PI-kinase inhibitors with anti-infective activity
Compounds and methods are provided for the treatment of pathogen infections. In some embodiments, the anti-infective compounds have broad spectrum activity against a variety of infective diseases, where the diseases are caused by pathogens containing a basic amino acid PIP-2 pincer (BAAPP) domain that interacts with phosphatidylinositol 4,5-bisphosphate (PIP-2) to mediate pathogen replication. Also provided are methods of inhibiting a PI4-kinase and methods of inhibiting viral infection. In some embodiments, the compound is a PI4-kinase inhibiting compound that is a 5-aryl-thiazole or a 5-hetereoaryl-thiazole. The subject compounds may be formulated or provided to a subject in combination with a second anti-infective agent, e.g. interferon, ribivarin, and the like.
1. A compound selected from one of the following structures:
or a pharmaceutically acceptable salt thereof.
2. An anti-infective pharmaceutical composition comprising:
the compound of claim 1 ; and
a pharmaceutically acceptable excipient.
3. A method of inhibiting a PI4-kinase, the method comprising contacting a sample comprising the PI4-kinase with the compound of claim 1 .
4. The method of claim 3 , wherein the PI4-kinase is a PI4-III kinase.
5. The method of claim 4 , wherein the PI4-III kinase is a PI4KIIIα- or PI4KIIIβ-kinase.
6. The method of claim 3 , wherein the contacting comprises treating a subject for an infective disease condition, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound, or a pharmaceutically acceptable salt thereof, wherein the infective disease condition is caused by infection of a pathogen susceptible to PI4-kinase inhibition.
7. The method of claim 6 , wherein the infective disease condition results from infection with a virus selected from the Picornaviridae, Flaviviridae, Caliciviridae, Filoviridae, Hepeviridae and Coronavirinae families.
8. The method of claim 6 , wherein the infective disease condition results from infection with a pathogen selected from HCV, rhinovirus, P. falciparum , ebola virus, Francisella tularensis , hantavirus, SARS virus, MERS virus, vaccinia, smallpox, Japanese encephalitis virus, hepatitis A virus, and influenza virus, Norovirus, PolioVirus, Enterovirus, HEV, EV71, EV68, West Nile Virus, cytomegalovirus, P. aeruginosa , and Dengue Virus.
9. The method of claim 8 , wherein the pathogen is selected from EV71, EV68, human rhinoviruses, hepatitis A virus, HCV, norovirus and ebola virus.
10. The method of claim 6 , wherein the compound has activity against two or more pathogens.
11. A compound of formula (XXIII):
wherein:
R 31 -R 35 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, acyl, substituted acyl and —CO 2 R, wherein R is H, alkyl or substituted alkyl, provided that:
R 33 is hydroxy, and R 31 , R 32 , R 34 , and R 35 are independently selected from hydrogen, alkyl, and halogen; or
R 31 -R 35 are independently selected from hydrogen and halogen, wherein 0, 1 or 2 of R 31 -R 35 are halogen; wherein
R 2 is selected from hydrogen, a halogen, an alkyl, a substituted alkyl, an alkoxy and a substituted alkoxy;
R 3 is hydrogen, a lower alkyl or a substituted lower alkyl;
Y 3 is CH; and
R 10 is selected from tetrahydropyran and substituted tetrahydropyran.
12. The compound of claim 11 , having the following structure:
13. The compound of claim 11 , wherein R 33 is hydroxy, and R 31 , R 32 , R 34 and R 35 are independently selected from hydrogen, alkyl and halogen.
14. The compound of claim 11 , wherein R 31 -R 35 are independently selected from hydrogen and halogen, wherein 0, 1 or 2 of R 31 -R 35 are halogen.