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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.

SUBMITTER: Shukla NM

PROVIDER: S-EPMC3114175 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Preliminary evaluation of a 3H imidazoquinoline library as dual TLR7/TLR8 antagonists.

Shukla Nikunj M NM Malladi Subbalakshmi S SS Day Victor V David Sunil A SA

Bioorganic & medicinal chemistry 20110501 12

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 ...[more]

PMID: 21620714

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