Broad spectrum antivirals against coronavirus
Compounds exhibiting antiviral activity and/or inhibition of viral replication against viruses, particularly those belonging to the picornavirus-like supercluster, including coronavirus having a formula: (I) where X comprises a cyclic moiety, R 2 is a branched or unbranched alkyl, cycloalkyl, aryl, arylalkyl, alkenyl, alkynyl, amino acid side chain, bicyclic or tricyclic side chain, combinations, and substituted forms thereof, and Z is selected from the group consisting of C 1 -C 6 hydroxyalkyl, aldehydes, alpha-ketoamides, and bisulfite salts, and in particular —CH 2 OH, —CHO, —CH(0H)S0 3 − Na + , and -[0(C=0)R w ]S0 3 − Na + .
1 . A compound comprising of formula I:
or a pharmaceutically acceptable salt thereof, where:
X is selected from the following structures shown in brackets with the oxygen linkage from formula (I) depicted for clarity:
and
R 2 is a branched or unbranched C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6-10 aryl, C 1 -C 6 alkylene-C 6-10 aryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, bicyclic or tricyclic moiety, or a combination thereof, wherein C 1 -C 6 alkyl is optionally substituted with one or more halogen, —OH, —SH, —SCH 3 , —NH 2 , —COOH, —C(O)NH 2 , —NH(C═NH)NH 2 , C 3 -C 10 cycloalkyl, C 6-10 aryl optionally substituted with —OH, or 5-9 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; and
Z is selected from the group consisting of C 1 -C 6 hydroxyalkyl, aldehydes, alpha-ketoamides, and bisulfite salts, —CH 2 OH, —CHO, —CH(OH)SO 3 − Na + , —[O(C═O)CH 3 ]SO 3 − Na + , and —[O(C═O)CH 2 CH 3 ]SO 3 − Na + .
2 . The compound or salt of claim 1 , wherein Z is C 1 -C 6 hydroxyalkyl or an aldehyde.
3 . The compound or salt of claim 1 , wherein Z is —CH 2 OH or —CHO.
4 . The compound or salt of claim 1 , wherein R 2 is C 1 -C 6 alkyl optionally substituted with one or more halogen, —OH, —SH, —SCH 3 , —NH 2 , —COOH, —C(O)NH 2 , —NH(C═NH)NH 2 , C 3 -C 10 cycloalkyl, C 6-10 aryl optionally substituted with —OH, or 5-9 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S.
5 . The compound or salt of claim 1 , wherein R 2 is isobutyl.
6 . The compound or salt of claim 1 , wherein X is:
7 . The compound or salt of claim 1 , wherein X is:
8 . A compound according to claim 1 comprising a structure selected from
or a pharmaceutically acceptable salt thereof, where Z is CH(OH)SO 3 Na or CHO, and R 2 is leucine (Leu) or cyclohexylalanine (Cha).
9 . An antiviral composition comprising a first compound according to claim 1 and a pharmaceutically-acceptable carrier.
10 . A method of treating a viral infection in a subject, said method comprising administering to said subject a therapeutically-effective amount of a first compound according to claim 1 .
11 . The method of claim 10 , wherein the viral infection is a coronavirus, calicivirus, or picornavirus infection.
12 . A method of inhibiting replication of a virus in a cell, said method comprising contacting said cell with a compound according to claim 1 .