Toll-like receptor (TLR)-7 and -8 modulatory activities of dimeric imidazoquinolines

Nikunj M. Shukla, Cole A. Mutz, Subbalakshmi S. Malladi, Hemamali J. Warshakoon, Rajalakshmi Balakrishna, Sunil A. David

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62 Scopus citations


Toll-like receptors (TLRs) are pattern recognition receptors that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but are structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines are of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result in TLR7-antagonistic compounds which may be of value in addressing innate immune activation-driven immune exhaustion observed in HIV. We describe the syntheses and evaluation of TLR7 and TLR8 modulatory activities of dimeric constructs of imidazoquinoline linked at the C2, C4, C8, and N 1-aryl positions. Dimers linked at the C4, C8, and N 1-aryl positions were agonistic at TLR7; only the N 1-aryl dimer with a 12-carbon linker was dual TLR7/8 agonistic. Dimers linked at C2 position showed antagonistic activities at TLR7 and TLR8; the C2 dimer with a propylene spacer was maximally antagonistic at both TLR7 and TLR8.

Original languageEnglish (US)
Pages (from-to)1106-1116
Number of pages11
JournalJournal of medicinal chemistry
Issue number3
StatePublished - Feb 9 2012


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