound comprising two hydrogen bond acceptor (lipid) functions and two hydrophobic (aromatic) functions.

2. The pharmacophore of claim 1, wherein the pharmacophore is made by (a) generating a set of three-dimensional conformers for each of the compounds in a training set comprising at least five compounds known to exhibit the activity, (b) correlating each of the compounds of the training set with at least one observed IC₅₀ value of the activity, (c) generating from the set of three-dimensional conformers at least one hypothesis, (d) calculating the activity for each conformer of step (a) towards the hypothesis, (e) calculating the total cost for the hypothesis, and (f) selecting the hypothesis with the lowest cost as the pharmacophore.

3. The pharmacophore of claim 1, wherein the antiprotozoal activity is antimalarial activity.

4. The pharmacophore of claim 2, wherein the activity is antimalarial activity.

5. The pharmacophore of claim 2, wherein at least one of the compounds known to exhibit the activity is a tryptanthrin compound.

6. The pharmacophore of claim 2, wherein the steps are carried out using a molecular modeling software program.

7. The pharmacophore of claim 2, wherein the molecular modeling software program is CATALYST®

.

8. The pharmacophore of claim 4, wherein the observed IC₅₀ value of antimalarial activity ranges from about 0.4 ng/ml to about 50,000 ng/ml.

9. The pharmacophore of claim 1 wherein the energy range of the set of three-dimensional conformers is about 0 to about 25 Kcal/mole.

10. The pharmacophore of claim 1, wherein the X, Y, and Z coordinates of the hydrogen bond acceptor (lipid) functions and the hydrophobic (aromatic) functions are as follows

11. A pharmacophore having a root mean square equivalent functions of less than about 3.0 Å

of the hydrogen bond acceptor (lipid) functions and the hydrophobic (aromatic) functions of claim 10.

12. The pharmacophore of claim 11, wherein the root mean square is less than about 1.5 Å

.

13. The pharmacophore of claim 11, wherein the root mean square is less than about 1.0 Å

.

14. The pharmacophore of claim 11, wherein the root mean square is less than about 0.5 Å

.

15. A method for screening a candidate compound for antiproliferative, antibacterial, antifungal, or antiprotozoal activity which comprises (a) finding the best fit of the candidate compound to the pharmacophore of claim 2, and (b) calculating the activity value for the candidate compound.

16. The method of claim 15, wherein finding the best fit is determined using a fast-fit algorithm, a principle component analysis, a partial least squares technique, a linear regression technique, or a non-linear regression technique.

17. A compound having antiproliferative, antibacterial, antifungal, or antiprotozoal activity identified by the method of claim 15.

18. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable carrier.

19. The compound of claim 17, wherein the compound exhibits antimalarial activity.

20. The pharmaceutical composition of claim 18, wherein the compound exhibits antimalarial activity.

21. A method of treating, preventing, or inhibiting malaria in a subject which comprises administering to the subject a therapeutically effective amount of the compound of claim 19.

22. A method of treating, preventing, or inhibiting malaria in a subject which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 20.

23. A method of treating, preventing, or inhibiting malaria in a subject which comprises inhibiting or modulating the haem polymerase of the Plasmodium falciparum organisms present in the subject.

24. A method of optimizing hemin binding affinity of a tryptanthrin compound which comprises changing or modulating the substituent on the 8-position of the tryptanthrin compound.

25. A method of treating, preventing, or inhibiting malaria in a subject which comprises administering to the subject a therapeutically effective amount of at least one amino-quinazoline compound having the following structural formula A:

26. The method of claim 25, wherein the amino-quinazoline compound is

2,4-diamino-6-(naphthalen-1-ylsulfanyl)pyrido(3,2-d)pyrimidine;

2,4-diamino-6-(3,4-dichlorophenylsulfonyl)quinazoline;

2,4-diamino-6-(4-bromo-3-methylphenylsulfonyl)quinazoline;

2,4-diamino-6-(3-methoxyphenylsulfonyl)quinazoline;

or

2,4-diamino-6-(naphthalen-2-ylsulfonyl)quinazoline.

27. A method of determining the antimalarial activity or potency of a candidate compound which comprises (a) generating three-dimensional descriptors for the candidate compound, (b) inputting the three-dimensional descriptors into an equation relating to the observed antimalarial activity of a set of antimalarial compounds to a set of three-dimensional descriptors for the set of antimalarial compounds, and (c) solving the equation for the antimalarial activity or potency of the candidate compound corresponding to the three-dimensional descriptors of step (a).

28. A method of increasing the solubility, bioavailability, or both of a tryptanthrin compound which comprises dissolving the tryptanthrin compound in a solvent having at least one N—

H, OH, or (hetero)aromatic function, adding the solution to an aqueous solution, and removing the solvent by evaporation.

29. The method of claim 28, wherein the solvent is pyrrole, indole, pyridine, isoquinoline, nitrobenzene, aniline, N-methylbenzylamine, piperidine, pyrrolidine, phenol, benzyly alcohol, benzoic acid, or 1,4-dioxane.

30. The method of claim 28, wherein the aqueous solution is deionized water.

31. The method of claim 28, wherein the tryptanthrin compound has the following structural formula (II)

32. A method of treating, preventing, or inhibiting a disease or disorder associated with cell proliferation, bacterial infection, fungal infection, or protozoal infection, antifungal, or antiprotozoal in a subject which comprises administering to the subject a therapeutically effective amount of at least one tryptanthrin compound made by the method of claim 28 or a pharmaceutical composition comprising at least one tryptanthrin compound made by the method of claim 28.

33. The method of claim 32, wherein the disease or disorder related to cell proliferation is cancer, papillomas, acute or chronic inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, diabetic retinopathy, chronic obstrusive pulmonary disorder, tuberculosis, chronic cholecystitis, osteoarthritis, rheumatic carditis, bronchiectasis, Hashimoto'"'"'s thyroiditis, inflammatory bowel disease, or silicosis.

34. The method of claim 33, wherein the cancer is leukemia, CNS cancer, renal cancer, non-small cell lung cancer, melanoma, prostate cancer, colon cancer, ovarian cancer, or breast cancer.

35. The method of claim 32, wherein the bacterial infection is Streptococcal, Staphylococcal, bacterial meningitis, Yersinia pestis, Enterobacter, Helicobacter, Bacillus anthracis, Escherichia coli, Mycobacterium.

36. The method of claim 32, wherein the bacterial infection is caused by Mycobacterium tuberculosis.

37. The method of claim 32, wherein the fungal infection is histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, sporotrichosis, cryptococcosis, candidiasis, aspergillosis, or mucormycosis.

38. The method of claim 32, wherein the protozoal infection is malaria, leishmaniasis, or trypanosomiasis.

39. A tryptanthrin compound having the following structural formula (IV)