title: Preliminary evaluation of a 3H imidazoquinoline library as dual TLR7/TLR8 antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Nikunj M
authors.initials: NM
authors.lastname: Shukla
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Victor
authors.initials: V
authors.lastname: Day
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000478:Alkylation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors*; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors*
chemical_list: D048289:Imidazolidines; D011804:Quinolines; D054852:Small Molecule Libraries; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8