Loading...
Preliminary Evaluation of a 3H Imidazoquinoline Library as Dual TLR7/TLR8 Antagonists
Shukla, Nikunj M. Malladi, Subbalakshmi S. Day, Victor W. David, Sunil A.
Shukla, Nikunj M.
Malladi, Subbalakshmi S.
Day, Victor W.
David, Sunil A.
Citations
Altmetric:
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. Two-dimensional 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.
Description
Date
2011-06-15
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
Toll-like receptor, TLR7, TLR8, Imidazoquinoline, NOESY, HIV, Autoimmune diseases
Citation
Shukla, N. M., Malladi, S. S., Day, V., & David, S. A. (2011). Preliminary Evaluation of a 3H Imidazoquinoline Library as Dual TLR7/TLR8 Antagonists. Bioorganic & Medicinal Chemistry, 19(12), 3801–3811. http://doi.org/10.1016/j.bmc.2011.04.052