Abstract
Toll-like receptors (TLR) -7 and -8 are thought to play an important role in immune activation processes underlying the pathophysiology of HIV and several clinically important autoimmune diseases. Based on our earlier findings of TLR7-antagonistic activity in a 3H imidazoquinoline, we sought to examine a pilot library of 3H imidazoquinolines for dual TLR7/8 antagonists, since they remain a poorly explored chemotype. 2D-NOE experiments were employed to unequivocally characterize the compounds. A quinolinium compound 12, bearing p-methoxybenzyl substituents on N3 and N5 positions was identified as a lead. Compound 12 was found to inhibit both TLR7 and TLR8 at low micromolar concentrations. Our preliminary results suggest that alkylation with electron-rich substituents on the quinoline N5, or conversely, elimination of the fixed charge of the resultant quaternary amine on the quinolinium may yield more active compounds.
Original language | English (US) |
---|---|
Pages (from-to) | 3801-3811 |
Number of pages | 11 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 19 |
Issue number | 12 |
DOIs | |
State | Published - Jun 15 2011 |
Externally published | Yes |
Bibliographical note
Copyright:Copyright 2012 Elsevier B.V., All rights reserved.
Keywords
- Autoimmune diseases
- HIV
- Imidazoquinoline
- NOESY
- TLR7
- TLR8
- Toll-like receptor