Compounds and methods for inhibiting viral replication and methods of treating and preventing flaviviral infections
The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present disclosure further relates to methods of inhibiting viral replication including contacting one or more cells that have been infected with a virus with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the virus comprises a flavivirus. Also disclosed is a method of treating and/or preventing a flavivirus infection and/or a condition resulting from a flavivirus infection including administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof under conditions effective to treat and/or prevent a flavivirus infection and/or a condition resulting from a flavivirus infection.
1. A method of inhibiting viral replication comprising:
contacting one or more cells that have been infected with a virus with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof
wherein R 1 is independently selected from the group consisting of amine, amide, C 1 -C 23 alkyl, aryl, heteroaryl, carbocycle, heterocycle, halogen, trifluoromethyl, and hydrogen;
R 2 is independently selected from the group consisting of trihalomethane, hydrogen, nitrogen oxide, amine, amide, and alkyl;
R 3 is independently selected from the group consisting of halogen, hydrogen, nitrogen oxide, and sulfur;
R 4 is halogen or hydrogen;
R 5 is halogen or hydrogen; and
R 6 is nitrogen oxide or hydrogen;
R 8 is hydrogen, halogen, or trihalomethane;
R 9 is halogen or hydrogen;
X 1 , X 2 , and X 3 are independently selected from C and N;
wherein R 2 and R 3 may optionally form a heterocycle comprising one or more sulfur oxide; and
wherein R 1 is not hydrogen when R 2 is NO 2 , R 3 is hydrogen, R 4 is chlorine, R 5 is chlorine, R 6 is hydrogen, R 8 is hydrogen, and R 9 is hydrogen; and wherein the virus comprises a flavivirus.
2. The method of claim 1 , wherein, in the compound of formula (I), R 3 is fluorine or hydrogen.
3. The method of claim 1 , wherein, in the compound of formula (I), R 4 is chlorine or hydrogen.
4. The method of claim 1 , wherein, in the compound of formula (I), R 5 is chlorine or hydrogen.
5. The method of claim 1 , wherein in the compound of formula (I), when R 2 or R 6 is nitrogen oxide, R 2 or R 6 is independently selected from the group consisting of NO 2 , NO, N 2 O, and N 2 O 5 .
6. The method of claim 1 , wherein the compound of formula (I) is selected from the compound of formulae (Ia)-(Il) and (In)-(Ip):
7. The method of claim 1 , wherein the contacting one or more cells that have been infected with a flavivirus comprises administering the compound to a subject.
8. The method of claim 7 , wherein the flavivirus is selected from the group consisting of Zika virus, Dengue virus serotype 1, Dengue virus serotype 2, Dengue virus serotype 3, Dengue virus serotype 4, yellow fever virus, West Nile virus, and Japanese encephalitis virus.
9. The method of claim 8 , wherein the flavivirus is Zika virus.
10. A method of treating and/or preventing a flavivirus infection and/or a condition resulting from a flavivirus infection, said method comprising:
administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof
wherein R 1 is independently selected from the group consisting of amine, amide, C 1 -C 23 alkyl, aryl, heteroaryl, carbocycle, heterocycle, halogen, trifluoromethyl, and hydrogen;
R 2 is independently selected from the group consisting of trihalomethane, hydrogen, nitrogen oxide, amine, amide, and alkyl;
R 3 is independently selected from the group consisting of halogen, hydrogen, nitrogen oxide, and sulfur;
R 4 is halogen or hydrogen;
R 5 is halogen or hydrogen; and
R 6 is nitrogen oxide or hydrogen;
R 8 is hydrogen, halogen, or trihalomethane;
R 9 is halogen or hydrogen;
X 1 , X 2 , and X 3 are independently selected from C and N;
wherein R 2 and R 3 may optionally form a heterocycle comprising one or more sulfur oxide; and
wherein R 1 is not hydrogen when R 2 is NO 2 , R 3 is hydrogen, R 4 is chlorine, R 5 is chlorine, R 6 is hydrogen, R 8 is hydrogen, and R 9 is hydrogen, under conditions effective to treat and/or prevent a flavivirus infection and/or a condition resulting from a flavivirus infection.
11. The method of claim 10 , wherein, in the compound of formula (I), R 3 is fluorine or hydrogen.
12. The method of claim 10 , wherein, in the compound of formula (I), R 4 is chlorine or hydrogen.
13. The method of claim 10 , wherein, in the compound of formula (I), R 5 is chlorine or hydrogen.
14. The method of claim 10 , wherein in the compound of formula (I), R 2 or R 6 is nitrogen oxide, R 2 or R 6 is independently selected from the group consisting of NO 2 , NO, N 2 O, and N 2 O 5 .
15. The method of claim 10 , wherein the compound of formula (I) is selected from the compound of formulae (Ia)-(Il) and (In)-(Ip):
16. The method of claim 10 further comprising:
selecting a subject that has an infection caused by a flavivirus or is at risk of developing an infection caused by a flavivirus.
17. The method of claim 10 , wherein the flavivirus is selected from the group consisting of Zika virus, Dengue virus serotype 1, Dengue virus serotype 2, Dengue virus serotype 3, Dengue virus serotype 4, yellow fever virus, West Nile virus, and Japanese encephalitis virus.
18. The method of claim 17 , wherein the flavivirus is Zika virus.
19. The method of claim 10 , wherein said method further comprises:
administering the compound of formula (I) to a selected subject orally, by inhalation, by intranasal instillation, topically, transdermally, intradermally, parenterally, subcutaneously, intravenous injection, intra-arterial injection, intramuscular injection, intrapleurally, intraperitoneally, intrathecally, or by application to a mucous membrane.
20. The method of claim 10 further comprising:
repeating said administering formula (I).
21. The method of claim 10 further comprising:
administering one or more additional agents.
22. The method of claim 10 , wherein the subject is an infant, a juvenile, or an adult.
23. The method of claim 10 , wherein the flavivirus infection is prevented.
24. The method of claim 10 , wherein the flavivirus infection is treated.
25. A method of inhibiting viral replication comprising:
contacting one or more cells that have been infected with a virus with an effective amount of a compound selected from formulae (Ia)-(Il) and (In)-(Ip):
or a pharmaceutically acceptable salt thereof, wherein the virus comprises a flavivirus.
26. The method of claim 25 , wherein the contacting one or more cells that have been infected with a flavivirus comprises administering the compound to a subject.
27. The method of claim 25 , wherein the flavivirus is selected from the group consisting of Zika virus, Dengue virus serotype 1, Dengue virus serotype 2, Dengue virus serotype 3, Dengue virus serotype 4, yellow fever virus, West Nile virus, and Japanese encephalitis virus.
28. The method of claim 27 , wherein the flavivirus is Zika virus.