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

• US 7,259,167 B2
• Filed: 02/07/2003
• Issued: 08/21/2007
• Est. Priority Date: 02/09/2002
• Status: Expired due to Fees

• Current Assignee: United States Army (U.S. Department Of Defense)
• Original Assignee: United States Of America As Represented By The Secretary Of The Army (Government of the United States of America)
• Inventors: Bhattacharjee, Apurba K., Hicks, Rickey P., Nichols, Daniel A.
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US10/359,625
• Publication Number:
  US 20040033934A1
• Time in Patent Office: 1,656 Days
• Field of Search: 514/256, 514/257, 514/250, 514/229.5
• US Class Current: 514/257
• 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 tryptanthrin compound having the following structural formula (IV)

2. A pharmaceutical composition comprising the tryptanthrin compound of claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein the tryptanthrin compound was dissolved a solvent selected from the group consisting of pyrrole, indole, pyridine, isoquinoline, nitrobenzene, aniline, N-methylbenzylamine, piperidine, pyrrolidine, phenol, benzyly alcohol, benzoic acid, and 1,4-dioxane then added to an aqueous solution, and then the solvent was evaporated.

4. The pharmaceutical composition of claim 3, wherein the solvent is pyrrole, indole, pyridine, isoquinoline, nitrobenzene, aniline, N-methylbenzylamine, piperidine, pyrrolidine, phenol, benzyly alcohol, benzoic acid, or 1,4-dioxane.

5. The pharmaceutical composition of claim 3, wherein the aqueous solution is deionized water.

6. A method of treating or inhibiting malaria, leishmaniasis, trypanosomiasis and tuberculosis in a subject which comprises administering to the subject a therapeutically effective amount of at least one tryptanthrin compound of claim 1.

7. A method of treating or inhibiting infection caused by Plasmodium, Leishmania, Trypanosoma or Mycobacterium in a subject which comprises administering to the subject a therapeutically effective amount of at least one tryptanthrin compound of claim 1.