Human toll-like receptor 8-selective agonistic activities in 1-alkyl-1 h -benzimidazol-2-amines

Mallesh Beesu, Subbalakshmi S. Malladi, Lauren M. Fox, Cassandra D. Jones, Anshuman Dixit, Sunil A. David

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Toll-like receptor (TLR)-8 agonists strongly induce the production of T helper 1-polarizing cytokines and may therefore serve as promising candidate vaccine adjuvants, especially for the very young and the elderly. Earlier structure-based ligand design led to the identification of 3-pentyl-quinoline-2-amine as a novel, human TLR8-specific agonist. Comprehensive structure-activity relationships in ring-contracted 1-alkyl-1H-benzimidazol-2-amines were undertaken, and the best-in-class compound, 4-methyl-1-pentyl-1H-benzo[d]imidazol-2-amine, was found to be a pure TLR8 agonist, evoking strong proinflammatory cytokine and Type II interferon responses in human PBMCs, with no attendant CD69 upregulation in natural lymphocytic subsets. The 1-alkyl-1H-benzimidazol-2-amines represent a novel, alternate chemotype with pure TLR8-agonistic activities and will likely prove useful not only in understanding TLR8 signaling but also perhaps as a candidate vaccine adjuvant.

Original languageEnglish (US)
Pages (from-to)7325-7341
Number of pages17
JournalJournal of medicinal chemistry
Issue number17
StatePublished - Sep 11 2014
Externally publishedYes

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© 2014 American Chemical Society.


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