Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines.

doi:10.1021/JM301066H

Paper

Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines.

Published Sep 27, 2012 · D. Salunke, Euna Yoo, Nikunj M. Shukla

Journal of medicinal chemistry

Q1 SJR score

70

Citations

3

Influential Citations

Full textSemantic Scholar

Abstract

In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke-Blackburn-Bienaymé multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3-c]pyridines, rather than the expected imidazo[1,2-a]pyridines, were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-κB signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3-c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity.

In Vitro Study

Highly Cited

Study Snapshot

Novel furo[2,3-c]pyridines show strong adjuvantic activity without proinflammatory cytokine induction, making them an attractive class of compounds for vaccine adjuvants without local or systemic reactogenicity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines.

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Dimeric imidazoquinolines with minor modifications can modulate TLR7 and TLR8 and may help address immune exhaustion in HIV.

Citations

Recent synthetic strategies for the functionalization of fused bicyclic heteroaromatics using organo-Li, -Mg and -Zn reagents.

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TIC10g is a novel small molecule that effectively inhibits endosomal TLR7 and TLR9 signaling pathways, disrupting MAPK- and NF-B-mediated proinflammatory gene expression.

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Copper-catalyzed oxidative [3 + 2] cyclization of N-alkyl pyridinium salts to imidazo[1,2-a]pyridines allows for the single-step construction of biologically important 2-cyanoimidazo[1,2-a]pyridine from readily available

Experimental investigation of salicylaldehydes in Groebke-Blackburn-Bienayme -3-component reaction

Different substitutions in salicylaldehydes affect the reaction process, leading to different products.