Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines

Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidat...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2013-02, Vol.11 (7), p.1179-1198
Main Authors: Kokatla, Hari Prasad, Yoo, Euna, Salunke, Deepak B, Sil, Diptesh, Ng, Cameron F, Balakrishna, Rajalakshmi, Malladi, Subbalakshmi S, Fox, Lauren M, David, Sunil A
Format: Article
Language:English
Subjects:
Dose-Response Relationship, Drug
Humans
Molecular Structure
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
Toll-Like Receptor 8 - agonists
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Summary:Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines 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. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. 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 lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers.
ISSN:1477-0520
1477-0539
DOI:10.1039/c2ob26705e