Inhibition of Toxoplasma gondii replication by pyridinylimidazoles

• US 20020132843A1
• Filed: 03/15/2002
• Published: 09/19/2002
• Est. Priority Date: 03/16/2001
• Status: Active Grant

• Current Assignee: Tyler Curiel
• Original Assignee: Tyler Curiel
• Inventors: Curiel, Tyler
• Granted Patent: US 6,649,637 B2
• Time in Patent Office: Days
• US Class Current: 514/396
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• 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

Substituted pyridinylimidazoles SB203580 and SB202190 strongly inhibit replication and cause stage conversion from active tachyzoites to relatively dormant bradyzoites of the medically important, obligate intracellular parasite Toxoplasma gondii. The pyridinylimidazoles probably mediate these effects by acting on a presently unidentified homologue(s) of human p38-mitogen activated protein kinase present in the tachyzoites. SB203580 also significantly enhanced in vitro inhibition of T. gondii replication by the approved anti-Toxoplasma drug pyrimethamine. The pyridinylimidazoles and related compounds disclosed herein could thus be significant adjuncts to currently available therapies.

Claims

1. A method of inhibiting intracellular replication of a parasite that possesses endogenous mitogen activated protein kinase activity, comprising the step of:

contacting cells infected with said parasite with a substituted imidazole drug that specifically inhibits a human p38 mitogen activated protein kinase homologue expressed in said parasite, wherein said drug inhibits intracellular replication of said parasite in said cells.

2. The method of claim 1, wherein said parasite is selected from the group consisting of Plasmodium, Leishmania and Toxoplasma.

3. The method of claim 1, wherein said substituted imidazole agent is selected from the group consisting of SB203580 and SB202190,

4. A method of inhibiting intracellular replication of parasite that possesses endogenous mitogen activated protein kinase activity, comprising the step of:

contacting cells infected with said parasite with a substituted pyridinylimidazole agent selected from the group consisting of SB203580 and SB202190, wherein said agent inhibits intracellular replication of said parasite in said cells.

5. The method of claim 4, wherein said parasite is selected from the group consisting of Plasmodia, Leishmania and Toxoplasma.

6. A method of inhibiting intracellular replication of a parasite that possesses endogenous mitogen activated protein kinase activity, comprising the step of:

contacting cells infected with said parasite with a halogenated imidazole drug that specifically inhibits mitogen activated protein kinases endogenous to said parasite, wherein said drug would inhibits intracellular replication of said parasite in said cells.

7. The method of claim 6, wherein said parasite is selected from the group consisting of Plasmodium, Leishmania and Toxoplasma.

8. A method of inhibiting intracellular replication of Toxoplasma gondii, comprising the step of:

contacting cells infected with Toxoplasma gondii with a substituted pyridinylimidazole agent selected from the group consisting of SB203580 and SB202190, wherein said agent inhibits intracellular replication of Toxoplasma gondii in said cells.

9. The method of claim 8, wherein treatment with said pyridinylimidazole agent causes stage conversion of Toxoplasma gondii from tachyzoites to bradyzoites.

10. A method of inhibiting intracellular replication of Toxoplasma gondii, comprising the step of:

contacting cells infected with Toxoplasma gondii with a n anti-Toxoplasma drug and a halogenated imidazole drug that specifically inhibits a human p38 mitogen activated protein kinase homologue expressed in Toxoplasma gondii, wherein treatment with said drugs increases inhibition of intracellular Toxoplasma gondii replication in said cells in comparison to treatment with either drug alone.

11. The method of claim 10, wherein said antiToxoplasma drug is pyrimethamine.

13. The method of claim 12, wherein said antiToxoplasma drug is pyrimethamine.

17. The method of claim 16, wherein said parasite is selected from the group consisting of T. gondii , and agents of malaria and Leishmaniasis.

12. A method of inhibiting intracellular replication of Toxoplasma gondii, comprising the step of:

contacting cells infected with Toxoplasma gondii with a n anti-Toxoplasma drug and a substituted pyridinylimidazole drug selected from the group consisting of SB203580 and SB202190, wherein treatment with said drugs increases inhibition of intracellular Toxoplasma gondii replication in said cells in comparison to treatment with either drug alone.

14. A method of treating an individual infected with Toxoplasma gondii, comprising the step of:

administering to said individual a pharmacologically effective dose of pyrimethamine and a halogenated imidazole drug that specifically inhibits a human p38 mitogen activated protein kinase homologue expressed in Toxoplasma gondii, wherein treatment with said drugs inhibits intracellular replication of Toxoplasma gondii in said individual.

15. A method of treating an individual infected with Toxoplasma gondii, comprising the step of:

administering to said individual a pharmacologically effective dose of pyrimethamine and a substituted pyridinylimidazole drug selected from the group consisting of SB203580 and SB202190, wherein treatment with said drugs inhibits intracellular replication of Toxoplasma gondii in said individual.

16. A method of inhibiting replication of a parasite, comprising the step of contacting said parasite with an inhibitor of p38 MAPK activation.