Kokatla 2013

Toll-like Receptor-8 Agonistic  Activities in C2, C4, and C8 Modified 2-Alkylthiazolo[4,5-c]quinolines

Hari Prasad Kokatla, Sunil A. David*

Department of Medicinal Chemistry University of Kansas

Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are thought to be uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate vaccine adjuvants, especially for neonatal vaccines. Analogues with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the most potent TLR8 agonist showed dramatic enhancements of antigen-specific antibody titers.